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Opioidergic Transmission in the Dorsal Horn

  • Juan Carlos Marvizon
Chapter

Abstract

The potent analgesia produced by opiate drugs is induced, at least in part, in the spinal cord. The three “classical” opioid receptors, µ, δ and κ, are found in dorsal horn neurons and primary afferent terminals. Dorsal horn neurons expressing opioid receptors are mostly excitatory, and their inhibition by opioids decreases pain intensity. In primary afferents, opioid receptors inhibit the release of the pro-nociceptive neuropeptides substance P and CGRP. The spinal cord also contains “atypical” opioid receptors: the nociceptin receptor, the opioid growth factor receptor and toll-like receptors, which modulate pain in ways still not well understood. Enkephalins and dynorphins are the main opioid peptides in the dorsal horn, and are expressed by different neuronal populations. Endorphins are not found in the dorsal horn, and recent studies question whether endomorphins are indeed endogenous. Enkephalins and dynorphins are highly susceptible to peptidase degradation, which has prompted the use of peptidase inhibitors as analgesics. Endogenous peptidase inhibitors with analgesic properties have also been found. Opioid release in the spinal cord is inhibited by several neurotransmitter receptors, including adrenergic α2C receptors, serotonin 5-HT1A receptors and NMDA receptors. Spinal opioid release appears to be driven by signals originating in both in primary afferents and supraspinally. Pain modality appears to determine whether pain induces spinal opioid release through local or supraspinal circuits. Some forms of stress-induced analgesia are also mediated by spinal opioid release. This involves a circuit originating in the dorsal raphe nucleus involved in the fear/anxiety response. Spinal opioids also mediate the analgesia induced by acupuncture.

Keywords

Opioid Receptor Dorsal Horn Opioid Peptide Dorsal Raphe Nucleus Dorsal Horn Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

