Skip to main content

Advertisement

Log in

Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Almost a half century of research has elaborated the discoveries of the central mechanisms governing the analgesic responses of opiates, including their receptors, endogenous peptides, genes and their putative spinal and supraspinal sites of action. One of the central tenets of “gate-control theories of pain” was the activation of descending supraspinal sites by opiate drugs and opioid peptides thereby controlling further noxious input. This review in the Special Issue dedicated to the research of Dr. Gavril Pasternak indicates his contributions to the understanding of supraspinal mediation of opioid analgesic action within the context of the large body of work over this period. This review will examine (a) the relevant supraspinal sites mediating opioid analgesia, (b) the opioid receptor subtypes and opioid peptides involved, (c) supraspinal site analgesic interactions and their underlying neurophysiology, (d) molecular (particularly AS) tools identifying opioid receptor actions, and (e) relevant physiological variables affecting site-specific opioid analgesia. This review will build on classic initial studies, specify the contributions that Gavril Pasternak and his colleagues did in this specific area, and follow through with studies up to the present.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

APV:

dl-2-Amino-5-phosphono-valerate

AS:

Antisense

BEND:

Beta-endorphin

BFNA:

Beta-funaltrexamine

Bupr:

Buprenorphine

CCK:

Cholecystokinin

DADL:

d-Ala2, d-Leu5-enkephalin

DAMGO:

d-Ala2, MePhe4, Gly(ol)5-enkephalin

Delt:

d-Ala2, Glu4 deltorphin

DOR-1:

Delta opioid receptor clone

DPDPE:

d-Pen2, d-Pen5-enkephalin

DSLET:

d-Ser2, Leu5-enkephalin-Thr6

EAA:

Excitatory amino acid

EKC:

Ethylketocyclazocine

GI:

Gastrointestinal

GPCR:

G-protein coupled receptor

IBNtxA:

39-Iodobenzoyl-6b-naltrexamide

icv:

Intracerebroventricular

it:

Intrathecal

KO:

Knockout

KOR-1:

Kappa-1 opioid receptor clone

KOR-3:

Kappa-3 opioid receptor clone

LC:

Locus coeruleus

MA:

Mercaptoacetate

mPFC:

Medial prefrontal cortex

MOR-1:

Mu opioid receptor clone

MPOA:

Medial preoptic hypothalamus

M3G:

Morphine-3 glucuronide

M6G:

Morphine-6 glucuronide

NAC:

Nucleus accumbens

NalBzoH:

Naloxone benzoylhydrazone

NBNI:

Nor-binaltorphimine

NE:

Norepinephrine

NMDA:

N-methyl-d-aspartate

NPY:

Neuropeptide Y

NRGC:

Nucleus reticularis gigantocellularis

NRM:

Nucleus raphe magnus

NTI:

Naltrindole

NTII:

Naltrindole isothiocyanate

ODNs:

Oligodeoxynucleotides

OFQ/N:

Orphanin/FQ

PCB:

1-(p-Chlorobenzoyl)-piperazine-2,3-dicarboxylate

PPENK:

Prepro-enkephalin

ppOFQ/N:

Prepro-orphanin/FQ/nociception

SPA:

Stimulation-produced analgesia

TP:

Testosterone propionate

TRH:

Thyrotropin-releasing hormone

VMH:

Ventromedial hypothalamus

vlPAG:

Ventrolateral periaqueductal gray

VTA:

Ventral tegmental area

2DG:

2-Deoxy-d-glucose

5HT:

Serotonin

References

  • Abbadie C, Rossi GC, Orciuolo A, Zadina JE, Pasternak GW (2002) Anatomical and functional correlation of the endomorphins with mu opioid receptor splice variants: endomorphins and mu opioid receptor splice variants. Eur J Neurosci 16:1075–1082

    Article  CAS  PubMed  Google Scholar 

  • Abbadie C, Pan YX, Pasternak GW (2004) Immunohistochemical study of the expression of exon11-containing mu opioid receptor variants in mouse brain. Neuroscience 127:419–430. https://doi.org/10.1016/j.neuroscience.2004.03.033

    Article  CAS  PubMed  Google Scholar 

  • Abbott FV, Palmour RM (1988) Morphine-6-glucuronide: analgesic effects and receptor binding profile in rats. Life Sci 43:1685–1695. https://doi.org/10.1016/0024-3205(88)90479-1

    Article  CAS  PubMed  Google Scholar 

  • Abols IA, Basbaum AI (1981) Afferent connections of the rostral medulla of the cat: a neural substrate for midbrain-medullary interactions in the modulation of pain. J Comp Neurol 201:285–297

    Article  CAS  PubMed  Google Scholar 

  • Aimone L, Gebhart G (1986) Stimulation-produced spinal inhibition from the midbrain in the rat is mediated by an excitatory amino acid neurotransmitter in the medial medulla. J Neurosci 6:1803–1813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akaike A, Shibata T, Satoh M, Takagi H (1978) Analgesia induced by microinjection of morphine into, and electrical stimulation of, the nucleus reticularis paragigantocellularis of rat medulla oblongata. Neuropharmacology 17:775–778

    Article  CAS  PubMed  Google Scholar 

  • Akil H, Watson SJ, Young E, Lewis ME, Khachaturian H, Walker JM (1984) Endogenous opioids: biology and function. Annu Rev Neurosci 7:223–255

    Article  CAS  PubMed  Google Scholar 

  • Al-Hasani R, McCall JG, Shin G, Gomez AM, Schmitz GP, Bernardi JM, Pyo C-O, Park SI, Marcinkiewcz CM, Crowley NA, Krashes MJ, Lowell BB, Kash TL, Rogers JA, Bruchas MR (2015) Distinct subpopulations of nucleus accumbens dynorphin neurons drive aversion and reward. Neuron 87:1063–1077. https://doi.org/10.1016/j.neuron.2015.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Al-Rodhan N, Chipkin R, Yaksh TL (1990) The antinociceptive effects of SCH-32615, a neutral endopeptidase (enkephalinase) inhibitor, microinjected into the periaqueductal, ventral medulla and amygdala. Brain Res 520:123–130

    Article  CAS  PubMed  Google Scholar 

  • Appelbaum BD, Holtzman SG (1984) Characterization of stress-induced potentiation of opioid effects in the rat. J Pharmacol Exp Ther 231:555–565

    CAS  PubMed  Google Scholar 

  • Appelbaum BD, Holtzman SG (1985) Restraint stress enhances morphine-induced analgesia in the rat without changing apparent affinity of receptor. Life Sci 36:1069–1074. https://doi.org/10.1016/0024-3205(85)90492-8

    Article  CAS  PubMed  Google Scholar 

  • Arjune D, Bodnar RJ (1990) Suppression of nocturnal, palatable and glucoprivic intake in rats by the κ opioid antagonist, nor-binaltorphamine. Brain Res 534:313–316

    Article  CAS  PubMed  Google Scholar 

  • Arjune D, Standifer KM, Pasternak GW, Bodnar RJ (1990) Reduction by central ß-funaltrexamine of food intake in rats under freely-feeding, deprivation and glucoprivic conditions. Brain Res 535:101–109

    Article  CAS  PubMed  Google Scholar 

  • Arjune D, Bowen WD, Bodnar RJ (1991) Ingestive behavior following central [D-Ala2, Leu5, Cys6]-enkephalin (DALCE), a short-acting agonist and long-acting antagonist at the delta opioid receptor. Pharmacol Biochem Behav 39:429–436

    Article  CAS  PubMed  Google Scholar 

  • Aston-Jones G, Ennis M, Pieribone V, Nickell W, Shipley M (1986) The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234:734–737

    Article  CAS  PubMed  Google Scholar 

  • Atweh SF, Kuhar MJ (1977a) Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla. Brain Res 124:53–67

    Article  CAS  PubMed  Google Scholar 

  • Atweh SF, Kuhar MJ (1977b) Autoradiographic localization of opiate receptors in rat brain. II. The brain stem. Brain Res 129:1–12

    Article  CAS  PubMed  Google Scholar 

  • Azami J, Wright DM, Roberts MHT (1981) Effects of morphine and naloxone on the responses to noxious stimulation of neurones in the nucleus reticularis paragigantocellularis. Neuropharmacology 20:869–876

    Article  CAS  PubMed  Google Scholar 

  • Azami J, Llewelyn MB, Roberts MHT (1982) The contribution of nucleus reticularis paragigantocellularis and nucleus raphe magnus to the analgesia produced by systemically administered morphine, investigated with the microinjection technique. Pain 12:229–246

    Article  CAS  PubMed  Google Scholar 

  • Baamonde AI, Hidalgo A, Andrés-Trelles F (1989) Sex-related differences in the effects of morphine and stress on visceral pain. Neuropharmacology 28:967–970

    Article  CAS  PubMed  Google Scholar 

  • Badillo-Martinez D, Kirchgessner AL, Butler PD, Bodnar RJ (1984a) Monosodium glutamate and analgesia induced by morphine. Test-specific effects. Neuropharmacology 23:1141–1149. https://doi.org/10.1016/0028-3908(84)90231-4

    Article  CAS  PubMed  Google Scholar 

  • Badillo-Martinez D, Nicotera N, Butler PD, Kirchgessner AL, Bodnar RJ (1984b) Impairments in analgesic, hypothermic, and glucoprivic stress responses following neonatal monosodium glutamate. Neuroendocrinology 38:438–446. https://doi.org/10.1159/000123932

    Article  CAS  PubMed  Google Scholar 

  • Bajic D, Proudfit HK (1999) Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception. J Comp Neurol 405:359–379

    Article  CAS  PubMed  Google Scholar 

  • Baliki MN, Geha PY, Fields HL, Apkarian AV (2010) Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron 66:149–160. https://doi.org/10.1016/j.neuron.2010.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baliki MN, Mansour A, Baria AT, Huang L, Berger SE, Fields HL, Apkarian AV (2013) Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain. J Neurosci 33:16383–16393. https://doi.org/10.1523/JNEUROSCI.1731-13.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bandler R, Shipley MT (1994) Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci 17:379–389

    Article  CAS  PubMed  Google Scholar 

  • Banerjee P, Chatterjee TK, Ghosh JJ (1983) Ovarian steroids and modulation of morphine-induced analgesia and catalepsy in female rats. Eur J Pharmacol 96:291–294

    Article  CAS  PubMed  Google Scholar 

  • Barbaro NM, Hammond DL, Fields HL (1985) Effects of intrathecally administered methysergide and yohimbine on microstimulation-produced antinociception in the rat. Brain Res 343:223–229

    Article  CAS  PubMed  Google Scholar 

  • Barbaro NM, Heinricher MM, Fields HL (1986) Putative pain modulating neurons in the rostral ventral medulla: reflex-related activity predicts effects of morphine. Brain Res 366:203–210

    Article  CAS  PubMed  Google Scholar 

  • Barr GA, Wang S (2013) Analgesia induced by localized injection of opiate peptides into the brain of infant rats. Eur J Pain 17:676–691. https://doi.org/10.1002/j.1532-2149.2012.00245.x

    Article  CAS  PubMed  Google Scholar 

  • Bartok RE, Craft RM (1997) Sex differences in opioid antinociception. J Pharmacol Exp Ther 282:769–778

    CAS  PubMed  Google Scholar 

  • Basbaum AI, Fields HL (1984) Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 7:309–338

    Article  CAS  PubMed  Google Scholar 

  • Beatty WW, Beatty PA (1970) Hormonal determinants of sex differences in avoidance behavior and reactivity to electric shock in the rat. J Comp Physiol Psychol 73:446–455

    Article  CAS  PubMed  Google Scholar 

  • Beczkowska IW, Bodnar RJ (1991) Mediation of insulin hyperphagia by specific central opiate receptor antagonists. Brain Res 547:315–318. https://doi.org/10.1016/0006-8993(91)90977-4

    Article  CAS  PubMed  Google Scholar 

  • Behbehani MM, Fields HL (1979) Evidence that an excitatory connection between the periaqueductal gray and nucleus raphe magnus mediates stimulation produced analgesia. Brain Res 170:85–93

