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Opioid Selective Antinociception Following Microinjection Into the Periaqueductal Gray of the Rat

Published:August 05, 2014DOI:https://doi.org/10.1016/j.jpain.2014.07.008

      Highlights

      • The periaqueductal gray (PAG) contributes to morphine and oxycodone antinociception.
      • PAG microinjection of methadone or buprenorphine does not produce antinociception.
      • These mu-opioid receptor agonists produce antinociception via distinct mechanisms.
      • This functionally selective antinociception contributes to opioid variability.

      Abstract

      Morphine and fentanyl produce antinociception in part by binding to mu-opioid receptors in the periaqueductal gray (PAG). The present study tested the hypothesis that the PAG also contributes to the antinociceptive effects of other commonly used opioids (oxycodone, methadone, and buprenorphine). Microinjection of high doses of oxycodone (32–188 μg/.4 μL) into the ventrolateral PAG of the rat produced a dose-dependent increase in hot plate latency. This antinociception was evident within 5 minutes and nearly gone by 30 minutes. In contrast, no antinociception was evident following microinjection of methadone or buprenorphine into the ventrolateral PAG despite use of a wide range of doses and test times. Antinociception was evident following subsequent microinjection of morphine into the same injection sites or following systemic administration of buprenorphine, demonstrating that the injections sites and drugs could support antinociception. Antinociception to systemic, but not PAG, administration of buprenorphine occurred in both male and female rats. These and previous data demonstrate that the mu-opioid receptor signaling pathway for antinociception in the PAG is selectively activated by some commonly used opioids (eg, morphine, fentanyl, and oxycodone) but not others (eg, methadone or buprenorphine). The fact that methadone and buprenorphine produce antinociception following systemic administration demonstrates that mu-opioid receptor signaling varies depending on location in the nervous system.

      Perspective

      This study demonstrates that the PAG contributes to the antinociceptive effects of some commonly used opioids (morphine, fentanyl, and oxycodone) but not others (methadone or buprenorphine). Such functional selectivity in PAG-mediated opioid antinociception helps explain why the analgesic profile of opioids is so variable.