5-HT

5-hydroxytriptamine

ACTH

adrenocorticotropin hormone

BK channels

Ca2+-sensitive large conductance potassium channels

CaV2.2

N-type voltage-gated Ca2+ channels

CCK

cholecystokinin

CGRP

calcitonin gene-related peptide

CNS

central nervous system

CTAP

D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2

CRF

corticotrophin-releasing factor

DAMGO

[D-Ala2, N-methyl-Phe4, Gly-ol5]enkephalin

DOR

δ-opioid receptor

DLF

dorsolateral funiculus

DPDPE

[D-penicillamine2, D- penicillamine5]enkephalin; DRN, dorsal raphe nucleus

DRG

dorsal root ganglia

GPCR

G protein-coupled receptor

KOR

κ-opioid receptor

HPLC

high pressure liquid chromatography

MOR

µ-opioid receptor

NRM

nucleus raphe magnus

NK1R

neurokinin 1 receptor

NOP1

nociceptin receptor

OFQ/N

orphanin FQ/nociceptin

OGF

opioid growth factor

PAG

periaqueductal gray

POMC

proopiomelanocortin

RVM

rostral-ventral medulla

SIA

stress-induced analgesia

VGLUT2

vesicular glutamate transporter 2

References

  1. Abbadie C, Trafton J, Liu H, Mantyh PW, Basbaum AI (1997) Inflammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and non-noxious stimulation. J Neurosci 17:8049–8060.PubMedGoogle Scholar
  2. Abbadie C, Lombard MC, Besson JM, Trafton JA, Basbaum AI (2002) Mu and delta opioid receptor-like immunoreactivity in the cervical spinal cord of the rat after dorsal rhizotomy or neonatal capsaicin: an analysis of pre- and postsynaptic receptor distributions. Brain Res 930:150–162.PubMedGoogle Scholar
  3. Adamson P, Xiang JZ, Mantzourides T, Brammer MJ, Campbell IC (1989) Presynaptic alpha 2-adrenoceptor and kappa-opiate receptor occupancy promotes closure of neuronal (N-type) calcium channels. Eur J Pharmacol 174:63–70.PubMedGoogle Scholar
  4. Aimone LD, Yaksh TL (1989) Opioid modulation of capsaicin-evoked release of substance P from rat spinal cord in vivo. Peptides 10:1127–1131.PubMedGoogle Scholar
  5. Aimone LD, Jones SL, Gebhart GF (1987) Stimulation-produced descending inhibition from the periaqueductal gray and nucleus raphe magnus in the rat: mediation by spinal monoamines but not opioids. Pain 31:123–136.PubMedGoogle Scholar
  6. Allen BJ, Rogers SD, Ghilardi JR, Menning PM, Kuskowski MA, Basbaum AI, Simone DA, Mantyh PW (1997) Noxious cutaneous thermal stimuli induce a graded release of endogenous substance P in the spinal cord: imaging peptide action in vivo. J Neurosci 17:5921–5927.PubMedGoogle Scholar
  7. Amat J, Paul E, Zarza C, Watkins LR, Maier SF (2006) Previous experience with behavioral control over stress blocks the behavioral and dorsal raphe nucleus activating effects of later uncontrollable stress: role of the ventral medial prefrontal cortex. J Neurosci 26:13264–13272.PubMedGoogle Scholar
  8. Aoki K, Kajiwara M, Oka T (1984) The role of bestatin-sensitive aminopeptidase, angiotensin converting enzyme and thiorphan-sensitive “enkephalinase” in the potency of enkephalins in the guinea-pig ileum. JpnJ Pharmacol 36:59–65.Google Scholar
  9. Arvidsson U, Riedl M, Chakrabarti S, Lee JH, Nakano AH, Dado RJ, Loh HH, Law PY, Wessendorf MW, Elde R (1995) Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord. J Neurosci 15:3328–3341.PubMedGoogle Scholar
  10. Ballet S, Mauborgne A, Gouarderes C, Bourgoin AS, Zajac JM, Hamon M, Cesselin F (1999) The neuropeptide FF analogue, 1DME, enhances in vivo met- enkephalin release from the rat spinal cord. Neuropharmacology 38:1317–1324.PubMedGoogle Scholar
  11. Ballet S, Mauborgne A, Hamon M, Cesselin F, Collin E (2000) Altered opioid-mediated control of the spinal release of dynorphin and met-enkephalin in polyarthritic rats. Synapse 37:262–272.PubMedGoogle Scholar
  12. Bao L, Jin SX, Zhang C, Wang LH, Xu ZZ, Zhang FX, Wang LC, Ning FS, Cai HJ, Guan JS, Xiao HS, Xu ZQ, He C, Hokfelt T, Zhou Z, Zhang X (2003) Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. Neuron 37:121–133.PubMedGoogle Scholar
  13. Basbaum AI, Fields HL (1979) The origin of descending pathways in the dorsolateral funiculus of the spinal cord of the cat and rat: further studies on the anatomy of pain modulation. J Comp Neurol 187:513–531.PubMedGoogle Scholar
  14. Basbaum AI, Fields HL (1984) Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. Annu Rev Neurosci 7:309–338.PubMedGoogle Scholar
  15. Basbaum AI, Clanton CH, Fields HL (1976) Opiate and stimulus-produced analgesia: functional anatomy of a medullospinal pathway. Proc Natl Acad Sci USA 73:4685–4688.PubMedGoogle Scholar
  16. Basbaum AI, Cruz L, Weber E (1986) Immunoreactive dynorphin B in sacral primary afferent fibers of the cat. J Neurosci 6:127–133.PubMedGoogle Scholar
  17. Besse D, Lombard MC, Zajac JM, Roques BP, Besson JM (1990) Pre- and postsynaptic distribution of mu, delta and kappa opioid receptors in the superficial layers of the cervical dorsal horn of the rat spinal cord. Brain Res 521:15–22.PubMedGoogle Scholar
  18. Bewley TA, Li CH (1985) Tertiary structure in deletion analogues of human beta-endorphin: resistance to leucine aminopeptidase action. Biochemistry 24:6568–6571.PubMedGoogle Scholar
  19. Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR (2008) The Runner's High: Opioidergic Mechanisms in the Human Brain. Cereb Cortex.Google Scholar
  20. Bossut DF, Mayer DJ (1991) Electroacupuncture analgesia in naive rats: effects of brainstem and spinal cord lesions, and role of pituitary-adrenal axis. Brain Res 549:52–58.PubMedGoogle Scholar
  21. Botticelli LJ, Cox BM, Goldstein A (1981) Immunoreactive dynorphin in mammalian spinal cord and dorsal root ganglia. Proc Natl Acad Sci USA 78:7783–7786.PubMedGoogle Scholar
  22. Bourgoin S, Le Bars D, Clot AM, Hamon M, Cesselin F (1990) Subcutaneous formalin induces a segmental release of Met-enkephalin-like material from the rat spinal cord. Pain 41:323–329.PubMedGoogle Scholar
  23. Bras JMA, Becker C, Bourgoin S, Lombard MC, Cesselin F, Hamon M, Pohl M (2001) Met-enkephalin is preferentially transported into the peripheral processes of primary afferent fibres in both control and HSV1-driven proenkephalin a overexpressing rats. Neuroscience 103:1073–1083.Google Scholar
  24. Budai D, Fields HL (1998) Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons. J Neurophysiol 79:677–687.PubMedGoogle Scholar
  25. Budai D, Harasawa I, Fields HL (1998) Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through alpha(2)- adrenergic receptors. J Neurophysiol 80:2244–2254.PubMedGoogle Scholar
  26. Burbach JP, De Kloet ER (1982) Proteolysis of beta-endorphin in brain tissue. Peptides 3:451–453.PubMedGoogle Scholar
  27. Cahill CM, Morinville A, Lee MC, Vincent JP, Collier B, Beaudet A (2001) Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception. J Neurosci 21:7598–7607.PubMedGoogle Scholar
  28. Cahill CM, Morinville A, Hoffert C, O'Donnell D, Beaudet A (2003) Up-regulation and trafficking of delta opioid receptor in a model of chronic inflammation: implications for pain control. Pain 101:199–208.PubMedGoogle Scholar
