Nociceptin opioid peptide (NOP) receptor modulates pain transmission and is considered a prospective target for pain management. Under acute pain conditions in rodents, however, no definitive conclusions about effects of systemically intervening NOP receptors on nociception, classical opioid-induced antinociception, tolerance and physical dependence have been drawn. Given that opioid analgesia has sex differences, and females experience greater pain and consume more opioids, clarifying these issues in females will help develop novel analgesics. To clarify the role of NOP receptors on the pharmacological profiles of µ-opioid receptor agonists, in this study, a selective agonist (SCH221510) and antagonist (SB612111) of the NOP receptor were subcutaneously administered in female mice in multiple animal models. In hot-plate test, neither SCH221510 (3 and 10 mg/kg, sc) nor SB612111 (10 mg/kg, sc) produced significant antinociception. SCH221510 (3 mg/kg, sc) attenuated but SB612111 (10 mg/kg, sc) enhanced morphine-induced antinociception, with rightward and leftward shift of morphine dose-response curves, respectively. SCH221510 (3 mg/kg, sc) combined with morphine (10 mg/kg, sc) accelerated the development of morphine antinociceptive tolerance. Conversely, SB612111 (10 mg/kg, sc) delayed morphine tolerance development. Neither SCH221510 (3 mg/kg, sc) nor SB612111 (10 mg/kg, sc) statistically significantly altered the development of morphine-induced physical dependence. Therefore, systemic activation of NOP receptors attenuated morphine antinociception to acute thermal stimuli, facilitated morphine-induced antinociceptive tolerance but did not robustly alter physical dependence in female mice. Systemic blockade of NOP receptors produced opposite actions. These findings demonstrate that N/OFQ-NOP receptor system plays diverse roles in modulating pharmacological profiles of µ-opioid receptor agonists.
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Ahmed A, Khan F, Ali M, Haqnawaz F, Hussain A, Azam SI (2012) Effect of the menstrual cycle phase on post-operative pain perception and analgesic requirements. Acta Anaesthesiol Scand 56: 629–35. https://doi.org/10.1111/j.1399-6576.2012.02661.x
Calo G, Lambert DG (2018) Nociceptin/orphanin FQ receptor ligands and translational challenges: focus on cebranopadol as an innovative analgesic. Br J Anaesth 121:1105–1114. https://doi.org/10.1016/j.bja.2018.06.024
Chung S, Pohl S, Zeng J, Civelli O, Reinscheid RK (2006) Endogenous orphanin FQ/nociceptin is involved in the development of morphine tolerance. J Pharmacol Exp Ther 318:262–267. https://doi.org/10.1124/jpet.106.103960
Ciccocioppo R, Angeletti S, Sanna PP, WeissF MassiM (2000) Effect of nociceptin/orphanin FQ on the rewarding properties of morphine. Eur J Pharmacol 404:153–159. https://doi.org/10.1016/s0014-2999(00)00590-2
Cicero TJ, Nock B, Meyer ER (1996) Gender-related differences in the antinociceptive properties of morphine. J Pharmacol Exp Ther 279:767–773
Cremeans CM, Gruley E, KyleDJ, Ko MC (2012) Roles of µ-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates. J Pharmacol Exp Ther 343:72–81. https://doi.org/10.1124/jpet.112.194308
Dautzenberg FM, Wichmann J, Higelin J, Py-Lang G, Kratzeisen C, Malherbe P, KilpatrickGJJenck F (2001) Pharmacological characterization of the novel nonpeptide orphanin FQ/nociceptin receptor agonist Ro 64-6198: rapid and reversible desensitization of the ORL1 receptor in vitroand lack of tolerance in vivo. J Pharmacol Exp Ther 298:812–819