    Article  CAS  PubMed  Google Scholar 

  • Beitz A (1982a) The sites of origin brain stem neurotensin and serotonin projections to the rodent nucleus raphe magnus. J Neurosci 2:829–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beitz AJ (1982b) The organization of afferent projections to the midbrain periaqueductal gray of the rat. Neuroscience 7:133–159

    Article  CAS  PubMed  Google Scholar 

  • Beitz AJ (1982c) The nuclei of origin of brain stem enkephalin and substance P projections to the rodent nucleus raphe magnus. Neuroscience 7:2753–2768

    Article  CAS  PubMed  Google Scholar 

  • Beitz AJ (1990) Relationship of glutamate and aspartate to the periaqueductal gray-raphe magnus projection: analysis using immunocytochemistry and microdialysis. J Histochem Cytochem 38:1755–1765

    Article  CAS  PubMed  Google Scholar 

  • Beitz AJ (1995) Periaqueductal gray. In: Paxinos G (ed) The rat nervous system, vol xvii, 2nd edn. Academic Press, San Diego, pp 173–182

    Google Scholar 

  • Beitz AJ, Mullett MA, Weiner LL (1983) The periaqueductal gray projections to the rat spinal trigeminal, raphe magnus, gigantocellular pars alpha and paragigantocellular nuclei arise from separate neurons. Brain Res 288:307–314

    Article  CAS  PubMed  Google Scholar 

  • Bhargava HN, Way EL (1972) Acetylcholinesterase inhibition and morphine effects in morphine tolerant and dependent mice. J Pharmacol Exp Ther 183:31–40

    CAS  PubMed  Google Scholar 

  • Bilsky EJ, Bernstein RN, Pasternak GW, Hruby VJ, Patel D, Porreca F, Lai J (1994) Selective inhibition of [D-ALA2, GLU4]deltrophin antinociception by supraspinal, but not spinal, administration of an antisense oligodeoxynucleotide to an opioid delta receptor. Life Sci 55:PL37–PL43

    Article  CAS  PubMed  Google Scholar 

  • Bobeck EN, McNeal AL, Morgan MM (2009) Drug dependent sex-differences in periaqueducatal gray mediated antinociception in the rat. Pain 147:210–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bodnar RJ (1990) Effects of opioid peptides on peripheral stimulation and “stress”-induced analgesia in animals. Crit Rev Neurobiol 6:39–49

    CAS  PubMed  Google Scholar 

  • Bodnar RJ (2004) Endogenous opioids and feeding behavior: a 30-year historical perspective. Peptides 25:697–725

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ (2015) Endogenous opioids and feeding behavior: a decade of further progress (2004-2014). A Festschrift to Dr. Abba Kastin. Peptides 72:20–33. https://doi.org/10.1016/j.peptides.2015.03.019

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ (2019) Endogenous opioid modulation of food intake and body weight: implications for opioid influences upon motivation and addiction. Peptides 116:42–62

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Kelly DD, Spiaggia A, Ehrenberg C, Glusman M (1978a) Dose-dependent reductions by naloxone of analgesia induced by cold-water stress. Pharmacol Biochem Behav 8:667–672

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Kelly DD, Steiner SS, Glusman M (1978b) Stress-produced analgesia and morphine-produced analgesia: lack of cross-tolerance. Pharmacol Biochem Behav 8:661–666

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Glusman M, Brutus M, Spiaggia A, Kelly DD (1979a) Analgesia induced by cold-water stress: attenuation following hypophysectomy. Physiol Behav 23:53–62

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Kelly DD, Mansour A, Murray G (1979b) Differential effects of hypophysectomy upon analgesia induced by two glucoprivic stressors and morphine. Pharmacol Biochem Behav 11:303–308

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Abrams GM, Zimmerman EA, Krieger DT, Nicholson G, Kizer JS (1980a) Neonatal monosodium glutamate. Neuroendocrinology 30:280–284

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Kelly DD, Brutus M, Glusman M (1980b) Stress-induced analgesia: neural and hormonal determinants. Neurosci Biobehav Rev 4:87–100. https://doi.org/10.1016/0149-7634(80)90028-7

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Zimmerman EA, Nilaver G, Mansour A, Thomas LW, Kelly DD, Glusman M (1980c) Dissociation of cold-water swim and morphine analgesia in Brattleboro rats with diabetes insipidus. Life Sci 26:1581–1590

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Sharpless NS, Kordower JH, Potegal M, Barr GA (1982) Analgesic responses following adrenal demedullation and peripheral catecholamine depletion. Physiol Behav 29:1105–1109

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Portzline T, Nilaver G (1985) Differential alterations in opioid analgesia following neonatal monosodium glutamate treatment. Brain Res Bull 15:299–305

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Williams CL, Lee SJ, Pasternak GW (1988) Role of μ1-opiate receptors in supraspinal opiate analgesia: a microinjection study. Brain Res 447:25–34

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Paul D, Pasternak GW (1990a) Proglumide selectively potentiates supraspinal μ1 opioid analgesia in mice. Neuropharmacology 29:507–510

    Article  CAS  PubMed  Google Scholar 

  • Bodnar RJ, Paul D, Rosenblum M, Liu L, Pasternak GW (1990b) Blockade of morphine analgesia by both pertussis and cholera toxins in the periaqueductal gray and locus coeruleus. Brain Res 529:324–328

    Article  CAS  PubMed  Google Scholar 

  • Bodnar R, Paul D, Pasternak GW (1991) Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus. Brain Res 558:224–230

    Article  CAS  PubMed  Google Scholar 

  • Boschi G, Desiles M, Reny V, Rips R, Wrigglesworth S (1983) Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine. Br J Pharmacol 79:85–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyer JS, Morgan MM, Craft RM (1998) Microinjection of morphine into the rostral ventromedial medulla produces greater antinociception in male compared to female rats. Brain Res 796(1–2):315–318. https://doi.org/10.1016/S0006-8993(98)00353-9

    Article  CAS  PubMed  Google Scholar 

  • Brodie MS, Proudfit HK (1984) Hypoalgesia induced by the local injection of carbachol into the nucleus raphe magnus. Brain Res 291:337–342. https://doi.org/10.1016/0006-8993(84)91266-6

    Article  CAS  PubMed  Google Scholar 

  • Brodie MS, Proudfit HK (1986) Antinociception induced by local injections of carbachol into the nucleus raphe magnus in rats: alteration by intrathecal injection of monoaminergic antagonists. Brain Res 371:70–79. https://doi.org/10.1016/0006-8993(86)90811-5

    Article  CAS  PubMed  Google Scholar 

  • Brooks AI, Standifer KM, Rossi GC, Mathis JP, Pasternak GW (1996) Characterizing kappa3 opioid receptors with a selective monoclonal antibody. Synapse 22:247–252

    Article  CAS  PubMed  Google Scholar 

  • Brown GP, Yang K, King MA, Rossi GC, Leventhal L, Chang A, Pasternak WG (1997) 3-Methoxynaltrexone, a selective heroin/morphine-6β-glucuronide antagonist. FEBS Lett 412:35–38

    Article  CAS  PubMed  Google Scholar 

  • Brown TG, Xu J, Hurd YL, Pan YX (2020) Dysregulated expression of the alternatively spliced variant mRNAs of the mu opioid receptor gene, OPRM1, in the medial prefrontal cortex of male human heroin abusers and heroin self-administering male rats. J Neurosci Res. https://doi.org/10.1002/jnr.24640

    Article  PubMed  PubMed Central  Google Scholar 

  • Brownstein MJ, Palkovits M, Saavedra JM, Bassiri RM, Utiger RD (1974) Thyrotropin-releasing hormone in specific nuclei of rat. Brain Sci 185:267–269

    CAS  Google Scholar 

  • Bunzow JR, Saez C, Mortrud M, Bouvier C, Williams JT, Low M, Grandy DK (1994) Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, δ or κ opioid receptor type. FEBS Lett 347:284–288

    Article  CAS  PubMed  Google Scholar 

  • Burdick K et al (1998) Antisense mapping of opioid receptor clones: effects upon 2-deoxy-d-glucose-induced hyperphagia. Brain Res 794:359–363

    Article  CAS  PubMed  Google Scholar 

  • Cameron AA, Khan IA, Westlund KN, Willis WD (1995) The efferent projections of the periaqueductal gray in the rat: a Phaseolus vulgaris-leucoagglutinin study. II. Descending projections. J Comp Neurol 351:585–601

    Article  CAS  PubMed  Google Scholar 

  • Candido J, Lutfy K, Billings B, Sierra V, Duttaroy A, Inturrisi CE, Yoburn BC (1992) Effect of adrenal and sex hormones on opioid analgesia and opioid receptor regulation. Pharmacol Biochem Behav 42:685–692

    Article  CAS  PubMed  Google Scholar 

  • Cannon JT, Prieto GJ, Lee A, Liebeskind JC (1982) Evidence for opioid and non-opioid forms of stimulation-produced analgesia in the rat. Brain Res 243:315–321

    Article  CAS  PubMed  Google Scholar 

  • Cassel D, Selinger Z (1977) Mechanism of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. Proc Natl Acad Sci 74:3307–3311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro DC, Berridge KC (2014) Opioid hedonic hotspot in nucleus accumbens shell: mu, delta, and kappa maps for enhancement of sweetness “liking” and “wanting”. J Neurosci 34:4239–4250. https://doi.org/10.1523/JNEUROSCI.4458-13.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro DC, Bruchas MR (2019) A motivational and neuropeptidergic hub: anatomical and functional diversity within nucleus accumbens shell. Neuron 102:529–552. https://doi.org/10.1016/j.neuron.2019.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cataldo G, Bernal S, Markowitz A, Ogawa S, Ragnauth A, Pfaff DW, Bodnar RJ (2005) Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: effects of adult ovariectomy and estradiol replacement. Brain Res 1059:13–19

    Article  CAS  PubMed  Google Scholar 

  • Cataldo G, Lovric J, Chen C-C, Pytte CL, Bodnar RJ (2010) Ventromedial and medial preoptic hypothalamic ibotenic acid lesions potentiate systemic morphine analgesia in female, but not male rats. Behav Brain Res 214:301–316

    Article  CAS  PubMed  Google Scholar 

  • Chance WT (1980) Autoanalgesia: opiate and non-opiate mechanisms. Neurosci Biobehav Rev 4:55–67. https://doi.org/10.1016/0149-7634(80)90025-1

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Mestek A, Liu J, Hurley JA, Yu L (1993) Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol Pharmacol 44:8–12

    CAS  PubMed  Google Scholar 

  • Chen Y, Fan Y, Liu J, Mestek A, Tian M, Kozak CA, Yu L (1994) Molecular cloning, tissue distribution and chromosomal localization of a novel member of the opioid receptor gene family. FEBS Lett 347:279–283

    Article  CAS  PubMed  Google Scholar 

  • Chen T et al (2016) Mechanism underlying the analgesic effect exerted by endomorphin-1 in the rat ventrolateral periaqueductal gray. Mol Neurobiol 53:2036–2053. https://doi.org/10.1007/s12035-015-9159-5

    Article  CAS  PubMed  Google Scholar 

  • Cicero TJ, Nock B, Meyer ER (1996) Gender-related differences in the antinociceptive properties of morphine. J Pharmacol Exp Ther 279:767–773

    CAS  PubMed  Google Scholar 

  • Cicero TJ, Nock B, Meyer ER (1997) Sex-related differences in morphine’s antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther 282:939–944

    CAS  PubMed  Google Scholar 

  • Cicero TJ, Nock B, O’Connor L, Meyer ER (2002) Role of steroids in sex differences in morphine-induced analgesia: activational and organizational effects. J Pharmacol Exp Ther 300:695–701

    Article  CAS  PubMed  Google Scholar 

  • Clark FM, Proudfit HK (1991a) Projections of neurons in the ventromedial medulla to pontine catecholamine cell groups involved in the modulation of nociception. Brain Res 540:105–115

    Article  CAS  PubMed  Google Scholar 

  • Clark FM, Proudfit HK (1991b) The projection of locus coeruleus neurons to the spinal cord in the rat determined by anterograde tracing combined with immunocytochemistry. Brain Res 538:231–245