  29. Cesselin F, Bourgoin S, Artaud F, Hamon M (1984) Basic and regulatory mechanisms of in vitro release of Met-enkephalin from the dorsal zone of the rat spinal cord. J Neurochem 43:763–774.PubMedGoogle Scholar
  30. Cesselin F, Le Bars D, Bourgoin S, Artaud F, Gozlan H, Clot AM, Besson JM, Hamon M (1985) Spontaneous and evoked release of methionine-enkephalin-like material from the rat spinal cord in vivo. Brain Res 339:305–313.PubMedGoogle Scholar
  31. Cesselin F, Bourgoin S, Clot AM, Hamon M, Le Bars D (1989) Segmental release of met-enkephalin-like material from the spinal-cord of rats, elicited by noxious thermal stimuli. Brain Res 484:71–77.PubMedGoogle Scholar
  32. Chen SR, Pan HL (2006) Blocking mu opioid receptors in the spinal cord prevents the analgesic action by subsequent systemic opioids. Brain Res 1081:119–125.PubMedGoogle Scholar
  33. Chen W, Song B, Lao L, Perez OA, Marvizon JC (2006) Intrathecal enkephalin requires inhibition of peptidases to produce analgesia and mu-opioid receptor internalization in dorsal horn neurons. Soc Neurosci Abstr 32:643.618.Google Scholar
  34. Chen W, Song B, Lao L, Perez OA, Kim W, Marvizon JCG (2007) Comparing analgesia and µ-opioid receptor internalization produced by intrathecal enkephalin: requirement for peptidase inhibition. Neuropharmacology 53:664–667.PubMedGoogle Scholar
  35. Chen W, Song B, Marvizon JC (2008a) Inhibition of opioid release in the rat spinal cord by α2C adrenergic receptors. Neuropharmacology 54:944–953.PubMedGoogle Scholar
  36. Chen W, Song B, Zhang G, Marvizon JC (2008b) Effects of veratridine and high potassium on µ-opioid receptor internalization in the rat spinal cord: stimulation of opioid release versus inhibition of internalization. J Neurosci Methods 170:285–293.PubMedGoogle Scholar
  37. Cho HJ, Basbaum AI (1988) Increased staining of immunoreactive dynorphin cell bodies in the deafferented spinal cord of the rat. Neurosci Lett 84:125–130.Google Scholar
  38. Citterio F, Corradini L, Smith RD, Bertorelli R (2000) Nociceptin attenuates opioid and gamma-aminobutyric acid(B) receptor-mediated analgesia in the mouse tail-flick assay. Neurosci Lett 292:83–86.PubMedGoogle Scholar
  39. Collin E, Mauborgne A, Bourgoin S, Benoliel JJ, Hamon M, Cesselin F (1994) Morphine reduces the release of met-enkephalin-like material from the rat spinal cord in vivo by acting at delta opioid receptors. Neuropeptides 27:75–83.PubMedGoogle Scholar
  40. Commons KG (2003) Translocation of presynaptic delta opioid receptors in the ventrolateral periaqueductal gray after swim stress. J Comp Neurol 464:197–207.PubMedGoogle Scholar
  41. Costa E, Mocchetti I, Supattapone S, Snyder SH (1987) Opioid peptide biosynthesis: enzymatic selectivity and regulatory mechanisms. FASEB J 1:16–21.PubMedGoogle Scholar
  42. Cruz L, Basbaum AI (1985) Multiple opioid peptides and the modulation of pain: immunohistochemical analysis of dynorphin and enkephalin in the trigeminal nucleus caudalis and spinal cord of the cat. J Comp Neurol 240:331–348.PubMedGoogle Scholar
  43. Cvejic S, Devi LA (1997) Dimerization of the delta opioid receptor: implication for a role in receptor internalization. J Biol Chem 272:26959–26964.PubMedGoogle Scholar
  44. Diverse-Pierluissi M, Remmers AE, Neubig RR, Dunlap K (1997) Novel form of crosstalk between G protein and tyrosine kinase pathways. Proc Natl Acad Sci USA 94:5417–5421.PubMedGoogle Scholar
  45. Dolphin AC (2003) G protein modulation of voltage-gated calcium channels. Pharmacol Rev 55:607–627.PubMedGoogle Scholar
  46. Duggan AW, Schaible HG, Hope PJ, Lang CW (1992) Effect of peptidase inhibition on the pattern of intraspinally released immunoreactive substance P detected with antibody microprobes. Brain Res 579:261–269.PubMedGoogle Scholar
  47. Dyer SH, Slaughter CA, Orth K, Moomaw CR, Hersh LB (1990) Comparison of the soluble and membrane-bound forms of the puromycin-sensitive enkephalin-degrading aminopeptidases from rat. J Neurochem 54:547–554.PubMedGoogle Scholar
  48. Eckersell CB, Popper P, Micevych PE (1998) Estrogen-induced alteration of μ-opioid receptor immunoreactivity in the medial preoptic nucleus and medial amygdala. J Neurosci 18:3967–3976.PubMedGoogle Scholar
  49. Eckert WA, III, McNaughton KK, Light AR (2003) Morphology and axonal arborization of rat spinal inner lamina II neurons hyperpolarized by mu-opioid-selective agonists. J Comp Neurol 458:240–256.PubMedGoogle Scholar
  50. Eskinazi DP, Jobst KA (1996) National institutes of health office of alternative medicine-food and drug administration workshop on acupuncture. J Altern Complement Med 2:3–6.PubMedGoogle Scholar
  51. Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL (2002) alpha(2C)-adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 300:282–290.PubMedGoogle Scholar
  52. Fichna J, Janecka A, Costentin J, Do Rego JC (2007) The endomorphin system and its evolving neurophysiological role. Pharmacol Rev 59:88–123.PubMedGoogle Scholar
  53. Fields HL, Emson PC, Leigh BK, Gilbert RF, Iversen LL (1980) Multiple opiate receptor sites on primary afferent fibres. Nature 284:351–353.PubMedGoogle Scholar
  54. Fields HL, Heinricher MM, Mason P (1991) Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 14:219–245.PubMedGoogle Scholar
  55. Fuxe K, Agnati LF (1991) Two principal modes of electrochemical communication in the brain: volume versus wiring transmission. In: Volume Transmission in the Brain, pp 1–9. New York: Raven Press.Google Scholar
  56. Gear RW, Levine JD (1995) Antinociception produced by an ascending spino-supraspinal pathway. JNeurosci 15:3154–3161.Google Scholar
  57. Gear RW, Aley KO, Levine JD (1999) Pain-induced analgesia mediated by mesolimbic reward circuits. J Neurosci 19:7175–7181.PubMedGoogle Scholar
  58. Go VL, Yaksh TL (1987) Release of substance P from the cat spinal cord. J Physiol 391:141–167.PubMedGoogle Scholar
  59. Gomes I, Jordan BA, Gupta A, Trapaidze N, Nagy V, Devi LA (2000) Heterodimerization of mu and delta opioid receptors: a role in opiate synergy. J Neurosci 20:RC110.PubMedGoogle Scholar
  60. Gomes I, Gupta A, Filipovska J, Szeto HH, Pintar JE, Devi LA (2004) A role for heterodimerization of mu and delta opiate receptors in enhancing morphine analgesia. Proc Natl Acad Sci USA 101:5135–5139.PubMedGoogle Scholar
  61. Graf L, Miglecz E, Bajusz S, Szekely JI (1979) Met-enkephalin attenuates morphine tolerance in rats. Eur J Pharmacol 58:345–346.PubMedGoogle Scholar
  62. Graf L, Paldi A, Patthy A (1985) Action of neutral metalloendopeptidase (“enkephalinase”) on beta-endorphin. Neuropeptides 6:13–19.PubMedGoogle Scholar
  63. Grahn RE, Maswood S, McQueen MB, Watkins LR, Maier SF (1999) Opioid-dependent effects of inescapable shock on escape behavior and conditioned fear responding are mediated by the dorsal raphe nucleus. Behav Brain Res 99:153–167.PubMedGoogle Scholar
  64. Gross RA, Macdonald RL (1987) Dynorphin A selectively reduces a large transient (N-type) calcium current of mouse dorsal root ganglion neurons in cell culture. Proc Natl Acad Sci USA 84:5469–5473.PubMedGoogle Scholar