Evans RM, You H, Hameed S, Altier C, Mezghrani A, BourinetE, Zamponi GW (2010) Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation. J Biol Chem 285:1032–1040. https://doi.org/10.1074/jbc.M109.040634
Fichna J, Sobczak M, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Cenac N, Sałaga M, Timmermans JP, Vergnolle N, Małecka-Panas E, Krajewska WM, Storr M (2014) Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea-predominant IBS. Neurogastroenterol Motil 26:1539–1550. https://doi.org/10.1111/nmo.12390
Florin S, MeunierJ, Costentin J (2000) Autoradiographic localization of [3H]nociceptinbinding sites in the rat brain. Brain Res 880:11–16. https://doi.org/10.1016/s0006-8993(00)02669-x
Heinricher MM, McGaraughty S, Grandy DK (1997) Circuitry underlying antiopioid actions of orphanin FQ in the rostral ventromedial medulla. J Neurophysiol 78:3351–3358. https://doi.org/10.1152/jn.19188.8.131.5251
Jenck F, Wichmann J, Dautzenberg FM, Moreau JL, Ouagazzal AM, Martin JR, Lundstrom K, Cesura AM, Poli SM, Roever S, Kolczewski S, AdamG, Kilpatrick G (2000) A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat. Proc Natl Acad Sci USA 97:4938–4943. https://doi.org/10.1073/pnas.090514397
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. https://doi.org/10.1016/0091-3057(89)90363-8
Kest B, Wilson SG, Mogil JS (1999) Sex differences in supraspinal morphine analgesia are dependent on genotype. J Pharmacol Exp Ther 289:1370–1375
Kest B, Hopkins E, Palmese CA, Chen ZP, Mogil JS, Pintar JE (2001) Morphine tolerance and dependence in nociceptin/orphanin FQ transgenic knock-out mice. Neuroscience 104:217–222. https://doi.org/10.1016/s0306-4522(01)00037-9
Khroyan TV, Zaveri NT, Polgar WE, Orduna J, Olsen C, Jiang F, Toll L (2007) SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice. J Pharmacol Exp Ther 320:934–943. https://doi.org/10.1124/jpet.106.111997
Khroyan TV, Polgar WE, Jiang F, ZaveriNT, Toll L (2009) Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists. J Pharmacol Exp Ther 331:946–953. https://doi.org/10.1124/jpet.109.156711
Khroyan TV, Polgar WE, Cami-Kobeci G, Husbands SM, ZaveriNT, Toll L (2011) The first universal opioid ligand, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028): characterization of the in vitro profile and in vivo behavioral effects in mouse models of acute pain and cocaine-induced reward. J Pharmacol Exp Ther 336:952–961. https://doi.org/10.1124/jpet.110.175620
Ko MC, Woods JH, Fantegrossi WE, Galuska CM, WichmannJ, Prinssen EP (2009) Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys. Neuropsychopharmacology 34:2088–2096. https://doi.org/10.1038/npp.2009.33
Kotlinska J, Suder P, Legowska A, RolkaK, Silberring J (2000) Orphanin FQ/nociceptin inhibits morphine withdrawal. Life Sci 66:1119–1123. https://doi.org/10.1016/s0024-3205(99)00648-7
Kotlinska J, Wichmann J, Rafalski P, Talarek S, DylagT, Silberring J (2003) Non-peptidergicOP4 receptor agonist inhibits morphine antinociception but does not influence morphine dependence. Neuroreport 14:601–604. https://doi.org/10.1097/00001756-200303240-00015
Linz K, Christoph T, Tzschentke TM, Koch T, Schiene K, Gautrois M, Schroder W, Kögel BY, Beier H, Englberger W, Schunk S, DeVry J, JahnelU, Frosch S (2014) Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther 349:535–548. https://doi.org/10.1124/jpet.114.213694
Loyd DR, Wang X, Murphy AZ (2008) 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
Lutfy K, Hossain SM, Khaliq I, Maidment NT (2001) Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br J Pharmacol 134:529–534. https://doi.org/10.1038/sj.bjp.0704279