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      References

        • Abbadie C.
        • Pasternak G.W.
        • Aicher S.A.
        Presynaptic localization of the carboxy-terminus epitopes of the mu opioid receptor splice variants MOR-1C and MOR-1D in the superficial laminae of the rat spinal cord.
        Neuroscience. 2001; 106: 833-842
        • Bartok R.E.
        • Craft R.M.
        Sex differences in opioid antinociception.
        J Pharmacol Exp Ther. 1997; 282: 769-778
        • Benamar K.
        • Palma J.
        • Cowan A.
        • Geller E.B.
        • Adler M.W.
        Analgesic efficacy of buprenorphine in the presence of high levels of SDF-1alpha/CXCL12 in the brain.
        Drug Alcohol Depend. 2011; 114: 246-248
        • Bobeck E.N.
        • Haseman R.A.
        • Hong D.
        • Ingram S.L.
        • Morgan M.M.
        Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat.
        J Pain. 2012; 13: 799-807
        • Bobeck E.N.
        • McNeal A.L.
        • Morgan M.M.
        Drug dependent sex-differences in periaqueductal gray mediated antinociception in the rat.
        Pain. 2009; 147: 210-216
        • Bodnar R.
        • Paul D.
        • Pasternak G.W.
        Synergistic analgesic interactions between the periaqueductal gray and the locus coeruleus.
        Brain Res. 1991; 558: 224-230
        • Bodnar R.J.
        • Williams C.L.
        • Lee S.J.
        • Pasternak G.W.
        Role of mu 1-opiate receptors in supraspinal opiate analgesia: A microinjection study.
        Brain Res. 1988; 447: 25-34
        • Bolan E.A.
        • Pan Y.X.
        • Pasternak G.W.
        Functional analysis of MOR-1 splice variants of the mouse mu opioid receptor gene Oprm.
        Synapse. 2004; 51: 11-18
        • Bryant R.M.
        • Olley J.E.
        • Tyers M.B.
        Involvement of the median raphe nucleus in antinociception induced by morphine, buprenorphine and tilidine in the rat.
        Br J Pharmacol. 1982; 77: 615-624
        • Cleary J.
        • Mikus G.
        • Somogyi A.
        • Bochner F.
        The influence of pharmacogenetics on opioid analgesia: Studies with codeine and oxycodone in the Sprague-Dawley/Dark Agouti rat model.
        J Pharmacol Exp Ther. 1994; 271: 1528-1534
        • Duttaroy A.
        • Yoburn B.C.
        The effect of intrinsic efficacy on opioid tolerance.
        Anesthesiology. 1995; 82: 1226-1236
        • Eidson L.N.
        • Murphy A.Z.
        Persistent peripheral inflammation attenuates morphine-induced periaqueductal gray glial cell activation and analgesic tolerance in the male rat.
        J Pain. 2013; 14: 393-404
        • Fukuda K.
        • Kato S.
        • Mori K.
        Location of regions of the opioid receptor involved in selective agonist binding.
        J Biol Chem. 1995; 270: 6702-6709
        • Garzon J.
        • Castro M.
        • Sanchez-Blazquez P.
        Influence of Gz and Gi2 transducer proteins in the affinity of opioid agonists to mu receptors.
        Eur J Neurosci. 1998; 10: 2557-2564
        • Garzon J.
        • Martinez-Pena Y.
        • Sanchez-Blazquez P.
        Dissimilar efficacy of opioids to produce mu-mediated analgesia: Role of Gx/z and Gi2 transducer proteins.
        Life Sci. 1994; 55: PL205-PL212
        • Gilbert A.K.
        • Franklin K.B.
        The role of descending fibers from the rostral ventromedial medulla in opioid analgesia in rats.
        Eur J Pharmacol. 2002; 449: 75-84
        • Gomez-Flores R.
        • Weber R.J.
        Differential effects of buprenorphine and morphine on immune and neuroendocrine functions following acute administration in the rat mesencephalon periaqueductal gray.
        Immunopharmacology. 2000; 48: 145-156
        • He L.
        • Kim J.
        • Ou C.
        • McFadden W.
        • van Rijn R.M.
        • Whistler J.L.
        Methadone antinociception is dependent on peripheral opioid receptors.
        J Pain. 2009; 10: 369-379
        • Jacquet Y.F.
        • Lajtha A.
        Paradoxical effects after microinjection of morphine in the periaqueductal gray matter in the rat.
        Science. 1974; 185: 1055-1057
        • Krzanowska E.K.
        • Bodnar R.J.
        Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats.
        Brain Res. 1999; 821: 224-230
        • Krzanowska E.K.
        • Bodnar R.J.