  65. Grudt TJ, Williams JT (1993) kappa-Opioid receptors also increase potassium conductance. Proc Natl Acad Sci USA 90:11429–11432.PubMedGoogle Scholar
  66. Grudt TJ, Williams JT (1994) mu-Opioid agonists inhibit spinal trigeminal substantia gelatinosa neurons in guinea pig and rat. J Neurosci 14:1646–1654.PubMedGoogle Scholar
  67. Gutstein HB, Bronstein DM, Akil H (1992) Beta-endorphin processing and cellular origins in rat spinal cord. Pain 51:241–247.PubMedGoogle Scholar
  68. Guyon A, Roques BP, Guyon F, Foucault A, Perdrisot R, Swerts JP, Schwartz JC (1979) Enkephalin degradation in mouse brain studied by a new H.P.L.C. method: further evidence for the involvement of carboxydipeptidase. Life Sci 25:1605–1611.PubMedGoogle Scholar
  69. Hackler L, Zadina JE, Ge LJ, Kastin AJ (1997) Isolation of relatively large amounts of endomorphin-1 and endomorphin-2 from human brain cortex. Peptides 18:1635–1639.PubMedGoogle Scholar
  70. Hajos N, Freund TF (2002) Distinct cannabinoid sensitive receptors regulate hippocampal excitation and inhibition. Chem Phys Lipids 121:73–82.PubMedGoogle Scholar
  71. Han JS (2003) Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 26:17–22.PubMedGoogle Scholar
  72. Harlan RE, Shivers BD, Romano GJ, Howells RD, Pfaff DW (1987) Localization of preproenkephalin mRNA in the rat brain and spinal cord by in situ hybridization. J Comp Neurol 258:159–184.PubMedGoogle Scholar
  73. Harris JA, Chang PC, Drake CT (2004) Kappa opioid receptors in rat spinal cord: sex-linked distribution differences. Neuroscience 124:879–890.PubMedGoogle Scholar
  74. Hazum E, Chang KJ, Leighton HJ, Lever OW, Jr., Cuatrecasas P (1982) Increased biological activity of dimers of oxymorphone and enkephalin: possible role of receptor crosslinking. Biochem Biophys Res Commun 104:347–353.PubMedGoogle Scholar
  75. He L, Fong J, von Zastrow M, Whistler JL (2002) Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization. Cell 108:271–282.PubMedGoogle Scholar
  76. Hiranuma T, Iwao K, Kitamura K, Matsumiya T, Oka T (1997) Almost complete protection from [Met5]-enkephalin-Arg6-Gly7-Leu8 (Met-enk-RGL) hydrolysis in membrane preparations by the combination of amastatin, captopril and phosphoramidon. J Pharmacol Exp Ther 281:769–774.PubMedGoogle Scholar
  77. Hiranuma T, Kitamura K, Taniguchi T, Kanai M, Arai Y, Iwao K, Oka T (1998) Protection against dynorphin-(1-8) hydrolysis in membrane preparations by the combination of amastatin, captopril and phosphoramidon. J Pharmacol Exp Ther 286:863–869.PubMedGoogle Scholar
  78. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112.PubMedGoogle Scholar
  79. Honda M, Okutsu H, Matsuura T, Miyagi T, Yamamoto Y, Hazato T, Ono H (2001) Spinorphin, an endogenous inhibitor of enkephalin-degrading enzymes, potentiates leu-enkephalin-induced anti-allodynic and antinociceptive effects in mice. Jpn J Pharmacol 87:261–267.PubMedGoogle Scholar
  80. Honore P, Menning PM, Rogers SD, Nichols ML, Basbaum AI, Besson JM, Mantyh PW (1999) Spinal cord substance P receptor expression and internalization in acute, short-term, and long-term inflammatory pain states. J Neurosci 19:7670–7678.Google Scholar
  81. Hui KS, Gioannini T, Hui M, Simon EJ, Lajtha A (1985) An opiate receptor-associated aminopeptidase that degrades enkephalins. Neurochem Res 10:1047–1058.PubMedGoogle Scholar
  82. Hui KS, Saito M, Hui M (1998) A novel neuron-specific aminopeptidase in rat brain synaptosomes. Its identification, purification, and characterization. J Biol Chem 273:31053–31060.PubMedGoogle Scholar
  83. Hunt SP, Kelly JS, Emson PC, Kimmel JR, Miller RJ, Wu JY (1981) An immunohistochemical study of neuronal populations containing neuropeptides or gamma-aminobutyrate within the superficial layers of the rat dorsal horn. Neuroscience 6:1883–1898.PubMedGoogle Scholar
  84. Hutchinson WD, Morton CR, Terenius L (1990) Dynorphin A: in vivo release in the spinal cord of the cat. Brain Res 532:299–306.Google Scholar
  85. Hutchinson MR, Bland ST, Johnson KW, Rice KC, Maier SF, Watkins LR (2007) Opioid-induced glial activation: mechanisms of activation and implications for opioid analgesia, dependence, and reward. ScientificWorld J 7:98–111.Google Scholar
  86. Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299:1237–1240.PubMedGoogle Scholar
  87. Isaacson JS, Murphy GJ (2001) Glutamate-mediated extrasynaptic inhibition: direct coupling of NMDA receptors to Ca(2+)-activated K+ channels. Neuron 31:1027–1034.PubMedGoogle Scholar
  88. 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.PubMedGoogle Scholar
  89. Jessell TM, Iversen LL (1977) Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature 268:549–551.PubMedGoogle Scholar
  90. Jordan BA, Devi LA (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399:697–700.PubMedGoogle Scholar
  91. Keith DE, Murray SR, Zaki PA, Chu PC, Lissin DV, Kang L, Evans CJ, von Zastrow M (1996) Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 271:19021–19024.PubMedGoogle Scholar
  92. Keith DE, Anton B, Murray SR, Zaki PA, Chu PC, Lissin DV, Monteillet-Agius G, Stewart PL, Evans CJ, von Zastrow M (1998) mu-Opioid receptor internalization: opiate drugs have differential effects on a conserved endocytic mechanism in vitro and in the mammalian brain. Mol Pharmacol 53:377–384.PubMedGoogle Scholar
  93. Kemp T, Spike RC, Watt C, Todd AJ (1996) The mu-opioid receptor (MOR1) is mainly restricted to neurons that do not contain GABA or glycine in the superficial dorsal horn of the rat spinal cord. Neuroscience 75:1231–1238.PubMedGoogle Scholar
  94. King M, Chang A, Pasternak GW (1998) Functional blockade of opioid analgesia by orphanin FQ/nociceptin. Biochem Pharmacol 55:1537–1540.PubMedGoogle Scholar
  95. Kishioka S, Miyamoto Y, Fukunaga Y, Nishida S, Yamamoto H (1994) Effects of a mixture of peptidase inhibitors (amastatin, captopril and phosphoramidon) on Met-enkephalin-, beta-endorphin-, dynorphin-(1-13)- and electroacupuncture-induced antinociception in rats. Jpn J Pharmacol 66:337–345.PubMedGoogle Scholar
  96. Kline RHt, Wiley RG (2008) Spinal mu-opioid receptor-expressing dorsal horn neurons: role in nociception and morphine antinociception. J Neurosci 28:904–913.PubMedGoogle Scholar
  97. Kondo I, Marvizon JC, Song B, Salgado F, Codeluppi S, Hua XY, Yaksh TL (2005) Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release. J Neurosci 25:3651–3660.PubMedGoogle Scholar
  98. Lao L, Song B, Marvizon JCG (2003) Neurokinin release produced by capsaicin acting on the central terminals and axons of primary afferents: relationship with NMDA and GABA B receptors. Neuroscience 121:667–680.PubMedGoogle Scholar
  99. Lao L, Song B, Chen W, Marvizon JC (2008) Noxious mechanical stimulation evokes the segmental release of opioid peptides that induce μ-opioid receptor internalization in the presence of peptidase inhibitors. Brain Res 1197:85–93.PubMedGoogle Scholar
