Buprenorphine-Induced Antinociception Is Mediated by μ-Opioid Receptors and Compromised by Concomitant Activation of Opioid Receptor-Like Receptors

Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Neuropsychiatric Institute, Los Angeles, California 90024, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 12/2003; 23(32):10331-7.
Source: PubMed

ABSTRACT Buprenorphine is a mixed opioid receptor agonist-antagonist used clinically for maintenance therapy in opiate addicts and pain management. Dose-response curves for buprenorphine-induced antinociception display ceiling effects or are bell shaped, which have been attributed to the partial agonist activity of buprenorphine at opioid receptors. Recently, buprenorphine has been shown to activate opioid receptor-like (ORL-1) receptors, also known as OP4 receptors. Here we demonstrate that buprenorphine, but not morphine, activates mitogen-activated protein kinase and Akt via ORL-1 receptors. Because the ORL-1 receptor agonist orphanin FQ/nociceptin blocks opioid-induced antinociception, we tested the hypothesis that buprenorphine-induced antinociception might be compromised by concomitant activation of ORL-1 receptors. In support of this hypothesis, the antinociceptive effect of buprenorphine, but not morphine, was markedly enhanced in mice lacking ORL-1 receptors using the tail-flick assay. Additional support for a modulatory role for ORL-1 receptors in buprenorphine-induced antinociception was that coadministration of J-113397, an ORL-1 receptor antagonist, enhanced the antinociceptive efficacy of buprenorphine in wild-type mice but not in mice lacking ORL-1 receptors. The ORL-1 antagonist also eliminated the bell-shaped dose-response curve for buprenorphine-induced antinociception in wild-type mice. Although buprenorphine has been shown to interact with multiple opioid receptors, mice lacking micro-opioid receptors failed to exhibit antinociception after buprenorphine administration. Our results indicate that the antinociceptive effect of buprenorphine in mice is micro-opioid receptor-mediated yet severely compromised by concomitant activation of ORL-1 receptors.

