Skip to main content
SpringerLink
Log in

Class A GPCRs: Cannabinoid and Opioid Receptor Heteromers

  • Chapter
  • First Online:
G-Protein-Coupled Receptor Dimers

Part of the book series: The Receptors ((REC,volume 33))

Abstract

Cannabinoid and opioid receptors mediate a variety of physiological processes including pain and drug reward. Both receptors couple to Gαi/o proteins and their activation leads to inhibition of adenylyl cyclase and potassium channel activity ultimately leading to inhibition of synaptic transmission. Over the last decade increasing anatomical, biochemical and pharmacological evidence demonstrated interactions between the opioid and cannabinoid receptor systems that could modulate not only the physiological but also the pathophysiological roles of these receptors. The present review aims to summarize the literature surrounding the properties of cannabinoid and opioid receptors and the unique signaling following their interaction as well as the novel interventions in the management of disorders ranging from pain to addiction.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Aicher SA, Punnoose A, Goldberg A. mu-Opioid receptors often colocalize with the substance P receptor (NK1) in the trigeminal dorsal horn. J Neurosci. 2000;20:4345–54.

    CAS  PubMed  Google Scholar 

  2. Altun A, Yildirim K, Ozdemir E, Bagcivan I, Gursoy S, Durmus N. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. J Physiol Sci. 2015;65:407–15.

    Article  CAS  PubMed  Google Scholar 

  3. Ansonoff MA, Zhang J, Czyzyk T, Rothman RB, Stewart J, Xu H, et al. Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice. J Pharmacol Exp Ther. 2006;318:641–8.

    Article  CAS  PubMed  Google Scholar 

  4. Arvidsson U, Dado RJ, Riedl M, Lee JH, Law PY, Loh HH, et al. Delta-Opioid receptor immunoreactivity: distribution in brainstem and spinal cord, and relationship to biogenic amines and enkephalin. J Neurosci. 1995;15:1215–35.

    CAS  PubMed  Google Scholar 

  5. Bambico FR, Cassano T, Dominguez-Lopez S, Katz N, Walker CD, Piomelli D, et al. Genetic deletion of fatty acid amide hydrolase alters emotional behavior and serotonergic transmission in the dorsal raphe, prefrontal cortex, and hippocampus. Neuropsychopharmacology. 2010;35:2083–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Basavarajappa BS, Nagre NN, Xie S, Subbanna S. Elevation of endogenous anandamide impairs LTP, learning, and memory through CB1 receptor signaling in mice. Hippocampus. 2014;24:808–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Benard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E, et al. Mitochondrial CB(1) receptors regulate neuronal energy metabolism. Nat Neurosci. 2012;15:558–64.

    Article  CAS  PubMed  Google Scholar 

  8. Berrendero F, Mendizabal V, Murtra P, Kieffer BL, Maldonado R. Cannabinoid receptor and WIN 55 212-2-stimulated [35S]-GTPgammaS binding in the brain of mu-, delta- and kappa-opioid receptor knockout mice. Eur J Neurosci. 2003;18:2197–202.

    Article  PubMed  Google Scholar 

  9. Berrendero F, Mendizabal V, Robledo P, Galeote L, Bilkei-Gorzo A, Zimmer A, et al. Nicotine-induced antinociception, rewarding effects, and physical dependence are decreased in mice lacking the preproenkephalin gene. J Neurosci. 2005;25:1103–12.

    Article  CAS  PubMed  Google Scholar 

  10. Bertran-Gonzalez J, Laurent V, Chieng BC, Christie MJ, Balleine BW. Learning-related translocation of delta-opioid receptors on ventral striatal cholinergic interneurons mediates choice between goal-directed actions. J Neurosci. 2013;33:16060–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Besse D, Lombard MC, Perrot S, Besson JM. Regulation of opioid binding sites in the superficial dorsal horn of the rat spinal cord following loose ligation of the sciatic nerve: comparison with sciatic nerve section and lumbar dorsal rhizotomy. Neuroscience. 1992;50:921–33.

    Article  CAS  PubMed  Google Scholar 

  12. Besse D, Lombard MC, Zajac JM, Roques BP, Besson JM. Pre- and postsynaptic location of mu, delta and kappa opioid receptors in the superficial layers of the dorsal horn of the rat spinal cord. Prog Clin Biol Res. 1990;328:183–6.

    CAS  PubMed  Google Scholar 

  13. Bhaskaran M, Chen HF, Chen ZM, Liu L. Hemoglobin is expressed in alveolar epithelial type II cells. Biochem Biophys Res Commun. 2005;333:1348–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Biagioli M, Pinto M, Cesselli D, Zaninello M, Lazarevic D, Roncaglia P, et al. Unexpected expression of alpha- and beta-globin in mesencephalic dopaminergic neurons and glial cells. Proc Natl Acad Sci U S A. 2009;106:15454–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Billet F, Costentin J, Dourmap N. Influence of corticostriatal delta-opioid receptors on abnormal involuntary movements induced by L-DOPA in hemiparkinsonian rats. Exp Neurol. 2012;236:339–50.

    Article  CAS  PubMed  Google Scholar 

  16. Bisogno T, Berrendero F, Ambrosino G, Cebeira M, Ramos JA, Fernancez-Ruiz JJ, et al. Brain regional distribution of endocannabinoids: implications for their biosynthesis and biological function. Biochem Biophys Res Commun. 1999;256(2):377–80.