  100. Le Bars D, Bourgoin S, Clot AM, Hamon M, Cesselin F (1987a) Noxious mechanical stimuli increase the release of Met-enkephalin-like material heterosegmentally in the rat spinal cord. Brain Res 402:188–192.PubMedGoogle Scholar
  101. Le Bars D, Bourgoin S, Villanueva L, Clot AM, Hamon M, Cesselin F (1987b) Involvement of the dorsolateral funiculi in the spinal release of met-enkephalin-like material triggered by heterosegmental noxious mechanical stimuli. Brain Res 412:190–195.PubMedGoogle Scholar
  102. Lever IJ, Malcangio M (2002) CB(1) receptor antagonist SR141716A increases capsaicin-evoked release of Substance P from the adult mouse spinal cord. Br J Pharmacol 135:21–24.PubMedGoogle Scholar
  103. Lever IJ, Bradbury EJ, Cunningham JR, Adelson DW, Jones MG, McMahon SB, Marvizon JC, Malcangio M (2001) Brain-derived neurotrophic factor is released in the dorsal horn by distinctive patterns of afferent fiber stimulation. J Neurosci 21:4469–4477.PubMedGoogle Scholar
  104. Lewis JW, Sherman JE, Liebeskind JC (1981) Opioid and non-opioid stress analgesia: assessment of tolerance and cross-tolerance with morphine. J Neurosci 1:358–363.PubMedGoogle Scholar
  105. Li YW, Bayliss DA (1998) Activation of alpha 2-adrenoceptors causes inhibition of calcium channels but does not modulate inwardly-rectifying K+ channels in caudal raphe neurons. Neuroscience 82:753–765.PubMedGoogle Scholar
  106. Lisi TL, Sluka KA (2006) A new electrochemical HPLC method for analysis of enkephalins and endomorphins. J Neurosci Methods 150:74–79.PubMedGoogle Scholar
  107. Liu NJ, Xu T, Xu C, Li CQ, Yu YX, Kang HG, Han JS (1995) Cholecystokinin octapeptide reverses mu-opioid-receptor-mediated inhibition of calcium current in rat dorsal root ganglion neurons. J Pharmacol ExpTher 275:1293–1299.Google Scholar
  108. Macdonald RL, Werz MA (1986) Dynorphin A decreases voltage-dependent calcium conductance of mouse dorsal root ganglion neurones. J Physiol 377:237–249.PubMedGoogle Scholar
  109. Maier SF, Watkins LR (2005) Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev 29:829–841.PubMedGoogle Scholar
  110. Malcangio M, Fernandes K, Tomlinson DR (1998) NMDA receptor activation modulates evoked release of substance P from rat spinal cord. Br J Pharmacol 125:1625–1626.PubMedGoogle Scholar
  111. Malmberg AB, Yaksh TL (1992) Isobolographic and dose-response analyses of the interaction between intrathecal mu and delta agonists: effects of naltrindole and its benzofuran analog (NTB). J Pharmacol ExpTher 263:264–275.Google Scholar
  112. Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ (1988) Anatomy of CNS opioid receptors. Trends Neurosci 11:308–314.PubMedGoogle Scholar
  113. Mansour A, Fox CA, Akil H, Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18:22–29.PubMedGoogle Scholar
  114. Mantyh PW, DeMaster E, Malhotra A, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, Maggio JE (1995) Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268:1629–1632.PubMedGoogle Scholar
  115. Martin-Schild S, Gerall AA, Kastin AJ, Zadina JE (1998) Endomorphin-2 is an endogenous opioid in primary sensory afferent fibers. Peptides 19:1783–1789.PubMedGoogle Scholar
  116. Marvizon JC, Martinez V, Grady EF, Bunnett NW, Mayer EA (1997) Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. J Neurosci 17:8129–8136.PubMedGoogle Scholar
  117. Marvizon JC, Grady EF, Waszak-McGee J, Mayer EA (1999) Internalization of μ-opioid receptors in rat spinal cord slices. Neuroreport 10:2329–2334.PubMedGoogle Scholar
  118. Marvizon JC, Wang X, Matsuka Y, Neubert JK, Spigelman I (2003a) Relationship between capsaicin-evoked substance P release and neurokinin 1 receptor internalization in the rat spinal cord. Neuroscience 118:535–545.PubMedGoogle Scholar
  119. Marvizon JCG, Wang X, Lao L, Song B (2003b) Effect of peptidases on the ability of exogenous and endogenous neurokinins to produce neurokinin 1 receptor internalization in the rat spinal cord. Br J Pharmacol 140:1389–1398.PubMedGoogle Scholar
  120. Marvizon JC, Perez OA, Song B, Chen W, Bunnett NW, Grady EF, Todd AJ (2007) Calcitonin receptor-like receptor and receptor activity modifying protein 1 in the rat dorsal horn: localization in glutamatergic presynaptic terminals containing opioids and adrenergic α2C receptors. Neuroscience 148:250–265.PubMedGoogle Scholar
  121. Mason P (1999) Central mechanisms of pain modulation. Curr Opin Neurobiol 9:436–441.PubMedGoogle Scholar
  122. Mauborgne A, Bourgoin S, Polienor H, Roumy M, Simonnet G, Zajac JM, Cesselin F (2001) The neuropeptide FF analogue, 1DMe, acts as a functional opioid autoreceptor antagonist in the rat spinal cord. Eur J Pharmacol 430:273–276.PubMedGoogle Scholar
  123. Mayer DJ (2000) Biological mechanisms of acupuncture. Prog Brain Res 122:457–477.PubMedGoogle Scholar
  124. Meunier JC, Mollereau C, Toll L, Suaudeau C, Moisand C, Alvinerie P, Butour JL, Guillemot JC, Ferrara P, Monsarrat B (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377:532–535.PubMedGoogle Scholar
  125. Mills RH, Sohn RK, Micevych PE (2004) Estrogen-induced μ-opioid receptor internalization in the medial preoptic nucleus is mediated via neuropeptide Y–Y1 receptor activation in the arcuate nucleus of female rats. J Neurosci 24:947–955.PubMedGoogle Scholar
  126. Minami M, Satoh M (1995) Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res 23:121–145.PubMedGoogle Scholar
  127. Mogil JS, Pasternak GW (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381–415.PubMedGoogle Scholar
  128. Mogil JS, Grisel JE, Reinscheid RK, Civelli O, Belknap JK, Grandy DK (1996) Orphanin FQ is a functional anti-opioid peptide. Neuroscience 75:333–337.PubMedGoogle Scholar
  129. Moises HC, Rusin KI, Macdonald RL (1994) Mu- and kappa-opioid receptors selectively reduce the same transient components of high-threshold calcium current in rat dorsal root ganglion sensory neurons. J Neurosci 14:5903–5916.PubMedGoogle Scholar
  130. Morgan MM, Gold MS, Liebeskind JC, Stein C (1991) Periaqueductal gray stimulation produces a spinally mediated, opioid antinociception for the inflamed hindpaw of the rat. Brain Res 545:17–23.PubMedGoogle Scholar
  131. Morinville A, Cahill CM, Esdaile MJ, Aibak H, Collier B, Kieffer BL, Beaudet A (2003) Regulation of delta-opioid receptor trafficking via mu-opioid receptor stimulation: evidence from mu-opioid receptor knock-out mice. J Neurosci 23:4888–4898.PubMedGoogle Scholar
  132. Morinville A, Cahill CM, Aibak H, Rymar VV, Pradhan A, Hoffert C, Mennicken F, Stroh T, Sadikot AF, O'Donnell D, Clarke PBS, Collier B, Henry JL, Vincent JP, Beaudet A (2004) Morphine-induced changes in δ opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord. J Neurosci 24:5549–5559.PubMedGoogle Scholar
  133. Morris BJ, Herz A (1987) Distinct distribution of opioid receptor types in rat lumbar spinal cord. Naunyn Schmiedebergs Arch Pharmacol 336:240–243.PubMedGoogle Scholar
  134. Neal CR, Jr., Mansour A, Reinscheid R, Nothacker HP, Civelli O, Watson SJ, Jr. (1999a) Localization of orphanin FQ (nociceptin) peptide and messenger RNA in the central nervous system of the rat. J Comp Neurol 406:503–547.PubMedGoogle Scholar