    Article  CAS  PubMed  Google Scholar 

  • Clark FM, Proudfit HK (1991c) The projection of noradrenergic neurons in the A7 catecholamine cell group to the spinal cord in the rat demonstrated by anterograde tracing combined with immunocytochemistry. Brain Res 547:279–288

    Article  CAS  PubMed  Google Scholar 

  • Clark FM, Proudfit HK (1993) The projections of noradrenergic neurons in the A5 catecholamine cell group to the spinal cord in the rat: anatomical evidence that A5 neurons modulate nociception. Brain Res 616:200–210

    Article  CAS  PubMed  Google Scholar 

  • Clark JA, Itzhak Y, Hruby VJ, Yamamura HI, Pasternak GW (1986) [D-Pen2, D-Pen5]enkephalin (DPDPE): a δ-selective enkephalin with low affinity for μ1 opiate binding sites. Eur J Pharmacol 128:303–304

    Article  CAS  PubMed  Google Scholar 

  • Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW (1989) Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype. J Pharmacol Exp Ther 251:461–468

    CAS  PubMed  Google Scholar 

  • Clements JR, Madl JE, Johnson RL, Larson AA, Beitz AJ (1987) Localization of glutamate, glutaminase, aspartate and aspartate aminotransferase in the rat midbrain periaqueductal gray. Exp Brain Res 67:594–602. https://doi.org/10.1007/BF00247290

    Article  CAS  PubMed  Google Scholar 

  • Cortés R, Palacios JM (1986) Muscarinic cholinergic receptor subtypes in the rat brain. I. Quantitative autoradiographic studies. Brain Res 362:227–238. https://doi.org/10.1016/0006-8993(86)90448-8

    Article  PubMed  Google Scholar 

  • Craft RM, Stratmann JA, Bartok RE, Walpole TI, King SJ (1999) Sex differences in development of morphine tolerance and dependence in the rat. Psychopharmacology 143:1–7

    Article  CAS  PubMed  Google Scholar 

  • Czlonkowski A, Millan MJ, Herz A (1987) The selective κ-opioid agonist, U-50,488H, produces antinociception in the rat via a supraspinal action. Eur J Pharmacol 142:183–184

    Article  CAS  PubMed  Google Scholar 

  • Dever SM, Costin BN, Xu R, El-Hage N, Balinang J, Samoshkin A, O’Brien MA, McRae M, Diatchenko L, Knapp PE, Hauser KF (2014) Differential expression of the alternatively spliced OPRM1 isoform μ-opioid receptor-1K in HIV-infected individuals. AIDS 28(1):19–30

    Article  CAS  PubMed  Google Scholar 

  • Dickenson AH, Oliveras J-L, Besson J-M (1979) Role of the nucleus raphe magnus in opiate analgesia as studied by the microinjection technique in the rat. Brain Res 170:95–111

    Article  CAS  PubMed  Google Scholar 

  • DiFeliceantonio AG, Berridge KC (2012) Which cue to ‘want’? Opioid stimulation of central amygdala makes goal-trackers show stronger goal-tracking, just as sign-trackers show stronger sign-tracking. Behav Brain Res 230:399–408. https://doi.org/10.1016/j.bbr.2012.02.032

    Article  PubMed  PubMed Central  Google Scholar 

  • Doyle HH, Murphy AZ (2018) Sex-dependent influences of morphine and its metabolites on pain sensitivity in the rat. Physiol Behav 187:32–41. https://doi.org/10.1016/j.physbeh.2017.11.030

    Article  CAS  PubMed  Google Scholar 

  • Drugan RC, Grau JW, Maier SF, Madden J, Barchas JD (1981) Cross tolerance between morphine and the long-term analgesic reaction to inescapable shock. Pharmacol Biochem Behav 14:677–682

    Article  CAS  PubMed  Google Scholar 

  • Ennis M, Behbehani M, Shipley MT, van Bockstaele EJ, Aston-Jones G (1991) Projections from the periaqueductal gray to the rostromedial pericoerulear region and nucleus locus coeruleus: anatomic and physiologic studies. J Comp Neurol 306:480–494

    Article  CAS  PubMed  Google Scholar 

  • Eppler CM et al (1993) Purification and partial amino acid sequence of a mu opioid receptor from rat brain. J Biol Chem 268:26447–26451

    Article  CAS  PubMed  Google Scholar 

  • Evans C, Keith D, Morrison H, Magendzo K, Edwards R (1992) Cloning of a delta opioid receptor by functional expression. Science 258:1952–1955

    Article  CAS  PubMed  Google Scholar 

  • Fang FG, Fields HL, Lee NM (1986) Action at the mu receptor is sufficient to explain the supraspinal analgesic effect of opiates. J Pharmacol Exp Ther 238:1039–1044

    CAS  PubMed  Google Scholar 

  • Fields HL, Basbaum AI (1978) Brainstem control of spinal pain-transmission neurons. Annu Rev Physiol 40:217–248

    Article  CAS  PubMed  Google Scholar 

  • Fields HL, Margolis EB (2015) Understanding opioid reward. Trends Neurosci 38:217–225. https://doi.org/10.1016/j.tins.2015.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fields HL, Vanegas H, Hentall ID, Zorman G (1983) Evidence that disinhibition of brain stem neurones contributes to morphine analgesia. Nature 306:684–686

    Article  CAS  PubMed  Google Scholar 

  • Fields HL, Heinricher MM, Mason P (1991) Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 14:219–245

    Article  CAS  PubMed  Google Scholar 

  • Finley JCW, Maderdrut JL, Petrusz P (1981) The immunocytochemical localization of enkephalin in the central nervous system of the rat. J Comp Neurol 198:541–565

    Article  CAS  PubMed  Google Scholar 

  • Fowler C, Fraser G (1994) μ-, δ-, κ-Opioid receptors and their subtypes. A critical review with emphasis on radioligand binding experiments. Neurochem Int 24:401–426

    Article  CAS  PubMed  Google Scholar 

  • Fukuda K, Kato S, Mori K, Nishi M, Takeshima H (1993) Primary structures and expression from cDNAs of rat opioid receptor δ-and μ-subtypes. FEBS Lett 327:311–314

    Article  CAS  PubMed  Google Scholar 

  • Gallager DW, Pert A (1978) Afferents to brain stem nuclei (brain stem raphe, nucleus reticularis pontis caudalis and nucleus gigantocellularis) in the rat as demonstrated by microiontophoretically applied horseradish peroxidase. Brain Res 144:257–275

    Article  CAS  PubMed  Google Scholar 

  • Galligan JJ, Mosberg HI, Hurst R, Hruby VJ, Burks TF (1984) Cerebral delta opioid receptors mediate analgesia but not the intestinal motility effects of intracerebroventricularly administered opioids. J Pharmacol Exp Ther 229:641–648

    CAS  PubMed  Google Scholar 

  • Gao K, Mason P (1997) Somatodendritic and axonal anatomy of intracellularly labeled serotonergic neurons in the rat medulla. J Comp Neurol 389:309–328

    Article  CAS  PubMed  Google Scholar 

  • Gao K, Kim YH, Mason P (1997) SEROTONERGIC pontomedullary neurons are not activated by antinociceptive stimulation in the periaqueductal gray. J Neurosci 17:3285–3292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao K, Chen DO, Genzen JR, Mason P (1998) Activation of serotonergic neurons in the raphe magnus is not necessary for morphine analgesia. J Neurosci 18:1860–1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gebhart GF (1982) Opiate and opioid peptide effects on brain stem neurons: relevance to nociception and antinociceptive mechanisms. Pain 12:93–140

    Article  CAS  PubMed  Google Scholar 

  • Gilman AG (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56:615–649

    Article  CAS  PubMed  Google Scholar 

  • Girardot M, Holloway F (1984a) Cold water stress analgesia in rats: differential effects of naltrexone. Physiol Behav 32:547–555

    Article  CAS  PubMed  Google Scholar 

  • Girardot M-N, Holloway FA (1984b) Intermittent cold water stress-analgesia in rats: cross-tolerance to morphine. Pharmacol Biochem Behav 20:631–633

    Article  CAS  PubMed  Google Scholar 

  • Gistrak MA, Paul D, Hahn EF, Pasternak GW (1989) Pharmacological actions of a novel mixed opiate agonist/antagonist: naloxone benzoylhydrazone. J Pharmacol Exp Ther 251:469–476

    CAS  PubMed  Google Scholar 

  • Goldberg IE et al (1998) Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J Pharmacol Exp Ther 286:1007–1013

    CAS  PubMed  Google Scholar 

  • Goodman RR, Pasternak GW (1985) Visualization of mu1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique. Proc Natl Acad Sci 82:6667–6671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodman RR, Snyder SH, Kuhar MJ, Young WS (1980) Differentiation of delta and mu opiate receptor localizations by light microscopic autoradiography. Proc Natl Acad Sci 77:6239–6243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grau J, Hyson R, Maier S, Madden J, Barchas J (1981) Long-term stress-induced analgesia and activation of the opiate system. Science 213:1409–1411

    Article  CAS  PubMed  Google Scholar 

  • Green PG, Kitchen I (1986) Antinociception opioids and the cholinergic system. Prog Neurobiol 26:119–146

    Article  CAS  PubMed  Google Scholar 

  • Grinnell SG et al (2016) Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants. Synapse 70:395–407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grisel JE, Mogil JS, Belknap JK, Grandy DK (1996) Orphanin FQ acts as a supraspinal, but not a spinal, anti-opioid peptide. NeuroReport 7:2125–2129

    Article  CAS  PubMed  Google Scholar 

  • Guillemin R et al (1977) The endorphins, novel peptides of brain and hypophysial origin, with opiate-like activity: biochemical and biologic studies. Ann N Y Acad Sci 297:131–157

    Article  CAS  PubMed  Google Scholar 

  • Hadjimarkou MM, Silva RM, Rossi GC, Pasternak GW, Bodnar RJ (2002) Feeding induced by food deprivation is differentially reduced by G-protein α-subunit antisense probes in rats. Brain Res 955:45–54

    Article  CAS  PubMed  Google Scholar 

  • Hadjimarkou MM, Khaimova E, Pan Y-X, Rossi GC, Pasternak GW, Bodnar RJ (2003) Feeding induced by food deprivation is differentially reduced by opioid receptor antisense oligodeoxynucleotide probes in rats. Brain Res 987:223–232

    Article  CAS  PubMed  Google Scholar 

  • Hadjimarkou MM et al (2004) Opioid receptor involvement in food deprivation-induced feeding: evaluation of selective antagonist and antisense oligodeoxynucleotide probe effects in mice and rats. J Pharmacol Exp Ther 311:1188–1202

    Article  CAS  PubMed  Google Scholar 

  • Hadjimarkou MM, Abbadie C, Kasselman LJ, Pan Y-x, Pasternak GW, Bodnar RJ (2009) Changes in mouse mu opioid receptor Exon 7/8-like immunoreactivity following food restriction and food deprivation in rats. Synapse 63:585–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hammond DL, Yaksh TL (1984) Antagonism of stimulation-produced antinociception by intrathecal administration of methysergide or phentolamine. Brain Res 298:329–337

    Article  CAS  PubMed  Google Scholar 

  • Han W, Kasai S, Hata H, Takahashi T, Takamatsu Y, Yamamoto H, Uhl GR, Sora I, Ikeda K (2006) Intracisternal A-particle element in the 3′ noncoding region of the mu-opioid receptor gene in CXBK mice: a new genetic mechanism underlying differences in opioid sensitivity. Pharmacogenet Genom 16(6):451–460. https://doi.org/10.1097/01.fpc.0000215072.36965.8d

    Article  CAS  Google Scholar 

  • Harris HN, Peng YB (2020) Evidence and explanation for the involvement of the nucleus accumbens in pain processing. Neural Regen Res 15:597–605. https://doi.org/10.4103/1673-5374.266909

    Article  PubMed  Google Scholar 

  • Hasegawa Y, Kurachi M, Okuyama S, Araki H, Otomo S (1990) 5-HT3 receptor antagonists inhibit the response of κ oploid receptors in the morphine-reduced straub tail European. J Pharmacol 190:399–401