Mamiya T, Noda Y, Ren X, Nagai T, Takeshima H, UkaiM, Nabeshima T (2001) Morphine tolerance and dependence in the nociceptin receptor knockout mice. J Neural Transm (Vienna) 108:1349–1361. https://doi.org/10.1007/s007020100012
Mandyam CD, ThakkerDR, Standifer KM (2003) Mu-opioid-induced desensitization of opioid receptor-like 1 and mu-opioid receptors: differential intracellular signaling determines receptor sensitivity. J Pharmacol Exp Ther 306:965–972. https://doi.org/10.1124/jpet.103.051599
Mogil JS, Chesler EJ, Wilson SG, Juraska JM, Sternberg WF (2000) Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype. Neurosci Biobehav Rev 24: 375–389. https://doi.org/10.1016/s0149-7634(00)00015-4
Murphy NP, Maidment NT (1999) Orphanin FQ/nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis. J Neurochem 73:179–186. https://doi.org/10.1046/j.1471-4159.1999.0730179.x
Murphy NP, Ly HT, Maidment NT (1996) Intracerebroventricular orphanin FQ/nociceptin suppresses dopamine release in the nucleus accumbens of anaesthetized rats. Neuroscience 75:1–4. https://doi.org/10.1016/0306-4522(96)00322-3
Murphy NP, Lee Y, Maidment NT (1999) Orphanin FQ/nociceptin blocks acquisition of morphine place preference. Brain Res 832:168–170. https://doi.org/10.1016/s0006-8993(99)01425-0
Nasser SA, Afify EA (2019) Sex differences in pain and opioid mediated antinociception: Modulatory role of gonadal hormones. Life Sci 237: 116926. https://doi.org/10.1016/j.lfs.2019.116926
Neal CR, Mansour JrA, Reinscheid R, Nothacker HP, Civelli O, AkilH, Watson SJ (1999) 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
Olofsson C, Ekblom A, Ekman-Ordeberg G, Hjelm A, Irestedt L (1996) Lack of analgesic effect of systemically administered morphine or pethidine on labour pain. Br J Obstet Gynaecol 103: 968–972. https://doi.org/10.1111/j.1471-0528.1996.tb09545.x
Pan YX, Bolan E, Pasternak GW (2002) Dimerization of morphine and orphanin FQ/nociceptin receptors: generation of a novel opioid receptor subtype. Biochem Biophys Res Commun 297:659–663. https://doi.org/10.1016/s0006-291x(02)02258-1
Podlesnik CA, Ko MC, Winger G, Wichmann J, Prinssen EP, Woods JH (2011) The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. Psychopharmacology 213:53–60. https://doi.org/10.1007/s00213-010-2012-7
Reiss D, Wichmann J, Tekeshima H, KiefferBL, Ouagazzal AM (2008) Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: comparison to morphine. Eur J Pharmacol 579:141–148. https://doi.org/10.1016/j.ejphar.2007.10.031
Ribeiro-Dasilva MC, Shinal RM, Glover T, Williams RS, Staud R, Riley JL, Fillingim RB (2011) Evaluation of menstrual cycle effects on morphine and pentazocine analgesia. Pain 152: 614–622. https://doi.org/10.1016/j.pain.2010.11.033
Rutten K, De Vry J, Bruckmann W, Tzschentke TM (2010) Effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiate-and psychostimulant-induced conditioned place preference in rats. Eur J Pharmacol 645:119–126. https://doi.org/10.1016/j.ejphar.2010.07.036
Ruzza C, Holanda VA, Gavioli EC, TrapellaC, Calo G (2019) NOP agonist action of cebranopadol counteracts its liabilityto promote physical dependence. Peptides 112: 101–105. https://doi.org/10.1016/j.peptides.2018.12.001
Schroder W, Lambert DG, Ko MC, Koch T (2014) Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. Br J Pharmacol 171:3777–3800. https://doi.org/10.1111/bph.12744
Scoto GM, AricoG, Iemolo A, Ronsisvalle G, Parenti C (2010) Selective inhibition of the NOP receptor in the ventrolateral periaqueductal gray attenuates the development and the expression of tolerance to morphine-induced antinociception in rats. Peptides 31:696–700. https://doi.org/10.1016/j.peptides.2009.12.028