  135. Neal CR, Jr., Mansour A, Reinscheid R, Nothacker HP, Civelli O, Akil H, Watson SJ, Jr. (1999b) Opioid receptor-like (ORL1) receptor distribution in the rat central nervous system: comparison of ORL1 receptor mRNA expression with (125)I-[(14)Tyr]-orphanin FQ binding. J Comp Neurol 412:563–605.PubMedGoogle Scholar
  136. Nishimura K, Hazato T (1993) Isolation and identification of an endogenous inhibitor of enkephalin-degrading enzymes from bovine spinal cord. Biochem Biophys Res Commun 194:713–719.PubMedGoogle Scholar
  137. Noble F, Turcaud S, Fournie-Zaluski MC, Roques BP (1992a) Repeated systemic administration of the mixed inhibitor of enkephalin-degrading enzymes, RB101, does not induce either antinociceptive tolerance or cross-tolerance with morphine. Eur J Pharmacol 223:83–89.PubMedGoogle Scholar
  138. Noble F, Soleilhac JM, Soroca-Lucas E, Turcaud S, Fournie-Zaluski MC, Roques BP (1992b) Inhibition of the enkephalin-metabolizing enzymes by the first systemically active mixed inhibitor prodrug RB 101 induces potent analgesic responses in mice and rats. J Pharmacol Exp Ther 261:181–190.PubMedGoogle Scholar
  139. Noble F, Fournie-Zaluski MC, Roques BP (1993) Unlike morphine the endogenous enkephalins protected by RB101 are unable to establish a conditioned place preference in mice. Eur J Pharmacol 230:139–149.PubMedGoogle Scholar
  140. Noble F, Smadja C, Valverde O, Maldonado R, Coric P, Turcaud S, Fournie-Zaluski MC, Roques BP (1997) Pain-suppressive effects on various nociceptive stimuli (thermal, chemical, electrical and inflammatory) of the first orally active enkephalin-metabolizing enzyme inhibitor RB 120. Pain 73:383–391.PubMedGoogle Scholar
  141. Noble F, Banisadr G, Jardinaud F, Popovici T, Lai-Kuen R, Chen H, Bischoff L, Parsadaniantz SM, Fournie-Zaluski MC, Roques BP (2001) First discrete autoradiographic distribution of aminopeptidase N in various structures of rat brain and spinal cord using the selective iodinated inhibitor [125I]RB 129. Neuroscience 105:479–488.PubMedGoogle Scholar
  142. Numata H, Hiranuma T, Oka T (1988) Inactivation of dynorphin-(1-8) in isolated preparations by three peptidases. Jpn J Pharmacol 47:417–423.PubMedGoogle Scholar
  143. Nyberg F, Yaksh TL, Terenius L (1983) Opioid activity released from cat spinal cord by sciatic nerve stimulation. Life Sci 33 Suppl 1:17–20.Google Scholar
  144. Nydahl KS, Skinner K, Julius D, Basbaum AI (2004) Co-localization of endomorphin-2 and substance P in primary afferent nociceptors and effects of injury: a light and electron microscopic study in the rat. Eur J Neurosci 19:1789–1799.Google Scholar
  145. Oka T, Aoki K, Kajiwara M, Ishii K, Kuno Y, Hiranuma T, Matsumiya T (1986) Inactivation of [Leu5]-enkephalin in three isolated preparations: relative importance of aminopeptidase, endopeptidase-24.11 and peptidyl dipeptidase A. Nida Research Monograph 75:259–262.PubMedGoogle Scholar
  146. Olave MJ, Maxwell DJ (2002) An investigation of neurones that possess the alpha 2C-adrenergic receptor in the rat dorsal horn. Neuroscience 115:31–40.PubMedGoogle Scholar
  147. Olave MJ, Maxwell DJ (2003a) Axon terminals possessing the alpha 2c-adrenergic receptor in the rat dorsal horn are predominantly excitatory. Brain Res 965:269–273.PubMedGoogle Scholar
  148. Olave MJ, Maxwell DJ (2003b) Neurokinin-1 projection cells in the rat dorsal horn receive synaptic contacts from axons that possess alpha2C-adrenergic receptors. J Neurosci 23:6837–6846.PubMedGoogle Scholar
  149. Olave MJ, Maxwell DJ (2004) Axon terminals possessing alpha2C-adrenergic receptors densely innervate neurons in the rat lateral spinal nucleus which respond to noxious stimulation. Neuroscience 126:391–403.PubMedGoogle Scholar
  150. Pan YZ, Li DP, Pan HL (2002) Inhibition of glutamatergic synaptic input to spinal lamina II(o) neurons by presynaptic alpha(2)-adrenergic receptors. J Neurophysiol 87:1938–1947.PubMedGoogle Scholar
  151. Patierno S, Zellalem W, Ho A, Parsons CG, Lloyd KC, Tonini M, Sternini C (2005) N-Methyl-d-aspartate receptors mediate endogenous opioid release in enteric neurons after abdominal surgery. Gastroenterology 128:2009–2019.PubMedGoogle Scholar
  152. Pertovaara A (2006) Noradrenergic pain modulation. Prog Neurobiol 80:53–83.PubMedGoogle Scholar
  153. Pfaff DW, Martin EM, Ribeiro AC (2007) Relations between mechanisms of CNS arousal and mechanisms of stress. Stress 10:316–325.PubMedGoogle Scholar
  154. Pierce TL, Grahek MD, Wessendorf MW (1998) Immunoreactivity for endomorphin-2 occurs in primary afferents in rats and monkey. Neuroreport 9:385–389.PubMedGoogle Scholar
  155. Pohl M, Lombard MC, Bourgoin S, Carayon A, Benoliel JJ, Mauborgne A, Besson JM, Hamon M, Cesselin F (1989) Opioid control of the in vitro release of calcitonin gene-related peptide from primary afferent fibres projecting in the rat cervical cord. Neuropeptides 14:151–159.PubMedGoogle Scholar
  156. Pohl M, Collin E, Bourgoin S, Conrath M, Benoliel JJ, Nevo I, Hamon M, Giraud P, Cesselin F (1994) Expression of preproenkephalin-A gene and presence of Met-enkephalin in dorsal root ganglia of the adult rat J Neurochem 63:1226–1234.PubMedGoogle Scholar
  157. Przewlocki R, Lason W, Silberring J, Herz A, Przewlocka B (1986) Release of opioid peptides from the spinal cord of rats subjected to chronic pain. Nida Res Monograph 75:422–425.Google Scholar
  158. Raingo J, Castiglioni AJ, Lipscombe D (2007) Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors. Nat Neurosci 10:285–292.PubMedGoogle Scholar
  159. Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T (1993) Pharmacological characterization of the cloned κ-, δ-, and μ-opioid receptors. Mol Pharmacol 45:330–334.Google Scholar
  160. Reinscheid RK, Nothacker HP, Bourson A, Ardati A, Henningsen RA, Bunzow JR, Grandy DK, Langen H, Monsma FJ, Jr., Civelli O (1995) Orphanin FQ: a neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270:792–794.PubMedGoogle Scholar
  161. Ribeiro-da-Silva A, Pioro EP, Cuello AC (1991) Substance P- and enkephalin-like immunoreactivities are colocalized in certain neurons of the substantia gelatinosa of the rat spinal cord: an ultrastructural double-labeling study. J Neurosci 11:1068–1080.PubMedGoogle Scholar
  162. Ribeiro SC, Kennedy SE, Smith YR, Stohler CS, Zubieta JK (2005) Interface of physical and emotional stress regulation through the endogenous opioid system and mu-opioid receptors. Prog Neuropsychopharmacol Biol Psychiatry 29:1264–1280.PubMedGoogle Scholar
  163. Rios C, Gomes I, Devi LA (2004) Interactions between delta opioid receptors and alpha-adrenoceptors. Clin Exp Pharmacol Physiol 31:833–836.PubMedGoogle Scholar
  164. Roques BP (2000) Novel approaches to targeting neuropeptide systems. Trends Pharmacol Sci 21:475–483.PubMedGoogle Scholar
  165. Rougeot C, Messaoudi M, Hermitte V, Rigault AG, Blisnick T, Dugave C, Desor D, Rougeon F (2003) Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity. Proc Natl Acad Sci USA 100:8549–8554.PubMedGoogle Scholar