    CAS  Google Scholar 

  • Hazum E, Chang K-J, Cuatrecasas P, Pasternak GW (1981) Naloxazone irreversibly inhibits the high affinity binding of [125I]D-ala2-D-leu5-enkephalin. Life Sci 28:2973–2979

    Article  CAS  PubMed  Google Scholar 

  • Heinricher MM, Tortorici V (1994) Interference with GABA transmission in the rostral ventromedial medulla: disinhibition of off-cells as a central mechanism in nociceptive modulation. Neuroscience 63:533–546

    Article  CAS  PubMed  Google Scholar 

  • Heinricher MM, Haws CM, Fields HL (1991) Evidence for GABA-mediated control of putative nociceptive modulating neurons in the rostral ventromedial medulla: iontophoresis of bicuculline eliminates the off-cell pause. Somatosens Mot Res 8:215–225

    Article  CAS  PubMed  Google Scholar 

  • Heinricher MM, Morgan MM, Tortorici V, Fields HL (1994) Disinhibition of off-cells and antinociception produced by an opioid action within the rostral ventromedial medulla. Neuroscience 63:279–288

    Article  CAS  PubMed  Google Scholar 

  • Helmstetter FJ, Bellgowan PS, Tershner SA (1993) Inhibition of the tail flick reflex following microinjection of morphine into the amygdala. NeuroReport 4:471–474

    Article  CAS  PubMed  Google Scholar 

  • Helmstetter FJ, Bellgowan PS, Poore LH (1995) Microinfusion of mu but not delta or kappa opioid agonists into the basolateral amygdala results in inhibition of the tail flick reflex in pentobarbital-anesthetized rats. J Pharmacol Exp Ther 275:381–388

    CAS  PubMed  Google Scholar 

  • Henderson G, McKnight AT (1997) The orphan opioid receptor and its endogenous ligand–nociceptin/orphanin FQ. Trends Pharmacol Sci 18:293–300

    Article  CAS  PubMed  Google Scholar 

  • Herz A, Albus K, Metys̆ J, Schubert P, Teschemacher H (1970) On the central sites for the antinociceptive action of morphine and fentanyl. Neuropharmacology 9:539–551

    Article  CAS  PubMed  Google Scholar 

  • Heyman JS, Mulvaney SA, Mosberg HI, Porreca F (1987) Opioid δ-receptor involvement in supraspinal and spinal antinociception in mice. Brain Res 420:100–108

    Article  CAS  PubMed  Google Scholar 

  • Heyman JS, Williams CL, Burks TF, Mosberg HI, Porreca F (1988) Dissociation of opioid antinociception and central gastrointestinal propulsion in the mouse: studies with naloxonazine. J Pharmacol Exp Ther 245:238–243

    CAS  PubMed  Google Scholar 

  • Ho BY, Takemori AE (1990) Attenuation of the antinociceptive action of the selective κ-opioid receptor agonist, U-50,488H by ICS-205-930. Eur J Pharmacol 178:371–373

    Article  CAS  PubMed  Google Scholar 

  • Hoehn K, Reid A, Sawynok J (1988) Pertussis toxin inhibits antinociception produced by intrathecal injection of morphine, noradrenaline and baclofen. Eur J Pharmacol 146:65–72

    Article  CAS  PubMed  Google Scholar 

  • Hökfelt T, Elde R, Johansson O, Terenius L, Stein L (1977) The distribution of enkephalin-immunoreactive cell bodies in the rat central nervous system. Neurosci Lett 5:25–31

    Article  PubMed  Google Scholar 

  • Holtzman SG (1974) Behavioral effects of separate and combined administration of naloxone and d-amphetamine. J Pharmacol Exp Ther 189:51–60

    CAS  PubMed  Google Scholar 

  • Hough LB, Nalwalk JW, Yang W, Ding X (2015) Neuronal cytochrome P450 activity and opioid analgesia: relevant sites and mechanisms. Brain Res 1616:10–18. https://doi.org/10.1016/j.brainres.2015.04.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang YH, Wu YW, Chuang JY, Chang YC, Chang HF, Tao PL, Loh HH, Yeh SH (2020) Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variants. Pain 161(6):1177–1190. https://doi.org/10.1097/j.pain.0000000000001823.Pain

    Article  CAS  PubMed  Google Scholar 

  • Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR (1975) Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature 258:577–579

    Article  CAS  PubMed  Google Scholar 

  • Hyson RL, Ashcraft LJ, Drugan RC, Grau JW, Maier SF (1982) Extent and control of shock affects naltrexone sensitivity of stress-induced analgesia and reactivity to morphine. Pharmacol Biochem Behav 17:1019–1025

    Article  CAS  PubMed  Google Scholar 

  • Ikeda K, Kobayashi T, Ichikawa T, Kumanishi T, Niki H, Yano RJ (2001) The untranslated region of (mu)-opioid receptor mRNA contributes to reduced opioid sensitivity in CXBK mice. Neuroscience 21(4):1334–1339. https://doi.org/10.1523/JNEUROSCI.21-04-01334.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ireson JD (1970) A comparison of the antinociceptive actions of cholinomimetic and morphine-like drugs. Br J Pharmacol 40:92–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Islam AK, Cooper ML, Bodnar RJ (1993) Interactions among aging, gender, and gonadectomy effects upon morphine antinociception in rats. Physiol Behav 54:45–53

    Article  CAS  PubMed  Google Scholar 

  • Israel Y et al (2005) NPY-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats. Peptides 26:1167–1175

    Article  CAS  PubMed  Google Scholar 

  • Itzhak Y, Pasternak GW (1987) Interaction of [D-Ser2, Leu5]enkephalin-Thr6 (DSLET), a relatively selective delta ligand, with MU1 opioid binding sites. Life Sci 40:307–311

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto ET (1989) Antinociception after nicotine administration into the mesopontine tegmentum of rats: evidence for muscarinic actions. J Pharmacol Exp Ther 251:412–421

    CAS  PubMed  Google Scholar 

  • Iwamoto ET (1991) Characterization of the antinociception induced by nicotine in the pedunculopontine tegmental nucleus and the nucleus raphe magnus. J Pharmacol Exp Ther 257:120–133

    CAS  PubMed  Google Scholar 

  • Jacquet YF (1988) The NMDA receptor: central role in pain inhibition in rat periaqueductal gray. Eur J Pharmacol 154:271–276

    Article  CAS  PubMed  Google Scholar 

  • Jacquet YF, Lajtha A (1974) Paradoxical effects after microinjection of morphine in the periaqueductal gray matter in the rat. Science 185:1055–1057. https://doi.org/10.1126/science.185.4156.1055

    Article  CAS  PubMed  Google Scholar 

  • Jacquet YF, Lajtha A (1975) Morphine analgesia: 2-way cross tolerance between systematic and intracerebral (periaqueductal gray) administrations. Life Sci 17:1321–1324

    Article  CAS  PubMed  Google Scholar 

  • Jacquet YF, Lajtha A (1976) The periaqueductal gray: site of morphine analgesia and tolerance as shown by 2-way cross tolerance between systemic and intracerebral injections. Brain Res 103:501–513

    Article  CAS  PubMed  Google Scholar 

  • Jensen TS, Yaksh TL (1984) Spinal monoamine and opiate systems partly mediate the antinociceptive effects produced by glutamate at brainstem sites. Brain Res 321:287–297. https://doi.org/10.1016/0006-8993(84)90181-1

    Article  CAS  PubMed  Google Scholar 

  • Jensen TS, Yaksh TL (1986a) III. Comparison of the antinociceptive action of Mu and delta opioid receptor ligands in the periaqueductal gray matter, medial and paramedial ventral medulla in the rat as studied by the microinjection technique. Brain Res 372:301–312

    Article  CAS  PubMed  Google Scholar 

  • Jensen TS, Yaksh TL (1986b) II. Examination of spinal monoamine receptors through which brainstem opiate-sensitive systems act in the rat. Brain Res 363:114–127

    Article  CAS  PubMed  Google Scholar 

  • Jensen TS, Yaksh TL (1986c) I. Comparison of antinociceptive action of morphine in the periaqueductal gray, medial and paramedial medulla in rat. Brain Res 363:99–113

    Article  CAS  PubMed  Google Scholar 

  • Jiang Q, Takemori AE, Sultana M, Portoghese PS, Bowen WD, Mosberg HI, Porreca F (1991) Differential antagonism of opioid delta antinociception by [D-Ala2, Leu5, Cys6]enkephalin and naltrindole 5′-isothiocyanate: evidence for delta receptor subtypes. J Pharmacol Exp Ther 257:1069–1075

    CAS  PubMed  Google Scholar 

  • Kavaliers M, Innes DG (1990) Developmental changes in opiate-induced analgesia in deer mice: sex and population differences. Brain Res 516:326–331. https://doi.org/10.1016/0006-8993(90)90936-6

    Article  CAS  PubMed  Google Scholar 

  • Keith DE Jr, Anton B, Evans CJ (1993) Characterization and mapping of a delta opioid receptor clone from NG108-15 cells. Proc West Pharmacol Soc 36:299–306

    CAS  PubMed  Google Scholar 

  • Kelly DD, Silverman A-J, Glusman M, Bodnar RJ (1993) Characterization of pituitary mediation of stress-induced antinociception in rats. Physiol Behav 53:769–775

    Article  CAS  PubMed  Google Scholar 

  • Kepler KL, Kest B, Kiefel JM, Cooper ML, Bodnar RJ (1989) Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol Biochem Behav 34:119–127

    Article  CAS  PubMed  Google Scholar 

  • Kepler KL, Standifer KM, Paul D, Kest B, Pasternak GW, Bodnar RJ (1991) Gender effects and central opioid analgesia. Pain 45:87–94

    Article  CAS  PubMed  Google Scholar 

  • Kest B, Wilson SG, Mogil JS (1999) Sex differences in supraspinal morphine analgesia are dependent on genotype. J Pharmacol Exp Ther 289:1370–1375

    CAS  PubMed  Google Scholar 

  • Khachaturian H, Watson SJ, Lewis ME, Coy D, Goldstein A, Akil H (1982) Dynorphin immunocytochemistry in the rat central nervous system. Peptides 3:941–954

    Article  CAS  PubMed  Google Scholar 

  • Khachaturian H, Lewis M, Hollt V, Watson S (1983) Telencephalic enkephalinergic systems in the rat brain. J Neurosci 3:844–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khalilzadeh E, Saiah GV (2017) The possible mechanisms of analgesia produced by microinjection of morphine into the lateral habenula in the acute model of trigeminal pain in rats. Res Pharm Sci 12:241–248. https://doi.org/10.4103/1735-5362.207205

    Article  PubMed  PubMed Central  Google Scholar 

  • Kiefel JM, Cooper ML, Bodnar RJ (1992a) Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. Brain Res 597:331–338

    Article  CAS  PubMed  Google Scholar 

  • Kiefel JM, Cooper ML, Bodnar RJ (1992b) Inhibition of mesencephalic morphine analgesia by methysergide in the medial ventral medulla of rats. Physiol Behav 51:201–205

    Article  CAS  PubMed  Google Scholar 

  • Kiefel JM, Rossi GC, Bodnar RJ (1993) Medullary μ and δ opioid receptors modulate mesencephalic morphine analgesia in rats. Brain Res 624:151–161

    Article  CAS  PubMed  Google Scholar 

  • Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG (1992) The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci 89:12048–12052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King MA, Rossi GC, Chang AH, Williams L, Pasternak GW (1997) Spinal analgesic activity of orphanin FQ/nociceptin and its fragments. Neurosci Lett 223:113–116

    Article  CAS  PubMed  Google Scholar 

  • Kirchgessner AL, Bodnar RJ, Pasternak GW (1982) Naloxazone and pain-inhibitory systems: evidence for a collateral inhibition model. Pharmacol Biochem Behav 17:1175–1179

    Article  CAS  PubMed  Google Scholar 

  • Kitanaka N, Sora I, Kinsey S, Zeng Z, Uhl GR (1998) No heroin or morphine 6β-glucuronide analgesia in μ-opioid receptor knockout mice. Eur J Pharmacol 355:R1–R3

    Article  CAS  PubMed  Google Scholar 

  • Klamt JG, Prado WA (1991) Antinociception and behavioral changes induced by carbachol microinjected into identified sites of the rat brain. Brain Res 549:9–18