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Available from: Wendy Walwyn, Aug 04, 2014
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    • "Systemic injection of NOP receptor agonists has been shown to effectively block the analgesic responses of MOP and KOP receptor agonists and attenuate the rewarding effects of cocaine and morphine (Mogil et al., 1996; Murphy et al., 1999; Vazquez-DeRose et al., 2013). The oripavines, buprenorphine and etorphine both activate NOP receptors, and in the case of buprenorphine , the MOP receptor-mediated analgesic efficacy in acute pain assays is compromised by co-activation of NOP receptors (Butour et al., 1997; Lutfy et al., 2003). Opioid receptors are widely distributed throughout the peripheral nervous system and CNS, and the locations of these receptors mediate the diverse effects of opioid agonists (Le Merrer et al., 2009). "
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    ABSTRACT: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg−1), unmasked etorphine (3 mg·kg−1) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg−1) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg−1) and diazepam (1 mg·kg−1). Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit
    British Journal of Pharmacology 06/2014; 172(2). DOI:10.1111/bph.12810 · 4.84 Impact Factor
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    • "Buprenorphine has very low efficacy in the [ 35 S ] GTPS binding assay at NOP receptors ( Spagnolo et al . , 2008 ) , but has clear agonist activity at NOP receptors when measuring antinociception ( Khroyan et al . , 2009 ; Lutfy et al . , 2003 ) . As another example , the peptide [ Phe1psi ( CH2 - NH ) Gly2 ] - NC ( 1 - 13 ) - NH2 was described as the first NOP receptor antagonist when tested in the mouse vas deferens assay ( Guerrini et al . , 1998 ) , while further studies demonstrated that this compound has full agonist activity in transfected cells and is a potent as N / "
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    ABSTRACT: BACKGROUND AND PURPOSE: Buprenorphine is potent analgesic with high affinity at mu, delta, and kappa and moderate affinity at NOP receptors. Nevertheless, NOP receptor activation modulates the in vivo activity of buprenorphine. Structure activity studies were conducted to design buprenorphine analogs with high affinity at each of these receptors and to characterize them in in vitro and in vivo assays. EXPERIMENTAL APPROACH: Compounds were tested for binding affinity and functional activity using [35 S]GTPγS binding at each receptor and a whole cell fluorescent assay at mu receptors. BU08073 was evaluated for antinociceptive agonist and antagonist activity and for its effects on anxiety in mice. KEY RESULTS: BU08073 binds with high affinity to all opioid receptors. It has virtually no efficacy at delta, kappa, and NOP receptors, whereas at mu receptors, BU08073 has similar efficacy as buprenorphine in both functional assays. Alone, BU08073 has anxiogenic activity and produces very little antinociception. However, BU08073 blocks morphine and U50,488-mediated antinociception. This blockade is not evident at 1 h post-treatment, but is present at 6 h and remains for up to 3-6 days. CONCLUSIONS AND IMPLICATIONS: These studies provide structural requirements for synthesis of "universal" opioid ligands. BU08073 has high affinity at all the opioid receptors, with moderate efficacy at mu receptors and reduced efficacy at NOP receptors, a profile suggesting potential analgesic activity. On the contrary, BU08073 has long lasting antagonist activity, indicating that the pharmacokinetics of a compound dictates not only the time course of the behavior but also what receptor-mediated behavior will be observed. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 06/2014; 172(2). DOI:10.1111/bph.12796 · 4.84 Impact Factor
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    • "However, it was recently documented in rodents that antinociception produced by systemic buprenorphine is potentiated in the presence of systemically administered NOP antagonists and in NOP-receptor knockout mice (Lutfy et al., 2003; Ding and Raffa, 2009; Khroyan et al., 2009). Given that buprenorphine has an extremely low binding affinity at NOP versus MOP (K i 5 285 versus 0.08 nM) and is much less potent in activating NOP receptors in vitro (EC 50 5 35 versus 0.08 nM) (Huang et al., 2001), it seems unlikely that intrathecal buprenorphine activates the spinal NOP receptors at antiallodynic doses. "
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    ABSTRACT: Nociceptin/Orphanin FQ peptide receptor (NOP) agonists produce antinociceptive effects in animal models following spinal administration and potentiate mu-opioid receptor (MOP)-mediated antinociception. The aim of this study was to determine the antinociceptive effects of spinally administered bifunctional NOP/MOP ligands and the antinociceptive functions of spinal NOP and MOP receptors in mice. Antinociceptive effects of bifunctional NOP/MOP ligands BU08028 and SR16435 were pharmacologically compared with the putative bifunctional ligand buprenorphine, selective NOP agonist SCH221510 and selective MOP agonist morphine in neuropathic and inflammatory pain models. Additionally, the degree of tolerance development to the antiallodynic effects of SR16435 and buprenorphine were determined following repeated intrathecal administration. Our data indicated that BU08028 and SR16435 were more potent than morphine and SCH221510 in attenuating nerve injury-induced tactile allodynia and inflammation-induced thermal hyperalgesia. Co-administration of receptor-selective antagonists further revealed that both NOP and MOP in the spinal cord mediated the antiallodynic effects of BU08028 and SR16435, but intrathecal buprenorphine-induced antiallodynic effects were primarily mediated by MOP. Repeated intrathecal administration of SR16435 resulted in reduced and slower development of tolerance to its antiallodynic effects compared to buprenorphine. In conclusion, both NOP and MOP receptors in the spinal cord independently drive antinociception in mice. Spinally administered bifunctional NOP/MOP ligands not only can effectively attenuate neuropathic and inflammatory pain, but also have higher antinociceptive potency with reduced tolerance development to analgesia. Such ligands therefore display a promising profile as spinal analgesics.
    Journal of Pharmacology and Experimental Therapeutics 05/2013; 346(1):11-22. DOI:10.1124/jpet.113.203984 · 3.97 Impact Factor
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