  166. Ruda MA, Iadarola MJ, Cohen LV, Young WS, III (1988) In situ hybridization histochemistry and immunocytochemistry reveal an increase in spinal dynorphin biosynthesis in a rat model of peripheral inflammation and hyperalgesia. Proc Natl Acad Sci USA 85:622–626.PubMedGoogle Scholar
  167. Russell RD, Leslie JB, Su YF, Watkins WD, Chang KJ (1987) Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors. J Pharmacol Exp Ther 240:150–158.PubMedGoogle Scholar
  168. Sakurada T, Katsuyama S, Sakurada S, Inoue M, Tan-No K, Kisara K, Sakurada C, Ueda H, Sasaki J (1999) Nociceptin-induced scratching, biting and licking in mice: involvement of spinal NK1 receptors. Br J Pharmacol 127:1712–1718.PubMedGoogle Scholar
  169. Scherrer G, Befort K, Contet C, Becker J, Matifas A, Kieffer BL (2004) The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout mice. Eur J Neurosci 19:2239–2248.PubMedGoogle Scholar
  170. Schreff M, Schulz S, Wiborny D, Heollt V (1998) Immunofluorescent identification of endomorphin-2-containing nerve fibers and terminals in the rat brain and spinal cord. Neuroreport 9:1031–1034.PubMedGoogle Scholar
  171. Schroeder JE, Fischbach PS, Zheng D, McCleskey EW (1991) Activation of mu opioid receptors inhibits transient high- and low-threshold Ca2+ currents, but spares a sustained current. Neuron 6:13–20.PubMedGoogle Scholar
  172. Senba E, Yanaihara C, Yanaihara N, Tohyama M (1988) Co-localization of substance P and Met-enkephalin-Arg6-Gly7-Leu8 in the intraspinal neurons of the rat, with special reference to the neurons in the substantia gelatinosa. Brain Res 453:110–116.PubMedGoogle Scholar
  173. Shane R, Wilk S, Bodnar RJ (1999) Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV. Brain Res 815:278–286.PubMedGoogle Scholar
  174. Shimamura M, Hazato T, Katayama T (1983) A membrane-bound aminopeptidase isolated from monkey brain and its action on enkephalin. BiochimBiophys Acta 756:223–229.Google Scholar
  175. Sinchak K, Micevych PE (2001) Progesterone blockade of estrogen activation of mu-opioid receptors regulates reproductive behavior. J Neurosci 21:5723–5729.PubMedGoogle Scholar
  176. Soignier RD, Vaccarino AL, Fanti KA, Wilson AM, Zadina JE (2004) Analgesic tolerance and cross-tolerance to i.c.v. endomorphin-1, endomorphin-2, and morphine in mice. Neurosci Lett 366:211–214.PubMedGoogle Scholar
  177. Song B, Marvizon JCG (2003a) Dorsal horn neurons firing at high frequency, but not primary afferents, release opioid peptides that produce μ-opioid receptor internalization in the rat spinal cord. J Neurosci 23:9171–9184.PubMedGoogle Scholar
  178. Song B, Marvizon JC (2003b) Peptidases prevent μ-opioid receptor internalization in dorsal horn neurons by endogenously released opioids. J Neurosci 23:1847–1858.PubMedGoogle Scholar
  179. Song B, Marvizon JCG (2005) NMDA receptors and large conductance calcium-sensitive potassium channels inhibit the release of opioid peptides that induce μ-opioid receptor internalization in the rat spinal cord. Neuroscience 136:549–562.PubMedGoogle Scholar
  180. Song B, Chen W, Marvizon JC (2007) Inhibition of opioid release in the rat spinal cord by serotonin 5-HT1A receptors. Brain Res 1158:57–62.PubMedGoogle Scholar
  181. Spike RC, Puskar Z, Sakamoto H, Stewart W, Watt C, Todd AJ (2002) MOR-1-immunoreactive neurons in the dorsal horn of the rat spinal cord: evidence for nonsynaptic innervation by substance P-containing primary afferents and for selective activation by noxious thermal stimuli. Eur J Neurosci 15:1306–1316.PubMedGoogle Scholar
  182. Standaert DG, Watson SJ, Houghten RA, Saper CB (1986) Opioid peptide immunoreactivity in spinal and trigeminal dorsal horn neurons projecting to the parabrachial nucleus in the rat. J Neurosci 6:1220–1226.PubMedGoogle Scholar
  183. Stone LS, Broberger C, Vulchanova L, Wilcox GL, Hokfelt T, Riedl MS, Elde R (1998) Differential distribution of alpha(2A) and alpha(2C) adrenergic receptor immunoreactivity in the rat spinal cord. J Neurosci 18:5928–5937.PubMedGoogle Scholar
  184. Strock J, Diverse-Pierluissi MA (2004) Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol 66:1071–1076.PubMedGoogle Scholar
  185. Suplita RL, 2nd, Gutierrez T, Fegley D, Piomelli D, Hohmann AG (2006) Endocannabinoids at the spinal level regulate, but do not mediate, nonopioid stress-induced analgesia. Neuropharmacology 50:372–379.PubMedGoogle Scholar
  186. Suzuki H, Yanagisawa M, Yoshioka K, Hosoki R, Otsuka M (1997) Enzymatic inactivation of enkephalin neurotransmitters in the spinal cord of the neonatal rat. Neurosci Res 28:261–267.PubMedGoogle Scholar
  187. Takemori AE, Portoghese PS (1993) Enkephalin antinociception in mice is mediated by delta 1- and delta 2-opioid receptors in the brain and spinal cord, respectively. Eur J Pharmacol 242:145–150.PubMedGoogle Scholar
  188. Tambeli CH, Parada CA, Levine JD, Gear RW (2002) Inhibition of tonic spinal glutamatergic activity induces antinociception in the rat. Eur J Neurosci 16:1547–1553.PubMedGoogle Scholar
  189. Tambeli CH, Quang P, Levine JD, Gear RW (2003a) Contribution of spinal inhibitory receptors in heterosegmental antinociception induced by noxious stimulation. Eur J Neurosci 18:2999–3006.PubMedGoogle Scholar
  190. Tambeli CH, Young A, Levine JD, Gear RW (2003b) Contribution of spinal glutamatergic mechanisms in heterosegmental antinociception induced by noxious stimulation. Pain 106:173–179.PubMedGoogle Scholar
  191. Tang Q, Gandhoke R, Burritt A, Hruby VJ, Porreca F, Lai J (1999) High-affinity interaction of (des-Tyrosyl)dynorphin A(2-17) with NMDA receptors. J Pharmacol Exp Ther 291:760–765.PubMedGoogle Scholar
  192. Tang Q, Lynch RM, Porreca F, Lai J (2000) Dynorphin A elicits an increase in intracellular calcium in cultured neurons via a non-opioid, non-NMDA mechanism. J Neurophysiol 83:2610–2615.PubMedGoogle Scholar
  193. Terman GW, Lewis JW, Liebeskind JC (1986) Two opioid forms of stress analgesia: studies of tolerance and cross-tolerance. Brain Res 368:101–106.PubMedGoogle Scholar
  194. Tieku S, Hooper NM (1992) Inhibition of aminopeptidases N, A and W. A re-evaluation of the actions of bestatin and inhibitors of angiotensin converting enzyme. Biochem Pharmacol 44:1725–1730.PubMedGoogle Scholar
  195. Todd AJ, Spike RC (1992) Co-localization of Met-enkephalin and somatostatin in the spinal cord of the rat. Neurosci Lett 145:71–74.PubMedGoogle Scholar
  196. Todd AJ, Spike RC (1993) The localization of classical transmitters and neuropeptides within neurons in laminae I–III of the mammalian spinal dorsal horn. Prog Neurobiol 41:609–645.PubMedGoogle Scholar
  197. Todd AJ, Spike RC, Russell G, Johnston HM (1992) Immunohistochemical evidence that Met-enkephalin and GABA coexist in some neurones in rat dorsal horn. Brain Res 584:149–156.PubMedGoogle Scholar
  198. Todd AJ, McGill MM, Shehab SA (2000) Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur J Neurosci 12:689–700.PubMedGoogle Scholar