    Article  CAS  PubMed  Google Scholar 

  • Klatt DS, Guinan MJ, Culhane ES, Carstens E, Watkins LR (1988) The dorsal raphe nucleus: a re-evaluation of its proposed role in opiate analgesia systems. Brain Res 447:246–252

    Article  CAS  PubMed  Google Scholar 

  • Klein G, Rossi GC, Waxman AR, Arout C, Juni A, Inturrisi CE, Kest B (2009) The contribution of MOR-1 exons 1–4 to morphine and heroin analgesia and dependence. Neurosci Lett 457:115–119

    Article  CAS  PubMed  Google Scholar 

  • Knapp RJ et al (1994) Identification of a human delta opioid receptor: cloning and expression. Life Sci 54:PL463–PL469

    Article  CAS  PubMed  Google Scholar 

  • Knapp RJ et al (1995) Molecular biology and pharmacology of cloned opioid receptors sup1/sup. FASEB J 9:516–525

    Article  CAS  PubMed  Google Scholar 

  • Krettek JE, Price JL (1978) Amygdaloid projections to subcortical structures within the basal forebrain and brainstem in the rat and cat. J Comp Neurol 178:225–253

    Article  CAS  PubMed  Google Scholar 

  • Kringel D, Lötsch J, Kringel D et al (2016) Next-generation sequencing of human opioid receptor genes based on a custom AmpliSeq™ library and ion torrent personal genome machine. Clin Chim Acta 463:32–38. https://doi.org/10.1016/j.cca.2016.10.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krzanowska EK, Bodnar RJ (1999) Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res 821:224–230

    Article  CAS  PubMed  Google Scholar 

  • Krzanowska EK, Bodnar RJ (2000) Analysis of sex and gonadectomy differences in β-endorphin antinociception elicited from the ventrolateral periaqueductal gray in rats. Eur J Pharmacol 392:157–161

    Article  CAS  PubMed  Google Scholar 

  • Krzanowska EK, Rossi GC, Pasternak GW, Bodnar RJ (1998) Potency ratios of morphine and morphine-6β-glucuronide analgesia elicited from the periaqueductal gray, locus coeruleus or rostral ventromedial medulla of rats. Brain Res 799:329–333

    Article  CAS  PubMed  Google Scholar 

  • Krzanowska EK, Znamensky V, Wilk S, Bodnar RJ (2000) Antinociceptive and behavioral activation responses elicited by d-Pro(2)-endomorphin-2 in the ventrolateral periaqueductal gray are sensitive to sex and gonadectomy differences in rats. Peptides 21:705–715. https://doi.org/10.1016/s0196-9781(00)00191-1

    Article  CAS  PubMed  Google Scholar 

  • Krzanowska EK, Ogawa S, Pfaff DW, Bodnar RJ (2002) Reversal of sex differences in morphine analgesia elicited from the ventrolateral periaqueductal gray in rats by neonatal hormone manipulations. Brain Res 929:1–9

    Article  CAS  PubMed  Google Scholar 

  • Kuraishi Y, Fukui K, Shiomi H, Akaike A, Takagi H (1978) Microinjection of opioids into the nucleus reticularis gigantocellularis of the rat: analgesia and increase in the normetanephrine level in the spinal cord. Biochem Pharmacol 27:2756–2758. https://doi.org/10.1016/0006-2952(78)90054-0

    Article  CAS  PubMed  Google Scholar 

  • Lai J, Bilsky EJ, Rothman RB, Porreca F (1994) Treatment with antisense oligodeoxynucleotide to the opioid δ receptor selectively inhibits δ2-agonist antinociception. NeuroReport 5:1049–1052

    Article  CAS  PubMed  Google Scholar 

  • Lauber AH, Romano GJ, Mobbs CV, Howells RD, Pfaff DW (1990) Estradiol induction of proenkephalin messenger RNA in hypothalamus: dose-response and relation to reproductive behavior in the female rat. Mol Brain Res 8:47–54

    Article  CAS  PubMed  Google Scholar 

  • Letchworth SR, Mathis JP, Rossi GC, Bodnar RJ, Pasternak GW (2000) Autoradiographic localization of (125)I[Tyr(14)]orphanin FQ/nociceptin and (125)I[Tyr(10)]orphanin FQ/nociceptin(1-11) binding sites in rat brain. J Comp Neurol 423:319–329

    Article  CAS  PubMed  Google Scholar 

  • Leventhal L, Cole JL, Rossi GC, Pan YX, Pasternak GW, Bodnar RJ (1996) Antisense oligodeoxynucleotides against the MOR-1 clone alter weight and ingestive responses in rats. Brain Res 719:78–84

    Article  CAS  PubMed  Google Scholar 

  • Leventhal L, Stevens LB, Rossi GC, Pasternak GW, Bodnar RJ (1997) Antisense mapping of the MOR-1 opioid receptor clone: modulation of hyperphagia induced by DAMGO. J Pharmacol Exp Ther 282:1402–1407

    CAS  PubMed  Google Scholar 

  • Leventhal L, Mathis JP, Rossi GC, Pasternak GW, Bodnar RJ (1998a) Orphan opioid receptor antisense probes block orphanin FQ-induced hyperphagia. Eur J Pharmacol 349:R1–R3

    Article  CAS  PubMed  Google Scholar 

  • Leventhal L, Silva RM, Rossi GC, Pasternak GW, Bodnar RJ (1998b) Morphine-6beta-glucuronide-induced hyperphagia: characterization of opioid action by selective antagonists and antisense mapping in rats. J Pharmacol Exp Ther 287:538–544

    CAS  PubMed  Google Scholar 

  • Levy RA, Proudfit HK (1979) Analgesia produced by microinjection of baclofen and morphine at brain stem sites. Eur J Pharmacol 57:43–55

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, Cannon J, Liebeskind J (1980) Opioid and nonopioid mechanisms of stress analgesia. Science 208:623–625

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, Sherman J, Liebeskind J (1981) Opioid and non-opioid stress analgesia: assessment of tolerance and cross-tolerance with morphine. J Neurosci 1:358–363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lewis J, Tordoff M, Sherman J, Liebeskind J (1982) Adrenal medullary enkephalin-like peptides may mediate opioid stress analgesia. Science 217:557–559

    Article  CAS  PubMed  Google Scholar 

  • Lewis ME, Khachaturian H, Watson SJ (1985) Combined autoradiographic-immunocytochemical analysis of opioid receptors and opioid peptide neuronal systems in brain. Peptides 6:37–47

    Article  CAS  PubMed  Google Scholar 

  • Ling GS, Pasternak GW (1983) Spinal and supraspinal opioid analgesia in the mouse: the role of subpopulations of opioid binding sites. Brain Res 271:152–156. https://doi.org/10.1016/0006-8993(83)91376-8

    Article  CAS  PubMed  Google Scholar 

  • Ling GSF, Spiegel K, Nishimura SL, Pasternak GW (1983) Dissociation of morphine’s analgesic and respiratory depressant actions. Eur J Pharmacol 86:487–488

    Article  CAS  PubMed  Google Scholar 

  • Ling G, MacLeod J, Lee S, Lockhart S, Pasternak G (1984) Separation of morphine analgesia from physical dependence. Science 226:462–464

    Article  CAS  PubMed  Google Scholar 

  • Ling GS, Spiegel K, Lockhart SH, Pasternak GW (1985) Separation of opioid analgesia from respiratory depression: evidence for different receptor mechanisms. J Pharmacol Exp Ther 232:149–155

    CAS  PubMed  Google Scholar 

  • Ling GSF, Simantov R, Clark JA, Pasternak GW (1986) Naloxonazine actions in vivo. Eur J Pharmacol 129:33–38

    Article  CAS  PubMed  Google Scholar 

  • Lipman JJ, Spencer PSJ (1980) A comparison of muscarinic cholinergic involvement in the antinociceptive effects of morphine and clonidine in the mouse. Eur J Pharmacol 64:249–258

    Article  CAS  PubMed  Google Scholar 

  • Llewelyn M (1986) Brainstem mechanisms of antinociception Effects of electrical stimulation and injection of morphine into the nucleus raphe magnus. Neuropharmacology 25:727–735

    Article  CAS  PubMed  Google Scholar 

  • Llewelyn MB, Azami J, Gibbs M, Roberts MHT (1983a) A comparison of the sites at which pentazocine and morphine act to produce analgesia. Pain 16:313–331

    Article  CAS  PubMed  Google Scholar 

  • Llewelyn MB, Azami J, Roberts MHT (1983b) Effects of 5-hydroxytryptamine applied into nucleus raphe magnus on nociceptive thresholds and neuronal firing rate. Brain Res 258:59–68

    Article  CAS  PubMed  Google Scholar 

  • Llorca-Torralba M, Mico JA, Berrocoso E (2018) Behavioral effects of combined morphine and MK-801 administration to the locus coeruleus of a rat neuropathic pain model. Prog Neuropsychopharmacol Biol Psychiatry 84:257–266. https://doi.org/10.1016/j.pnpbp.2018.03.007

    Article  CAS  PubMed  Google Scholar 

  • Loh HH, Liu H-C, Cavalli A, Yang W, Chen Y-F, Wei L-N (1998) μ Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Mol Brain Res 54:321–326

    Article  CAS  PubMed  Google Scholar 

  • London ED, Waller SB, Wamsley JK (1985) Autoradiographic localization of [3H]nicotine binding sites in the rat brain. Neurosci Lett 53:179–184

    Article  CAS  PubMed  Google Scholar 

  • Loyd DR, Murphy AZ (2006) Sex differences in the anatomical and functional organization of the periaqueductal gray-rostral ventromedial medullary pathway in the rat: a potential circuit mediating the sexually dimorphic actions of morphine. J Comp Neurol 496:723–738

    Article  PubMed  PubMed Central  Google Scholar 

  • Loyd DR, Murphy AZ (2008) Androgen and estrogen (alpha) receptor localization on periaqueductal gray neurons projecting to the rostral ventromedial medulla in the male and female rat. J Chem Neuroanat 36:216–226. https://doi.org/10.1016/j.jchemneu.2008.08.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loyd DR, Morgan MM, Murphy AZ (2007) Morphine preferentially activates the periaqueductal gray–rostral ventromedial medullary pathway in the male rat: a potential mechanism for sex differences in antinociception. Neuroscience 147:456–468

    Article  CAS  PubMed  Google Scholar 

  • Loyd DR, Morgan MM, Murphy AZ (2008a) Sexually dimorphic activation of the periaqueductal gray-rostral ventromedial medullary circuit during the development of tolerance to morphine in the rat. Eur J Neurosci 27:1517–1524. https://doi.org/10.1111/j.1460-9568.2008.06100.x

    Article  PubMed  PubMed Central  Google Scholar 

  • Loyd DR, Wang X, Murphy AZ (2008b) Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia. J Neurosci 28:14007–14017. https://doi.org/10.1523/JNEUROSCI.4123-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu Z, Xu J, Rossi GC, Majumdar S, Pasternak GW, Pan Y-X (2015) Mediation of opioid analgesia by a truncated 6-transmembrane GPCR. J Clin Investig 125:2626–2630

    Article  PubMed  PubMed Central  Google Scholar 

  • Lu Z, Xu J, Xu M, Rossi GC, Majumdar S, Pasternak GW, Pan YX (2018) Truncated μ-opioid receptors with 6 transmembrane domains are essential for opioid analgesia. Anesth Analg 126:1050–1057. https://doi.org/10.1213/ANE.0000000000002538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma QP, Shi YS, Han JS (1992) Further studies on interactions between periaqueductal gray, nucleus accumbens and habenula in antinociception. Brain Res 583:292–295. https://doi.org/10.1016/s0006-8993(10)80036-8

    Article  CAS  PubMed  Google Scholar 

  • MacLennan A, Drugan R, Hyson R, Maier S, Madden J, Barchas J (1982a) Corticosterone: a critical factor in an opioid form of stress-induced analgesia. Science 215:1530–1532