        Analysis of sex and gonadectomy differences in beta-endorphin antinociception elicited from the ventrolateral periaqueductal gray in rats.
        Eur J Pharmacol. 2000; 392: 157-161
        • Lane D.A.
        • Patel P.A.
        • Morgan M.M.
        Evidence for an intrinsic mechanism of antinociceptive tolerance within the ventrolateral periaqueductal gray of rats.
        Neuroscience. 2005; 135: 227-234
        • Lemberg K.K.
        • Kontinen V.K.
        • Siiskonen A.O.
        • Viljakka K.M.
        • Yli-Kauhaluoma J.T.
        • Korpi E.R.
        • Kalso E.A.
        Antinociception by spinal and systemic oxycodone: Why does the route make a difference? In vitro and in vivo studies in rats.
        Anesthesiology. 2006; 105: 801-812
        • Loh H.H.
        • Smith A.P.
        Molecular characterization of opioid receptors.
        Annu Rev Pharmacol Toxicol. 1990; 30: 123-147
        • Loyd D.R.
        • Murphy A.Z.
        The role of the periaqueductal gray in the modulation of pain in males and females: Are the anatomy and physiology really that different?.
        Neural Plast. 2009; 2009: 462879
        • Lutfy K.
        • Eitan S.
        • Bryant C.D.
        • Yang Y.C.
        • Saliminejad N.
        • Walwyn W.
        • Kieffer B.L.
        • Takeshima H.
        • Carroll F.I.
        • Maidment N.T.
        • Evans C.J.
        Buprenorphine-induced antinociception is mediated by mu-opioid receptors and compromised by concomitant activation of opioid receptor-like receptors.
        J Neurosci. 2003; 23: 10331-10337
        • Macey T.A.
        • Ingram S.L.
        • Bobeck E.N.
        • Hegarty D.M.
        • Aicher S.A.
        • Arttamangkul S.
        • Morgan M.M.
        Opioid receptor internalization contributes to dermorphin-mediated antinociception.
        Neuroscience. 2010; 168: 543-550
        • Madia P.A.
        • Dighe S.V.
        • Sirohi S.
        • Walker E.A.
        • Yoburn B.C.
        Dosing protocol and analgesic efficacy determine opioid tolerance in the mouse.
        Psychopharmacology (Berl). 2009; 207: 413-422
        • McPherson J.
        • Rivero G.
        • Baptist M.
        • Llorente J.
        • Al-Sabah S.
        • Krasel C.
        • Dewey W.L.
        • Bailey C.P.
        • Rosethorne E.M.
        • Charlton S.J.
        • Henderson G.
        • Kelly E.
        mu-Opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization.
        Mol Pharmacol. 2010; 78: 756-766
        • Mehalick M.L.
        • Ingram S.L.
        • Aicher S.A.
        • Morgan M.M.
        Chronic inflammatory pain prevents tolerance to the antinociceptive effect of morphine microinjected into the ventrolateral periaqueductal gray of the rat.
        J Pain. 2013; 14: 1601-1610
        • Melief E.J.
        • Miyatake M.
        • Bruchas M.R.
        • Chavkin C.
        Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling.
        Proc Natl Acad Sci U S A. 2010; 107: 11608-11613
        • Morgan M.M.
        • Ashley M.D.
        • Ingram S.L.
        • Christie M.J.
        Behavioral consequences of delta-opioid receptor activation in the periaqueductal gray of morphine tolerant rats.
        Neural Plast. 2009; 2009: 516328
        • Morgan M.M.
        • Bobeck E.N.
        • Ingram S.L.
        Glutamate modulation of antinociception, but not tolerance, produced by morphine microinjection into the periaqueductal gray of the rat.
        Brain Res. 2009; 1295: 59-66
        • Morgan M.M.
        • Fossum E.N.
        • Levine C.S.
        • Ingram S.L.
        Antinociceptive tolerance revealed by cumulative intracranial microinjections of morphine into the periaqueductal gray in the rat.
        Pharmacol Biochem Behav. 2006; 85: 214-219
        • Morgan M.M.
        • Fossum E.N.
        • Stalding B.M.
        • King M.M.
        Morphine antinociceptive potency on chemical, mechanical, and thermal nociceptive tests in the rat.
        J Pain. 2006; 7: 358-366
        • Morgan M.M.
        • Whitney P.K.
        • Gold M.S.
        Immobility and flight associated with antinociception produced by activation of the ventral and lateral/dorsal regions of the rat periaqueductal gray.
        Brain Res. 1998; 804: 159-166
        • Morgan M.M.
        • Whittier K.L.
        • Hegarty D.M.
        • Aicher S.A.