  199. Trafton JA, Abbadie C, Marchand S, Mantyh PW, Basbaum AI (1999) Spinal opioid analgesia: how critical is the regulation of substance P signaling? J Neurosci 19:9642–9653.PubMedGoogle Scholar
  200. Trafton JA, Abbadie C, Marek K, Basbaum AI (2000) Postsynaptic signaling via the mu-opioid receptor: Responses of dorsal horn neurons to exogenous opioids and noxious stimulation. J Neurosci 20:8578–8584.PubMedGoogle Scholar
  201. Traub RJ (1996) The spinal contribution of substance P to the generation and maintenance of inflammatory hyperalgesia in the rat. Pain 67:151–161.PubMedGoogle Scholar
  202. Traub RJ (1997) Spinal modulation of the induction of central sensitization. Brain Res 778:34–42.PubMedGoogle Scholar
  203. Tsou K, Khachaturian H, Akil H, Watson SJ (1986) Immunocytochemical localization of pro-opiomelanocortin-derived peptides in the adult rat spinal cord. Brain Res 378:28–35.PubMedGoogle Scholar
  204. Tuchscherer MM, Seybold VS (1989) A quantitative study of the coexistence of peptides in varicosities within the superficial laminae of the dorsal horn of the rat spinal cord. J Neurosci 9:195–205.PubMedGoogle Scholar
  205. Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM, Zhang ET, Malan TP, Jr., Ossipov MH, Lai J, Porreca F (2000) Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. J Neurosci 20:7074–7079.PubMedGoogle Scholar
  206. Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL (2005) A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers. Proc Natl Acad Sci USA 102:9050–9055.Google Scholar
  207. Walwyn W, Maidment NT, Sanders M, Evans CJ, Kieffer BL, Hales TG (2005) Induction of delta opioid receptor function by up-regulation of membrane receptors in mouse primary afferent neurons. Mol Pharmacol 68:1688–1698.PubMedGoogle Scholar
  208. Watkins LR, Mayer DJ (1982) Involvement of spinal opioid systems in footshock-induced analgesia: antagonism by naloxone is possible only before induction of analgesia. Brain Res 242:309–326.PubMedGoogle Scholar
  209. Watkins LR, Cobelli DA, Mayer DJ (1982a) Classical conditioning of front paw and hind paw footshock induced analgesia (FSIA): naloxone reversibility and descending pathways. Brain Res 243:119–132.PubMedGoogle Scholar
  210. Watkins LR, Cobelli DA, Mayer DJ (1982b) Opiate vs non-opiate footshock induced analgesia (FSIA): descending and intraspinal components. Brain Res 245:97–106.PubMedGoogle Scholar
  211. Watkins LR, Cobelli DA, Faris P, Aceto MD, Mayer DJ (1982c) Opiate vs non-opiate footshock-induced analgesia (FSIA): the body region shocked is a critical factor. Brain Res 242:299–308.PubMedGoogle Scholar
  212. Watkins LR, Young EG, Kinscheck IB, Mayer DJ (1983) The neural basis of footshock analgesia: the role of specific ventral medullary nuclei. Brain Res 276:305–315.PubMedGoogle Scholar
  213. Watkins LR, Johannessen JN, Kinscheck IB, Mayer DJ (1984) The neurochemical basis of footshock analgesia: the role of spinal cord serotonin and norepinephrine. Brain Res 290:107–117.PubMedGoogle Scholar
  214. Watkins LR, Wiertelak EP, Maier SF (1992) Kappa opiate receptors mediate tail-shock induced antinociception at spinal levels. Brain Res 582:1–9.PubMedGoogle Scholar
  215. Watkins LR, Hutchinson MR, Johnston IN, Maier SF (2005) Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 28:661–669.PubMedGoogle Scholar
  216. Wei F, Dubner R, Ren K (1999) Dorsolateral funiculus-lesions unmask inhibitory or disfacilitatory mechanisms which modulate the effects of innocuous mechanical stimulation on spinal Fos expression after inflammation. Brain Res 820:112–116.PubMedGoogle Scholar
  217. Whistler JL, von Zastrow M (1998) Morphine-activated opioid receptors elude desensitization by beta-arrestin. Proc Natl Acad Sci USA 95:9914–9919.PubMedGoogle Scholar
  218. Whistler JL, Chuang HH, Chu P, Jan LY, von Zastrow M (1999) Functional dissociation of mu opioid receptor signaling and endocytosis: implications for the biology of opiate tolerance and addiction. Neuron 23:737–746.PubMedGoogle Scholar
  219. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682.PubMedGoogle Scholar
  220. Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Ungeheuer MN, Rougeot C (2006) Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways. Proc Natl Acad Sci USA 13:13.Google Scholar
  221. Yabaluri N, Medzihradsky F (1997) Down-regulation of mu-opioid receptor by full but not partial agonists is independent of G protein coupling. Mol Pharmacol 52:896–902.PubMedGoogle Scholar
  222. Yaksh TL (1981) Spinal opiate analgesia: characteristics and principles of action. Pain 11:293–346.PubMedGoogle Scholar
  223. Yaksh TL (1985) Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol BiochemBehav 22:845–858.Google Scholar
  224. Yaksh TL, Elde RP (1981) Factors governing release of methionine enkephalin-like immunoreactivity from mesencephalon and spinal cord of the cat in vivo. J Neurophysiol 46:1056–1075.PubMedGoogle Scholar
  225. Yaksh TL, Chipkin RE (1989) Studies on the effect of SCH-34826 and thiorphan on [Met5]enkephalin levels and release in rat spinal cord. Eur J Pharmacol 167:367–373.PubMedGoogle Scholar
  226. Yaksh TL, Jessell TM, Gamse R, Mudge AW, Leeman SE (1980) Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 286:155–157.PubMedGoogle Scholar
  227. Yaksh TL, Terenius L, Nyberg F, Jhamandas K, Wang JY (1983) Studies on the release by somatic stimulation from rat and cat spinal cord of active materials which displace dihydromorphine in an opiate-binding assay. Brain Res 268:119–128.PubMedGoogle Scholar
  228. Yoshimura M, North RA (1983) Substantia gelatinosa neurones hyperpolarized in vitro by enkephalin. Nature 305:529–530.PubMedGoogle Scholar
  229. Zadina JE, Hackler L, Ge LJ, Kastin AJ (1997) A potent and selective endogenous agonist for the μ-opiate receptor. Nature 386:499–502.PubMedGoogle Scholar
  230. Zagon IS, Verderame MF, McLaughlin PJ (2002) The biology of the opioid growth factor receptor (OGFr). Brain Res Brain Res Rev 38:351–376.PubMedGoogle Scholar
  231. Zhang X, Bao L, Arvidsson U, Elde R, Hokfelt T (1998) Localization and regulation of the delta-opioid receptor in dorsal root ganglia and spinal cord of the rat and monkey: evidence for association with the membrane of large dense-core vesicles. Neuroscience 82:1225–1242.PubMedGoogle Scholar
  232. Zoli M, Agnati LF (1996) Wiring and volume transmission in the central nervous system: the concept of closed and open synapses. Prog Neurobiol 49:363–380.PubMedGoogle Scholar
  233. Zorman G, Belcher G, Adams JE, Fields HL (1982) Lumbar intrathecal naloxone blocks analgesia produced by microstimulation of the ventromedial medulla in the rat. Brain Res 236:77–84.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Center for Neurobiology of Stress, Division of Digestive Diseases, Department of MedicineDavid Geffen School of Medicine at UCLALos AngelesUSA
  2. 2.Veteran Affairs Greater Los Angeles Healthcare SystemLos AngelesUSA

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