Abstract
Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of μ-, δ-, and κ-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous μ-opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type μ-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the δ-selective opioid antagonist naltrindole or the κ-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial δ-, μ-, and κ-agonist, support the ideas that μ-opioid receptors mediate most of analgesic properties of buprenorphine, but that μ- and δ- and/or κ-opioid receptors are each involved in the rewarding effects of this drug.
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References
Blake AD, Bot G, Freeman JC, Reisine T (1997). Differential opioid agonist regulation of the mouse mu opioid receptor. J Biol Chem 272: 782–790.
Bot G, Blake AD, Li S, Reisine T (1998). Mutagenesis of the mouse delta opioid receptor converts (−)-buprenorphine from a partial agonist to an antagonist. J Pharmacol Exp Ther 284: 283–290.
Cheskin LJ, Fudala PJ, Johnson RE (1994). A controlled comparison of buprenorphine and clonidine for acute detoxification from opioids. Drug Alcohol Depend 36: 115–121.
Comer SD, Collins ED, Fischman MW (2002). Intravenous buprenorphine self-administration by detoxified heroin abusers. J Pharmacol Exp Ther 301: 266–276.
Cowan A, Lewis JW, Macfarlane IR (1977). Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol 60: 537–545.
D’Amour F, Smith D (1941). A method for determining loss of pain sensation. J Pharmacol Exp Ther 72: 74–79.
Funada M, Suzuki T, Narita M, Misawa M, Nagase H (1993). Blockade of morphine reward through the activation of kappa-opioid receptors in mice. Neuropharmacology 32: 1315–1323.
Gibson AE, Doran CM, Bell JR, Ryan A, Lintzeris N (2003). A comparison of buprenorphine treatment in clinic and primary care settings: a randomised trial. Med J Aust 179: 38–42.
Greenwald MK, Johanson CE, Moody DE, Woods JH, Kilbourn MR, Koeppe RA et al (2003). Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology 28: 2000–2009.
Hoffman DC, Beninger RJ (1989). Preferential stimulation of D1 or D2 receptors disrupts food-rewarded operant responding in rats. Pharmacol Biochem Behav 34: 923–925.
Ikeda K, Ichikawa T, Kobayashi T, Kumanishi T, Oike S, Yano R (1999). Unique behavioural phenotypes of recombinant-inbred CXBK mice: partial deficiency of sensitivity to mu- and kappa-agonists. Neurosci Res 34: 149–155.
Ikeda K, Kobayashi T, Ichikawa T, Kumanishi T, Niki H, Yano R (2001). The untranslated region of (mu)-opioid receptor mRNA contributes to reduced opioid sensitivity in CXBK mice. J Neurosci 21: 1334–1339.
Iwamoto ET (1985). Place-conditioning properties of mu, kappa, and sigma opioid agonists. Alcohol Drug Res 6: 327–339.
Kamei J, Saitoh A, Suzuki T, Misawa M, Nagase H, Kasuya Y (1995). Buprenorphine exerts its antinociceptive activity via mu 1-opioid receptors. Life Sci 56: PL285–290.
Kamei J, Sodeyama M, Tsuda M, Suzuki T, Nagase H (1997). Antinociceptive effect of buprenorphine in mu1-opioid receptor deficient CXBK mice. Life Sci 60: PL333–PL337.
Katsumata S, Minami M, Nakagawa T, Iwamura T, Satoh M (1995). Pharmacological study of dihydroetorphine in cloned mu-, delta- and kappa-opioid receptors. Eur J Pharmacol 291: 367–373.
Kieffer BL (1999). Opioids: first lessons from knockout mice. Trends Pharmacol Sci 20: 19–26.
Leander JD (1988). Buprenorphine is a potent kappa-opioid receptor antagonist in pigeons and mice. Eur J Pharmacol 151: 457–461.
Lintzeris N, Bell J, Bammer G, Jolley DJ, Rushworth L (2002). A randomized controlled trial of buprenorphine in the management of short-term ambulatory heroin withdrawal. Addiction 97: 1395–1404.
Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN (1998). mu Opioid receptor knockout in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res 54: 321–326.
Longoni R, Cadoni C, Mulas A, Di Chiara G, Spina L (1998). Dopamine-dependent behavioural stimulation by non-peptide delta opioids BW373U86 and SNC 80: 2. Place-preference and brain microdialysis studies in rats. Behav Pharmacol 9: 9–14.
Lutfy K, Eitan S, Bryant CD, Yang YC, Saliminejad N, Walwyn W et al (2003). Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci 23: 10331–10337.
Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I et al (1996). Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383: 819–823.
Matthes HW, Smadja C, Valverde O, Vonesch JL, Foutz AS, Boudinot E et al (1998). Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor. J Neurosci 18: 7285–7295.
Mello NK, Lukas SE, Bree MP, Mendelson JH (1988). Progressive ratio performance maintained by buprenorphine, heroin and methadone in Macaque monkeys. Drug Alcohol Depend 21: 81–97.
Neilan CL, Akil H, Woods JH, Traynor JR (1999). Constitutive activity of the delta-opioid receptor expressed in C6 glioma cells: identification of non-peptide delta-inverse agonists. Br J Pharmacol 128: 556–562.
Pick CG, Peter Y, Schreiber S, Weizman R (1997). Pharmacological characterization of buprenorphine, a mixed agonist-antagonist with kappa 3 analgesia. Brain Res 744: 41–46.
Sante AB, Nobre MJ, Brandao ML (2000). Place aversion induced by blockade of mu or activation of kappa opioid receptors in the dorsal periaqueductal gray matter. Behav Pharmacol 11: 583–589.
Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A et al (1998). Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO J 17: 886–897.
Skoubis PD, Matthes HW, Walwyn WM, Kieffer BL, Maidment NT (2001). Naloxone fails to produce conditioned place aversion in mu-opioid receptor knock-out mice. Neuroscience 106: 757–763.
Sora I, Elmer G, Funada M, Pieper J, Li XF, Hall FS et al (2001). Mu opiate receptor gene dose effects on different morphine actions: evidence for differential in vivo mu receptor reserve. Neuropsychopharmacology 25: 41–54.
Sora I, Funada M, Uhl GR (1997a). The mu-opioid receptor is necessary for [D-Pen2,D-Pen5]enkephalin-induced analgesia. Eur J Pharmacol 324: R1–2.
Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM et al (1997b). Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA 94: 1544–1549.
Tejwani GA, Rattan AK (2002). The role of spinal opioid receptors in antinociceptive effects produced by intrathecal administration of hydromorphone and buprenorphine in the rat. Anesth Analg 94: 1542–1546.
Tzschentke TM (1998). Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56: 613–672.
Winger G, Woods JH (2001). The effects of chronic morphine on behavior reinforced by several opioids or by cocaine in rhesus monkeys. Drug Alcohol Depend 62: 181–189.
Woolfe G, MacDonald A (1944). The evaluation of the analgesic action of pethidine hydrochloride (demerol). J Pharmacol Exp Ther 80: 300–307.
Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP et al (1999). Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24: 243–252.
Zubieta J, Greenwald MK, Lombardi U, Woods JH, Kilbourn MR, Jewett DM et al (2000). Buprenorphine-induced changes in mu-opioid receptor availability in male heroin-dependent volunteers: a preliminary study. Neuropsychopharmacology 23: 326–334.
Acknowledgements
This study was supported by the Japanese Ministry of Health, Labour and Welfare; the Japanese Ministry of Education, Culture, Sports, Science, and Technology and the NIDA-IRP, NIH, DHSS. We thank Wenhua Han, Yukio Takamatsu, and Keiko Matsuoka for discussion, technical support, and animal care.
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Ide, S., Minami, M., Satoh, M. et al. Buprenorphine Antinociception is Abolished, but Naloxone-Sensitive Reward is Retained, in μ-Opioid Receptor Knockout Mice. Neuropsychopharmacol 29, 1656–1663 (2004). https://doi.org/10.1038/sj.npp.1300463
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DOI: https://doi.org/10.1038/sj.npp.1300463
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