    Article  CAS  PubMed  Google Scholar 

  • MacLennan AJ, Drugan RC, Hyson RL, Maier SF, Madden J, Barchas JD (1982b) Dissociation of long-term analgesia and the shuttle box escape deficit caused by inescapable shock. J Comp Physiol Psychol 96:904–912

    Article  CAS  PubMed  Google Scholar 

  • Majumdar S et al (2011) Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects. Proc Natl Acad Sci 108:19778–19783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majumdar S, Subrath J, Le Rouzic V, Polikar L, Burgman M, Nagakura K, Ocampo J, Haselton N, Pasternak AR, Grinnell S, Pan YX, Pasternak GW (2012) Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants. J Med Chem 55(14):6352–6362. https://doi.org/10.1021/jm300305c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1987) Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. J Neurosci 7:2445–2464

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mansour A, Fox CA, Akil H, Watson SJ (1995a) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18:22–29. https://doi.org/10.1016/0166-2236(95)93946-u

    Article  CAS  PubMed  Google Scholar 

  • Mansour A, Fox CA, Burke S, Akil H, Watson SJ (1995b) Immunohistochemical localization of the cloned μ opioid receptor in the rat CNS. J Chem Neuroanat 8:283–305

    Article  CAS  PubMed  Google Scholar 

  • Mansour A, Burke S, Pavlic RJ, Akil H, Watson SJ (1996) Immunohistochemical localization of the cloned κ1 receptor in the rat CNS and pituitary. Neuroscience 71:671–690

    Article  CAS  PubMed  Google Scholar 

  • Marek P, Panocka I, Hartmann G (1982) Enhancement of stress-induced analgesia in adrenalectomized mice: its reversal by dexamethasone. Pharmacol Biochem Behav 16:403–405

    Article  CAS  PubMed  Google Scholar 

  • Marek P, Panocka I, Sadowski B (1983) Dexamethasone reverses adrenalectomy enhancement of footshock induced analgesia in mice. Pharmacol Biochem Behav 18:167–169

    Article  CAS  PubMed  Google Scholar 

  • Marek P, Panocka I, Sadowski B (1986) Activation of anti- and pro-nociceptive mechanisms by front paw shock in spinal mice: involvement of humoral factors. Pharmacol Biochem Behav 24:791–793

    Article  CAS  PubMed  Google Scholar 

  • Marrone GF et al (2016a) Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS. Proc Natl Acad Sci 113:3663–3668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marrone GF et al (2016b) Tetrapeptide endomorphin analogs require both full length and truncated splice variants of the mu opioid receptor gene Oprm1 for analgesia. ACS Chem Neurosci 7:1717–1727. https://doi.org/10.1021/acschemneuro.6b00240

    Article  CAS  PubMed  Google Scholar 

  • Marrone GF et al (2017) Genetic dissociation of morphine analgesia from hyperalgesia in mice. Psychopharmacology 234:1891–1900. https://doi.org/10.1007/s00213-017-4600-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (1976) The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther 197:517–532

    CAS  PubMed  Google Scholar 

  • Mason P (1997) Physiological identification of pontomedullary serotonergic neurons in the rat. J Neurophysiol 77:1087–1098

    Article  CAS  PubMed  Google Scholar 

  • Massaly N, Copits BA, Wilson-Poe AR, Hipólito L, Markovic T, Yoon HJ, Liu S, Walicki MC, Bhatti DL, Sirohi S, Klaas A, Walker BM, Neve R, Cahill CM, Shoghi KI, Gereau RW IV, McCall JG, Al-Hasani R, Bruchas MR, Morón JA (2019) Pain-Induced negative affect is mediated via recruitment of the nucleus accumbens kappa opioid system. Neuron 102:564–573. https://doi.org/10.1016/j.neuron.2019.02.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mathis JP, Goldberg IE, Rossi GC, Leventhal L, Pasternak GW (1998) Antinociceptive analogs of orphanin FQ/nociceptin(1-11). Life Sci 63:PL161–PL166. https://doi.org/10.1016/s0024-3205(98)00358-0

    Article  CAS  Google Scholar 

  • Mathis JP, Rossi GC, Pellegrino MJ, Jimenez C, Pasternak GW, Allen RG (2001) Carboxyl terminal peptides derived from prepro-orphanin FQ/nociceptin (ppOFQ/N) are produced in the hypothalamus and possess analgesic bioactivities. Brain Res 895:89–94. https://doi.org/10.1016/s0006-8993(01)02035-2

    Article  CAS  PubMed  Google Scholar 

  • Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dollé P, Tzavara E, Hanoune J, Roques BP, Kieffer BL (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioidreceptorgene. Nature 383(6603):819–823. https://doi.org/10.1038/383819a0

    Article  CAS  PubMed  Google Scholar 

  • Mattia A, Vanderah T, Mosberg HI, Porreca F (1991) Lack of antinociceptive cross-tolerance between [D-Pen2, D-Pen5]enkephalin and [D-Ala2]deltorphin II in mice: evidence for delta receptor subtypes. J Pharmacol Exp Ther 258:583–587

    CAS  PubMed  Google Scholar 

  • Mattia A et al (1992) Spinal opioid delta antinociception in the mouse: mediation by a 5′-NTII-sensitive delta receptor subtype. J Pharmacol Exp Ther 260:518–525

    CAS  PubMed  Google Scholar 

  • Mayer DJ, Price DD (1976) Central nervous system mechanisms of analgesia. Pain 2:379–404

    Article  PubMed  Google Scholar 

  • McGowan MK, Hammond DL (1993a) Intrathecal GABAB antagonists attenuate the antinociception produced by microinjection ofl-glutamate into the ventromedial medulla of the rat. Brain Res 607:39–46

    Article  CAS  PubMed  Google Scholar 

  • McGowan MK, Hammond DL (1993b) Antinociception produced by microinjection ofl-glutamate into the ventromedial medulla of the rat: mediation by spinal GABAA receptors. Brain Res 620:86–96

    Article  CAS  PubMed  Google Scholar 

  • Meunier J-C et al (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Gramsch C, Przewłocki R, Höllt V, Herz A (1980a) Lesions of the hypothalamic arcuate nucleus produce a temporary hyperalgesia and attenuate stress-evoked analgesia. Life Sci 27:1513–1523

    Article  CAS  PubMed  Google Scholar 

  • Millan MJ, Przewlocki R, Herz A (1980b) A non-beta-endorphinergic adenohypophyseal mechanism is essential for an analgetic response to stress. Pain 8:343–353

    CAS  PubMed  Google Scholar 

  • Min BH, Augustin LB, Felsheim RF, Fuchs JA, Loh HH (1994) Genomic structure analysis of promoter sequence of a mouse mu opioid receptor gene. Proc Natl Acad Sci USA 91:9081–9085. https://doi.org/10.1073/pnas.91.19.9081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minami M et al (1993) Cloning and expression of a cDNA for the rat ik/i-opioid receptor. FEBS Lett 329:291–295

    Article  CAS  PubMed  Google Scholar 

  • Mitchell JM, Lowe D, Fields HL (1998) The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats. Neuroscience 87:123–133

    Article  CAS  PubMed  Google Scholar 

  • Mogil JS, Sternberg WF, Kest B, Marek P, Liebeskind JC (1993) Sex differences in the antagonism of swim stress-induced analgesia: effects of gonadectomy and estrogen replacement. Pain 53:17–25

    Article  PubMed  Google Scholar 

  • Mogil JSKB, Sadowski B, Belknap JK (1996a) Differential genetic mediation of sensitivity to morphine in genetic models of opiate antinociception: influence of nociceptive assay. J Pharmacol Exp Ther 276:532–544

    CAS  PubMed  Google Scholar 

  • Mogil JS, Grisel JE, Reinscheid RK, Civelli O, Belknap JK, Grandy DK (1996b) Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75:333–337. https://doi.org/10.1016/0306-4522(96)00338-7

    Article  CAS  PubMed  Google Scholar 

  • Mollereau C et al (1994) ORL1, a novel member of the opioid receptor family: cloning, functional expression and localization. FEBS Lett 341:33–38

    Article  CAS  PubMed  Google Scholar 

  • Monroe PJ, Hawranko AA, Smith DL, Smith DJ (1996) Biochemical and pharmacological characterization of multiple beta-endorphinergic antinociceptive systems in the rat periaqueductal gray. J Pharmacol Exp Ther 276:65–73

    CAS  PubMed  Google Scholar 

  • Morgan MM, Heinricher MM, Fields HL (1992) Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla. Neuroscience 47:863–871

    Article  CAS  PubMed  Google Scholar 

  • Morgan MM, Reid RA, Stormann TM, Lautermilch NJ (2014) Opioid selective antinociception following microinjection into the periaqueductal gray of the rat. J Pain 15:1102–1109. https://doi.org/10.1016/j.jpain.2014.07.008

    Article  CAS  PubMed  Google Scholar 

  • Mosberg HI, Hurst R, Hruby VJ, Galligan JJ, Burks TF, Gee K, Yamamura HI (1983a) Conformationally constrained cyclic enkephalin analogs with pronounced delta opioid receptor agonist selectivity. Life Sci 32:2565–2569. https://doi.org/10.1016/0024-3205(83)90239-4

    Article  CAS  PubMed  Google Scholar 

  • Mosberg HI, Hurst R, Hruby VJ, Gee K, Yamamura HI, Galligan JJ, Burks TF (1983b) Bis-penicillamine enkephalins possess highly improved specificity toward delta opioid receptors. Proc Natl Acad Sci 80:5871–5874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moskowitz AS, Goodman RR (1985a) Autoradiographic analysis of mu1, mu2, and delta opioid binding in the central nervous system of C57BL/6BY and CXBK (opioid receptor-deficient) mice. Brain Res 360:108–116

    Article  CAS  PubMed  Google Scholar 

  • Moskowitz AS, Goodman RR (1985b) Autoradiographic distribution of Mu1 and Mu2 opioid binding in the mouse central nervous system. Brain Res 360:117–129

    Article  CAS  PubMed  Google Scholar 

  • Mousa S, Miller CH Jr, Couri D (1981) Corticosteroid modulation and stress-induced analgesia in rats. Neuroendocrinology 33:317–319

    Article  CAS  PubMed  Google Scholar 

  • Mousa S, Miller CH Jr, Couri D (1983) Dexamethasone and stress-induced analgesia. Psychopharmacology 79:199–202. https://doi.org/10.1007/bf00427812

    Article  CAS  PubMed  Google Scholar 

  • Navratilova E, Xie JY, Okun A, Qu C, Eyde N, Ci S, Ossipov MH, King T, Fields HL, Porreca F (2012) Pain relief produces negative reinforcement through activation of mesolimbic reward–valuation circuitry. Proc Natl Acad Sci USA 109(50):20709–20713. https://doi.org/10.1073/pnas.1214605109

    Article  PubMed  PubMed Central  Google Scholar 

  • Nishimura SL, Recht LD, Pasternak GW (1984) Biochemical characterization of high-affinity 3H-opioid binding. Further evidence for Mu1 sites. Mol Pharmacol 25:29–37

    CAS  PubMed  Google Scholar 

  • Pan YX (2002) Identification and characterization of a novel promoter of the mouse mu opioid receptor gene (Oprm) that generates eight splice variants. Gene 295:97–108. https://doi.org/10.1016/s0378-1119(02)00825-9

    Article  CAS  PubMed  Google Scholar 

  • Pan ZZ, Fields HL (1996) Endogenous opioid-mediated inhibition of putative pain-modulating neurons in rat rostral ventromedial medulla. Neuroscience 74:855–862

    Article  CAS  PubMed  Google Scholar 

  • Pan Y-X, Pasternak GW (2011) Molecular biology of mu opioid receptors. In: Pasternak GW (ed) The opiate receptors. Humana Press, Totowa, pp 121–160. https://doi.org/10.1007/978-1-60761-993-2_6

    Chapter  Google Scholar 

  • Pan YX et al (1995) Cloning and functional characterization through antisense mapping of a kappa 3-related opioid receptor. Mol Pharmacol 47:1180–1188

    CAS  PubMed  Google Scholar 

  • Pan Y-X et al (1999) Identification and characterization of three new alternatively spliced μ-opioid receptor isoforms. Mol Pharmacol 56:396–403