Sobczak M, Mokrowiecka A, Cygankiewicz AI, Zakrzewski PK, Sałaga M, Storr M, Kordek R, Małecka-Panas E, KrajewskaWM, Fichna J (2014) Anti-inflammatory and antinociceptive action of an orally available nociceptin receptor agonist SCH 221510 in a mouse modelof inflammatory bowel diseases. J Pharmacol Exp Ther 348:401–409. https://doi.org/10.1124/jpet.113.209825
Stoffel EC, Ulibarri CM, Craft RM (2003) Gonadal steroid hormone modulation of nociception, morphine antinociception and reproductive indices in male and female rats. Pain 103: 285–302. https://doi.org/10.1016/s0304-3959(02)00457-8
Sukhtankar DD, LagorioCH, Ko MC (2014) Effects of the NOP agonist SCH221510 on producing and attenuating reinforcing effects as measured by drug self-administration in rats. Eur J Pharmacol 745:182–189. https://doi.org/10.1016/j.ejphar.2014.10.029
Toll L, Bruchas MR, Calo G, Cox BM, Zaveri NT (2016) Nociceptin/orphanin FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68:419–457. https://doi.org/10.1124/pr.114.009209
Tzschentke TM, Kögel BY, Frosch S, Linz K (2018) Limited potential of cebranopadol to produce opioid-type physical dependence in rodents. Addict Biol 23:1010–1019. https://doi.org/10.1111/adb.12550
Ueda H, Yamaguchi T, Tokuyama S, Inoue M, Nishi M, Takeshima H (1997) Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene. Neurosci Lett 237:136–138. https://doi.org/10.1016/s0304-3940(97)00832-x
Varty GB, Lu SX, Morgan CA, Cohen-Williams ME, Hodgson RA, Smith-Torhan A, Zhang H, Fawzi AB, Graziano MP, Ho GD, Matasi J, Tulshian D, Coffin VL, Carey GJ (2008) The anxiolytic-like effects of the novel, orally active nociceptin opioid receptor agonist 8-[bis(2-methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH221510). J Pharmacol Exp Ther 326:672–682. https://doi.org/10.1124/jpet.108.136937
Wang HL, Hsu CY, Huang PC, Kuo YL, Li AH, Yeh TH, Tso AS, Chen YL (2005) Heterodimerization of opioid receptor-like 1 and mu-opioid receptors impairs the potency of micro receptor agonist. J Neurochem 92:1285–1294. https://doi.org/10.1111/j.1471-4159.2004.02921.x
Wu Q, Liu L (2018) ORL(1) Activation mediates a novel ORL(1) receptor agonist SCH221510 analgesia in neuropathic pain in rats. J Mol Neurosci 66:10–16. https://doi.org/10.1007/s12031-018-1140-0
Zaveri NT (2011) The nociceptin/orphanin FQ receptor (NOP) as a target for drug abuse medications. Curr Top Med Chem 11:1151–1156. https://doi.org/10.2174/156802611795371341
Zhang Y, Donica CL, Standifer KM (2012) Sex differences in the Nociceptin/Orphanin FQ system in rat spinal cord following chronic morphine treatment. Neuropharmacology 63:427–433. https://doi.org/10.1016/j.neuropharm.2012.04.028
This work was supported by the National Natural Science Foundation of China (81874310).
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All animal procedures were approved by the Institutional Review Committee for the Use of Animals (Beijing Institute of Pharmacology and Toxicology, China; Ethical approval number: IACUC of AMMS-06-2019-002) and were performed in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80 − 23). None of the authors performed any human experiments as part of this research.
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Hao, XQ., Wang, ZY., Chen, JM. et al. Involvement of the nociceptin opioid peptide receptor in morphine-induced antinociception, tolerance and physical dependence in female mice. Metab Brain Dis (2021). https://doi.org/10.1007/s11011-021-00783-8
- Nociceptin opioid peptide receptor
- Acute pain
- Physical dependence