        Periaqueductal gray neurons project to spinally projecting GABAergic neurons in the rostral ventromedial medulla.
        Pain. 2008; 140: 376-386
        • Ocana M.
        • Del Pozo E.
        • Barrios M.
        • Baeyens J.M.
        Subgroups among mu-opioid receptor agonists distinguished by ATP-sensitive K+ channel-acting drugs.
        Br J Pharmacol. 1995; 114: 1296-1302
        • Ossipov M.H.
        • Goldstein F.J.
        • Malseed R.T.
        Feline analgesia following central administration of opioids.
        Neuropharmacology. 1984; 23: 925-929
        • Palma J.
        • Cowan A.
        • Geller E.B.
        • Adler M.W.
        • Benamar K.
        Differential antinociceptive effects of buprenorphine and methadone in the presence of HIV-gp120.
        Drug Alcohol Depend. 2011; 118: 497-499
        • Pan Y.X.
        • Xu J.
        • Bolan E.
        • Moskowitz H.S.
        • Xu M.
        • Pasternak G.W.
        Identification of four novel exon 5 splice variants of the mouse mu-opioid receptor gene: functional consequences of C-terminal splicing.
        Mol Pharmacol. 2005; 68: 866-875
        • Pasternak G.W.
        • Bodnar R.J.
        • Clark J.A.
        • Inturrisi C.E.
        Morphine-6-glucuronide, a potent mu agonist.
        Life Sci. 1987; 41: 2845-2849
        • Paxinos G.
        • Watson S.J.
        The Rat Brain, in Stereotaxic Coordinates.
        2nd ed. Academic Press, Sydney2005
        • Pergolizzi J.
        • Boger R.H.
        • Budd K.
        • Dahan A.
        • Erdine S.
        • Hans G.
        • Kress H.G.
        • Langford R.
        • Likar R.
        • Raffa R.B.
        • Sacerdote P.
        Opioids and the management of chronic severe pain in the elderly: Consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).
        Pain Pract. 2008; 8: 287-313
        • Raffa R.B.
        • Martinez R.P.
        The “glibenclamide-shift” of centrally-acting antinociceptive agents in mice.
        Brain Res. 1995; 677: 277-282
        • Rossi G.C.
        • Pan Y.X.
        • Brown G.P.
        • Pasternak G.W.
        Antisense mapping the MOR-1 opioid receptor: Evidence for alternative splicing and a novel morphine-6 beta-glucuronide receptor.
        FEBS Lett. 1995; 369: 192-196
        • Saidak Z.
        • Blake-Palmer K.
        • Hay D.L.
        • Northup J.K.
        • Glass M.
        Differential activation of G-proteins by mu-opioid receptor agonists.
        Br J Pharmacol. 2006; 147: 671-680
        • Sanchez-Blazquez P.
        • Gomez-Serranillos P.
        • Garzon J.
        Agonists determine the pattern of G-protein activation in mu-opioid receptor-mediated supraspinal analgesia.
        Brain Res Bull. 2001; 54: 229-235
        • Selley D.E.
        • Herbert J.T.
        • Morgan D.
        • Cook C.D.
        • Picker M.J.
        • Sim-Selley L.J.
        Effect of strain and sex on mu opioid receptor-mediated G-protein activation in rat brain.
        Brain Res Bull. 2003; 60: 201-208
        • Spinella M.
        • Znamensky V.
        • Moroz M.
        • Ragnauth A.
        • Bodnar R.J.
        Actions of NMDA and cholinergic receptor antagonists in the rostral ventromedial medulla upon beta-endorphin analgesia elicited from the ventrolateral periaqueductal gray.
        Brain Res. 1999; 829: 151-159
        • Yaksh T.L.
        • Rudy T.A.
        Narcotic analgesics: CNS sites and mechanisms of action as revealed by intracerebral injection techniques.
        Pain. 1978; 4: 299-359
        • Yamamoto T.
        • Shono K.
        • Tanabe S.
        Buprenorphine activates mu and opioid receptor like-1 receptors simultaneously, but the analgesic effect is mainly mediated by mu receptor activation in the rat formalin test.
        J Pharmacol Exp Ther. 2006; 318: 206-213
        • Zambotti F.
        • Zonta N.
        • Parenti M.
        • Tommasi R.
        • Vicentini L.
        • Conci F.
        • Mantegazza P.
        Periaqueductal gray matter involvement in the muscimol-induced decrease of morphine antinociception.
        Naunyn Schmiedebergs Arch Pharmacol. 1982; 318: 368-369
        • Zimprich A.
        • Simon T.
        • Hollt V.
        Cloning and expression of an isoform of the rat mu opioid receptor (rMOR1B) which differs in agonist induced desensitization from rMOR1.
        FEBS Lett. 1995; 359: 142-146