    Article  CAS  PubMed  Google Scholar 

  • Pan Y-X, Xu J, Bolan E, Chang A, Mahurter L, Rossi G, Pasternak GW (2000) Isolation and expression of a novel alternatively spliced mu opioid receptor isoform, MOR-1F. FEBS Lett 466:337–340

    Article  CAS  PubMed  Google Scholar 

  • Pan Y-X, Xu J, Mahurter L, Bolan E, Xu M, Pasternak GW (2001) Generation of the mu opioid receptor (MOR-1) protein by three new splice variants of the Oprm gene. Proc Natl Acad Sci 98:14084–14089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pan YX, Xu J, Mahurter L, Xu M, Gilbert AK, Pasternak GW (2003) Identification and characterization of two new human mu opioid receptor splice variants, hMOR-1O and hMOR-1X. Biochem Biophys Res Commun 301(4):1057–1061. https://doi.org/10.1016/s0006-291x(03)00089-5

    Article  CAS  PubMed  Google Scholar 

  • Pan L, Xu J, Yu R, Xu MM, Pan YX, Pasternak GW (2005a) Identification and characterization of six new alternatively spliced variants of the human mu opioid receptor gene, Oprm. Neuroscience 133(1):209–220. https://doi.org/10.1016/j.neuroscience.2004.12.033

    Article  CAS  PubMed  Google Scholar 

  • Pan Y-X, Xu J, Bolan E, Moskowitz HS, Xu M, Pasternak GW (2005b) Identification of four novel exon 5 splice variants of the mouse μ-opioid receptor gene: functional consequences of C-terminal splicing. Mol Pharmacol 68:866–875

    Article  CAS  PubMed  Google Scholar 

  • Pan Y-X, Xu J, Xu M, Rossi GC, Matulonis JE, Pasternak GW (2009) Involvement of exon 11-associated variants of the mu opioid receptor MOR-1 in heroin, but not morphine, actions. Proc Natl Acad Sci 106:4917–4922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Panocka I, Sadowski B, Marek P (1987) Adrenalectomy and dexamethasone differentially affect postswim antinociception in mice selectively bred for high and low stress-induced analgesia. Physiol Behav 40:597–601

    Article  CAS  PubMed  Google Scholar 

  • Pare WP (1969) Age, sex, and strain differences in the aversive threshold to grid shock in the rat. J Comp Physiol Psychol 69:214–218

    Article  CAS  PubMed  Google Scholar 

  • Parenti M, Tirone F, Giagnoni G, Pecora N, Parolaro D (1986) Pertussis toxin inhibits the antinociceptive action of morphine in the rat. Eur J Pharmacol 124:357–359

    Article  CAS  PubMed  Google Scholar 

  • Pasternak GW (1980) Multiple opiate receptors: [3H]ethylketocyclazocine receptor binding and ketocyclazocine analgesia. Proc Natl Acad Sci 77:3691–3694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasternak GW, Pan Y-X (2013) Mu opioids and their receptors: evolution of a concept. Pharmacol Rev 65:1257–1317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pasternak GW, Wood PJ (1986) Minireview: multiple MU opiate receptors. Life Sci 38:1889–1898

    Article  CAS  PubMed  Google Scholar 

  • Pasternak G, Childers, Snyder S (1980a) Opiate analgesia: evidence for mediation by a subpopulation of opiate receptors. Science 208:514–516

    Article  CAS  PubMed  Google Scholar 

  • Pasternak GW, Childers SR, Snyder SH (1980b) Naloxazone, a long-acting opiate antagonist: effects on analgesia in intact animals and on opiate receptor binding in vitro. J Pharmacol Exp Ther 214:455–462

    CAS  PubMed  Google Scholar 

  • Pasternak GW, Bodnar RJ, Clark JA, Inturrisi CE (1987) Morphine-6-glucuronide, a potent mu agonist. Life Sci 41:2845–2849. https://doi.org/10.1016/0024-3205(87)90431-0

    Article  CAS  PubMed  Google Scholar 

  • Pasternak KR, Rossi GC, Zuckerman A, Pasternak GW (1999) Antisense mapping KOR-1: evidence for multiple kappa analgesic mechanisms. Brain Res 826:289–292

    Article  CAS  PubMed  Google Scholar 

  • Paul D, Phillips AG (1986) Selective effects of pirenperone on analgesia produced by morphine or electrical stimulation at sites in the nucleus raphe magnus and periaqueductal gray. Psychopharmacology 88:172–176. https://doi.org/10.1007/bf00652235

    Article  CAS  PubMed  Google Scholar 

  • Paul D, Mana MJ, Pfaus JG, Pinel JP (1988) Attenuation of morphine analgesia by the S2 antagonists, pirenperone and ketanserin. Pharmacol Biochem Behav 31:641–647. https://doi.org/10.1016/0091-3057(88)90243-2

    Article  CAS  PubMed  Google Scholar 

  • Paul D, Bodnar RJ, Gistrak MA, Pasternak GW (1989a) Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice. Eur J Pharmacol 168:307–314. https://doi.org/10.1016/0014-2999(89)90792-9

    Article  CAS  PubMed  Google Scholar 

  • Paul D, Standifer KM, Inturrisi CE, Pasternak GW (1989b) Pharmacological characterization of morphine-6 beta-glucuronide, a very potent morphine metabolite. J Pharmacol Exp Ther 251:477–483

    CAS  PubMed  Google Scholar 

  • Paul D, Levison JA, Howard DH, Pick CG, Hahn EF, Pasternak GW (1990) Naloxone benzoylhydrazone (NalBzoH) analgesia. J Pharmacol Exp Ther 255:769–774

    CAS  PubMed  Google Scholar 

  • Pavlovic ZW, Bodnar RJ (1998a) U50488H-induced analgesia in the amygdala: test-specific effects and blockade by opioid antagonists in the periaqueductal gray. Analgesia 3:223–230

    Article  CAS  Google Scholar 

  • Pavlovic ZW, Bodnar RJ (1998b) Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats. Brain Res 779:158–169

    Article  CAS  PubMed  Google Scholar 

  • Pavlovic ZW, Cooper ML, Bodnar RJ (1996) Opioid antagonists in the periaqueductal gray inhibit morphine and β-endorphin analgesia elicited from the amygdala of rats. Brain Res 741:13–26

    Article  CAS  PubMed  Google Scholar 

  • Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors. Brain Res 346:205–230

    Article  CAS  PubMed  Google Scholar 

  • Pazos A, Cortés R, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors. Brain Res 346:231–249

    Article  CAS  PubMed  Google Scholar 

  • Pert CB, Snyder SH (1973) Opiate receptor: demonstration in nervous tissue. Science 179:1011–1014

    Article  CAS  PubMed  Google Scholar 

  • Pert A, Yaksh T (1974) Sites of morphine induced analgesia in the primate brain: relation to pain pathways. Brain Res 80:135–140. https://doi.org/10.1016/0006-8993(74)90731-8

    Article  CAS  PubMed  Google Scholar 

  • Phoenix CH, Goy RW, Gerall AA, Young WC (1959) Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65:369–382. https://doi.org/10.1210/endo-65-3-369

    Article  CAS  PubMed  Google Scholar 

  • Porreca F, Mosberg HI, Hurst R, Hruby VJ, Burks TF (1984) Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse. J Pharmacol Exp Ther 230:341–348

    CAS  PubMed  Google Scholar 

  • Porreca F, Heyman JS, Mosberg HI, Omnaas JR, Vaught JL (1987) Role of mu and delta receptors in the supraspinal and spinal analgesic effects of [D-Pen2, D-Pen5]enkephalin in the mouse. J Pharmacol Exp Ther 241:393–400

    CAS  PubMed  Google Scholar 

  • Potrebic S, Fields H, Mason P (1994) Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla. J Neurosci 14:1655–1665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potrebic S, Mason P, Fields H (1995) The density and distribution of serotonergic appositions onto identified neurons in the rat rostral ventromedial medulla. J Neurosci 15:3273–3283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prieto GJ, Cannon JT, Liebeskind JC (1983) N. raphe magnus lesions disrupt stimulation-produced analgesia from ventral but not dorsal midbrain areas in the rat. Brain Res 261:53–57

    Article  CAS  PubMed  Google Scholar 

  • Proudfit HK (1980) Reversible inactivation of raphe magnus neurons: effects on nociceptive threshold and morphine-induced analgesia. Brain Res 201:459–464

    Article  CAS  PubMed  Google Scholar 

  • Proudfit HK, Hammond DL (1981) Alterations in nociceptive threshold and morphine-induced analgesia produced by intrathecally administered amine antagonists. Brain Res 218:393–399

    Article  CAS  PubMed  Google Scholar 

  • Przewłocka B, Mika J, Łabuz D, Toth G, Przewłocki R (1999) Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats. Eur J Pharmacol 367:189–196

    Article  PubMed  Google Scholar 

  • Przewłocki R, Costa T, Lang J, Herz A (1987) Pertussis toxin abolishes the antinociception mediated by opioid receptors in rat spinal cord. Eur J Pharmacol 144:91–95

    Article  PubMed  Google Scholar 

  • Raffa RB, Martinez RP, Connelly CD (1994) G-protein antisense oligodeoxyribonucleotides and μ-opioid supraspinal antinociception. Eur J Pharmacol 258:R5–R7

    Article  CAS  PubMed  Google Scholar 

  • Rainbow TC, Schwartz RD, Parsons B, Kellar KJ (1984) Quantitative autoradiography of nicotinic [3H]acetylcholine binding sites in rat brain. Neurosci Lett 50:193–196

    Article  CAS  PubMed  Google Scholar 

  • Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T (1994) Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 45:330–334

    CAS  PubMed  Google Scholar 

  • Reinscheid RK et al (1995) Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270:792–794

    Article  CAS  PubMed  Google Scholar 

  • Reisine T, Bell GI (1993) Molecular biology of opioid receptors. Trends Neurosci 16:506–510

    Article  CAS  PubMed  Google Scholar 

  • Reny-Palasse V, Monier C, Rips R (1989) Opioid involvement in TRH-induced antinociception in the rat following intracerebral administration. Pain 38:193–201. https://doi.org/10.1016/0304-3959(89)90238-8

    Article  CAS  PubMed  Google Scholar 

  • Reynolds DV (1969) Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 164:444–445

    Article  CAS  PubMed  Google Scholar 

  • Rizvi TA, Ennis M, Behbehani MM, Shipley MT (1991) Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: topography and reciprocity. J Comp Neurol 303:121–131

    Article  CAS  PubMed  Google Scholar 

  • Robertson JA, Bodnar RJ (1993) Site-specific modulation of morphine and swim-induced antinociception following thyrotropin-releasing hormone in the rat periaqueductal gray. Pain 55:71–84

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ (1977) Elevation of aversive threshold in rats by intra-amygdaloid injection of morphine sulphate. Pharmacol Biochem Behav 6:385–390

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ (1978) Influence of intra-amygdaloid opiate injections on shock thresholds, tail-flick latencies and open field behaviour in rats. Brain Res 153:211–216

    Article  CAS  PubMed  Google Scholar 

  • Roerig SC, Fujimoto JM (1989) Multiplicative interaction between intrathecally and intracerebroventricularly administered mu opioid agonists but limited interactions between delta and kappa agonists for antinociception in mice. J Pharmacol Exp Ther 249:762–768

    CAS  PubMed  Google Scholar 

  • Roerig SC, Fujimoto JM, Tseng LF (1988) Comparisons of descending pain inhibitory pathways activated by beta-endorphin and morphine as characterized by supraspinal and spinal antinociceptive interactions in mice. J Pharmacol Exp Ther 247:1107–1113

    CAS  PubMed  Google Scholar 

  • Romano GJ, Harlan RE, Shivers BD, Howells RD, Pfaff DW (1988) Estrogen increases proenkephalin messenger ribonucleic acid levels in the ventromedial hypothalamus of the rat. Mol Endocrinol 2:1320–1328

    Article  CAS  PubMed  Google Scholar 

  • Romano GJ, Mobbs CV, Howells RD, Pfaff DW (1989) Estrogen regulation of proenkephalin gene expression in the ventromedial hypothalamus of the rat: temporal qualities and synergism with progesterone. Mol Brain Res 5:51–58

    Article  CAS  PubMed  Google Scholar 

  • Romano GJ, Mobbs CV, Lauber A, Howells RD, Pfaff DW (1990) Differential regulation of proenkephalin gene expression by estrogen in the ventromedial hypothalamus of male and female rats: implications for the molecular basis of a sexually differentiated behavior. Brain Res 536:63–68

    Article  CAS  PubMed  Google Scholar 

  • Romero M-T, Bodnar RJ (1986) Gender differences in two forms of cold-water swim analgesia. Physiol Behav 37:893–897

    Article  CAS  PubMed  Google Scholar 

  • Romero M-T, Kepler KL, Cooper ML, Komisaruk BR, Bodnar RJ (1987) Modulation of gender-specific effects upon swim analgesia in gonadectomized rats. Physiol Behav 40:39–45

    Article  CAS  PubMed  Google Scholar 

  • Romero M-T, Cooper ML, Komisaruk BR, Bodnar RJ (1988) Gender-specific and gonadectomy-specific effects upon swim analgesia: role of steroid replacement therapy. Physiol Behav 44:257–265

    Article  CAS  PubMed  Google Scholar 

  • Root DH, Melendez RI, Zaborszky L, Napier TC (2015) The ventral pallidum: subregion-specific functional anatomy and roles in motivated behaviors. Prog Neurobiol 130:29–70. https://doi.org/10.1016/j.pneurobio.2015.03.005

    Article  PubMed  PubMed Central  Google Scholar 

  • Rossi GC, Pasternak G (1997) Establishing the molecular biology of opioid behavior through antisense approaches. In: Weiss (ed) Antisense oligodeoxynucleotides and antisense RNA: novel pharmacological and therapeutics. CRC Press, New York, pp 115–130

    Google Scholar 

  • Rossi GC, Pasternak GW, Bodnar RJ (1993) Synergistic brainstem interactions for morphine analgesia. Brain Res 624:171–180

    Article  CAS  PubMed  Google Scholar 

  • Rossi G, Pan Y-X, Cheng J, Pasternak GW (1994a) Blockade of morphine analgesia by an antisense oligodeoxynucleotide against the mu receptor. Life Sciences 54:PL375–PL379

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Pasternak GW, Bodnar RJ (1994b) μ and δ opioid synergy between the periaqueductal gray and the rostro-ventral medulla. Brain Res 665:85–93

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Pan Y-X, Brown GP, Pasternak GW (1995a) Antisense mapping the MOR-1 opioid receptor: evidence for alternative splicing and a novel morphine-6β-glucuronide receptor. FEBS Lett 369:192–196

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Standifer KM, Pasternak GW (1995b) Differential blockade of morphine and morphine-6β-glucuronide analgesia by antisense oligodeoxynucleotides directed against MOR-1 and G-protein α subunits in rats. Neurosci Lett 198:99–102

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Brown GP, Leventhal L, Yang K, Pasternak GW (1996a) Novel receptor mechanisms for heroin and morphine-6β-glucuronide analgesia. Neurosci Lett 216:1–4

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Leventhal L, Pasternak GW (1996b) Naloxone sensitive orphanin FQ-induced analgesia in mice. Eur J Pharmacol 311:R7–R8

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Leventhal L, Bolan E, Pasternak GW (1997a) Pharmacological characterization of orphanin FQ/nociceptin and its fragments. J Pharmacol Exp Ther 282:858–865

    CAS  PubMed  Google Scholar 

  • Rossi GC, Leventhal L, Pan YX, Cole J, Su W, Bodnar RJ, Pasternak GW (1997b) Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6beta-glucuronide antinociception. J Pharmacol Exp Ther 281:109–114

    CAS  PubMed  Google Scholar 

  • Rossi GC, Su W, Leventhal L, Su H, Pasternak GW (1997c) Antisense mapping DOR-1 in mice: further support for δ receptor subtypes. Brain Res 753:176–179

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC, Mathis JP, Pasternak GW (1998a) Analgesic activity of orphanin FQ2, murine prepro-orphanin FQ141-157 in mice. NeuroReport 9:1165–1168

    CAS  PubMed  Google Scholar 

  • Rossi GC, Perlmutter M, Leventhal L, Talatti A, Pasternak GW (1998b) Orphanin FQ/nociceptin analgesia in the rat. Brain Res 792:327–330

    Article  CAS  PubMed  Google Scholar 

  • Rossi GC et al (2002) Characterization of rat prepro-orphanin FQ/nociceptin((154-181)): nociceptive processing in supraspinal sites. J Pharmacol Exp Ther 300:257–264. https://doi.org/10.1124/jpet.300.1.257

    Article  CAS  PubMed  Google Scholar 

  • Roychowdhury SM, Fields HL (1996) Endogenous opioids acting at a medullary μ-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray. Neuroscience 74:863–872

    Article  CAS  PubMed  Google Scholar 

  • Roychowdhury SM, Heinricher MM (1997) Effects of iontophoretically applied serotonin on three classes of physiologically characterized putative pain modulating neurons in the rostral ventromedial medulla of lightly anesthetized rats. Neurosci Lett 226:136–138

    Article  CAS  PubMed  Google Scholar 

  • Ryan SM, Maier SF (1988) The estrous cycle and estrogen modulate stress-induced analgesia. Behav Neurosci 102:371–380

    Article  CAS  PubMed  Google Scholar 

  • Rye DB, Lee HJ, Saper CB, Wainer BH (1988) Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat. J Comp Neurol 269:315–341

    Article  CAS  PubMed  Google Scholar 

  • Sanchez-Blazquez P, Garcia-Espana A, Garzon J (1995) In vivo injection of antisense oligodeoxynucleotides to G alpha subunits and supraspinal analgesia evoked by mu and delta opioid agonists. J Pharmacol Exp Ther 275:1590–1596

    CAS  PubMed  Google Scholar 

  • Sandkühler J, Gebhart GF (1984) Relative contributions of the nucleus raphe magnus and adjacent medullary reticular formation to the inhibition by stimulation in the periaqueductal gray of a spinal nociceptive reflex in the pentobarbital-anesthetized rat. Brain Res 305:77–87

    Article  PubMed  Google Scholar 

  • Sathaye N, Bodnar RJ (1989) Dissociation of opioid and nonopioid analgesic responses following adult monosodium glutamate pretreatment. Physiol Behav 46:217–222

    Article  CAS  PubMed  Google Scholar 

  • Satoh M, Kubota A, Iwama T, Wada T, Yasui M, Fujibayashi K, Takagi H (1983a) Comparison of analgesic potencies of mu, delta and kappa agonists locally applied to various CNS regions relevant to analgesia in rats. Life Sci 33:689–692

    Article  CAS  PubMed  Google Scholar 

  • Satoh M, Oku R, Akaike A (1983b) Analgesia produced by microinjection of-glutamate into the rostral ventromedial bulbar nuclei of the rat and its inhibition by intrathecal α-adrenergic blocking agents. Brain Res 261:361–364

    Article  CAS  PubMed  Google Scholar 

  • Schmauss C, Yaksh TL (1984) In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat. J Pharmacol Exp Ther 228:1–12

    CAS  PubMed  Google Scholar 

  • Schmidt BL, Tambeli CH, Barletta J, Luo L, Green P, Levine JD, Gear RW (2002) Altered nucleus accumbens circuitry mediates pain-induced antinociception in morphine-tolerant rats. J Neurosci 22:6773–6780. https://doi.org/10.1523/JNEUROSCI.22-15-06773.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schuller AG et al (1999) Retention of heroin and morphine-6 beta-glucuronide analgesia in a new line of mice lacking exon 1 of MOR-1. Nat Neurosci 2:151–156. https://doi.org/10.1038/5706

    Article  CAS  PubMed  Google Scholar 

  • Segal M, Sandberg D (1977) Analgesia produced by electrical stimulation of catecholamine nuclei in the rat brain. Brain Res 123:369–372

    Article  CAS  PubMed  Google Scholar 

  • Shabalina SA, Zaykin DV, Gris P, Ogurtsov AY, Gauthier J, Shibata K, Tchivileva IE, Belfer I, Mishra B, Kiselycznyk C, Wallace MR, Staud R, Spiridonov NA, Max MB, Goldman D, Fillingim RB, Maixner W, Diatchenko L (2009) Expansion of the human mu-opioid receptor gene architecture: novel functional variants. Hum Mol Genet 18(6):1037–1051

    Article  CAS  PubMed  Google Scholar 

  • Shane R, Wilk S, Bodnar RJ (1999) Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV. Brain Res 815:278–286. https://doi.org/10.1016/s0006-8993(98)01121-4

    Article  CAS  PubMed  Google Scholar 

  • Shane R, Lazar DA, Rossi GC, Pasternak GW, Bodnar RJ (2001) Analgesia elicited by OFQ/nociceptin and its fragments from the amygdala in rats. Brain Res 907:109–116

    Article  CAS  PubMed  Google Scholar 

  • Shane R, Acosta J, Rossi GC, Bodnar RJ (2003) Reciprocal interactions between the amygdala and ventrolateral periaqueductal gray in mediating of Q/N(1-17)-induced analgesia in the rat. Brain Res 980:57–70. https://doi.org/10.1016/s0006-8993(03)02887-7

    Article  CAS  PubMed  Google Scholar 

  • Sharpe LG, Garnett JE, Cicero TJ (1974) Analgesia and hyperreactivity produced by intracranial microinjections of morphine into the periaqueductal gray matter of the rat. Behav Biol 11:303–313

    Article  CAS  PubMed  Google Scholar 

  • Shimomura K, Kamata O, Ueki S, Ida S, Oguri K, Yoshimura H, Tsukamoto H (1971) Analgesic effect of morphine glucuronides. Tohoku J Exp Med 105:45–52. https://doi.org/10.1620/tjem.105.45

    Article  CAS  PubMed  Google Scholar 

  • Shiromani PJ, Armstrong DM, Gillin JC (1988) Cholinergic neurons from the dorsolateral pons project to the medial pons: a WGA-HRP and choline acetyltransferase immunohistochemical study. Neurosci Lett 95:19–23

    Article  CAS  PubMed  Google Scholar 

  • Siegfried B, de Souza RL (1989) NMDA receptor blockade in the periaqueductal grey prevents stress-induced analgesia in attacked mice. Eur J Pharmacol 168:239–242. https://doi.org/10.1016/0014-2999(89)90570-0

    Article  CAS  PubMed  Google Scholar 

  • Silva RM, Rossi GC, Mathis JP, Standifer KM, Pasternak GW, Bodnar RJ (2000) Morphine and morphine-6β-glucuronide-induced feeding are differentially reduced by G-protein α-subunit antisense probes in rats. Brain Res 876:62–75

    Article  CAS  PubMed  Google Scholar 

  • Silva RM, Hadjimarkou MM, Rossi GC, Pasternak GW, Bodnar RJ (2001) Beta-endorphin-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats. J Pharmacol Exp Ther 297:590–596

    CAS  PubMed  Google Scholar 

  • Silva RM, Grossman HC, Hadjimarkou MM, Rossi GC, Pasternak GW, Bodnar RJ (2002a) Dynorphin A(1-17)-induced feeding: pharmacological characterization using selective opioid antagonists and antisense probes in rats. J Pharmacol Exp Ther 301:513–518. https://doi.org/10.1124/jpet.301.2.513

    Article  CAS  PubMed  Google Scholar 

  • Silva RM, Grossman HC, Rossi GC, Pasternak GW, Bodnar RJ (2002b) Pharmacological characterization of β-endorphin- and dynorphin A1–17-induced feeding using G-protein α-subunit antisense probes in rats. Peptides 23:1101–1106

    Article  CAS  PubMed  Google Scholar 

  • Simon EJ, Hiller JM, Edelman I (1973) Stereospecific binding of the potent narcotic analgesic (3H) Etorphine to rat-brain homogenate. Proc Natl Acad Sci USA 70:1947–1949. https://doi.org/10.1073/pnas.70.7.1947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simone DA, Bodnar RJ, Goldman EJ, Pasternak GW (1985) Involvement of opioid receptor subtypes in rat feeding behavior. Life Sci 36:829–833

    Article  CAS  PubMed