    Article  CAS  PubMed  Google Scholar 

  17. Bisogno T, Sepe N, Melck D, Maurelli S, De Petrocellis L, Di Marzo V. Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. Biochem J. 1997;322(Pt 2):671–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Blais PA, Cote J, Morin J, Larouche A, Gendron G, Fortier A, Regoli D, Neugebauer W, Gobeil F Jr. Hypotensive effects of hemopressin and bradykinin in rabbits, rats and mice. A comparative study. Peptides. 2005;26:1317-1322.

    Google Scholar 

  19. Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol. 2007;14:1347–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bonhaus DW, Chang LK, Kwan J, Martin GR. Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. J Pharmacol Exp Ther. 1998;287:884–8.

    CAS  PubMed  Google Scholar 

  21. Botticelli LJ, Cox BM, Goldstein A. Immunoreactive dynorphin in mammalian spinal cord and dorsal root ganglia. Proc Natl Acad Sci U S A. 1981;78:7783–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bouaboula M, Poinot-Chazel C, Bourrie B, Canat X, Calandra B, Rinaldi-Carmona M, et al. Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J. 1995;312(Pt 2):637–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Braida D, Pozzi M, Cavallini R, Sala M. Conditioned place preference induced by the cannabinoid agonist CP 55,940: interaction with the opioid system. Neuroscience. 2001a;104:923–6.

    Article  CAS  PubMed  Google Scholar 

  24. Braida D, Pozzi M, Parolaro D, Sala M. Intracerebral self-administration of the cannabinoid receptor agonist CP 55,940 in the rat: interaction with the opioid system. Eur J Pharmacol. 2001b;413:227–34.

    Article  CAS  PubMed  Google Scholar 

  25. Bushlin I, Gupta A, Stockton SD Jr, Miller LK, Devi LA. Dimerization with cannabinoid receptors allosterically modulates delta opioid receptor activity during neuropathic pain. PLoS One. 2012;7:e49789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bushlin I, Rozenfeld R, Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol. 2010;10:80–6.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Google Scholar 

  28. Cai Q, Qiu CY, Qiu F, Liu TT, Qu ZW, Liu YM, et al. Morphine inhibits acid-sensing ion channel currents in rat dorsal root ganglion neurons. Brain Res. 2014;1554:12–20.

    Article  CAS  PubMed  Google Scholar 

  29. Canals M, Milligan G. Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opioid receptors. J Biol Chem. 2008;283:11424–34.

    Article  CAS  PubMed  Google Scholar 

  30. Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, et al. Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol. 2004;65:999–1007.

    Article  CAS  PubMed  Google Scholar 

  31. Cassano T, Gaetani S, Macheda T, Laconca L, Romano A, Morgese MG, et al. Evaluation of the emotional phenotype and serotonergic neurotransmission of fatty acid amide hydrolase-deficient mice. Psychopharmacology. 2011;214:465–76.

    Article  CAS  PubMed  Google Scholar 

  32. Castane A, Robledo P, Matifas A, Kieffer BL, Maldonado R. Cannabinoid withdrawal syndrome is reduced in ouble mu and delta opioid receptor knockout mice. Eur J Neurosci. 2003;17:155–9.

    Article  PubMed  Google Scholar 

  33. Chan JS, Chiu TT, Wong YH. Activation of type II adenylyl cyclase by the cloned mu-opioid receptor: coupling to multiple G proteins. J Neurochem. 1995;65:2682–9.

    Article  CAS  PubMed  Google Scholar 

  34. Chefer VI, Shippenberg TS. Paradoxical effects of prodynorphin gene deletion on basal and cocaine-evoked dopaminergic neurotransmission in the nucleus accumbens. Eur J Neurosci. 2006;23:229–38.

    Article  CAS  PubMed  Google Scholar 

  35. Chefer VI, Shippenberg TS. Augmentation of morphine-induced sensitization but reduction in morphine tolerance and reward in delta-opioid receptor knockout mice. Neuropsychopharmacology. 2009;34:887–98.

    Article  CAS  PubMed  Google Scholar 

  36. Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology. 1990;102:156–62.

    Article  CAS  PubMed  Google Scholar 

  37. Chen M, Zhao Y, Yang H, Luan W, Song J, Cui D, et al. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation. elife. 2015;4

    Google Scholar 

  38. Chen Y, Mestek A, Liu J, Hurley JA, Yu L. Molecular cloning and functional expression of a mu-opioid receptor from rat brain. Mol Pharmacol. 1993;44:8–12.

    CAS  PubMed  Google Scholar 

  39. Cheng PY, Liu-Chen LY, Pickel VM. Dual ultrastructural immunocytochemical labeling of mu and delta opioid receptors in the superficial layers of the rat cervical spinal cord. Brain Res. 1997;778:367–80.

    Article  CAS  PubMed  Google Scholar 

  40. Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74:1317–24.

    Article  CAS  PubMed  Google Scholar 

  41. Corchero J, Avila MA, Fuentes JA, Manzanares J. delta-9-Tetrahydrocannabinol increases prodynorphin and proenkephalin gene expression in the spinal cord of the rat. Life Sci. 1997a;61:PL39–43.

    Google Scholar 

  42. Corchero J, Fuentes JA, Manzanares J. delta 9-Tetrahydrocannabinol increases proopiomelanocortin gene expression in the arcuate nucleus of the rat hypothalamus. Eur J Pharmacol. 1997b;323:193–5.

    Article  CAS  PubMed  Google Scholar 

  43. Corchero J, Manzanares J, Fuentes JA. Cannabinoid/opioid crosstalk in the central nervous system. Crit Rev Neurobiol. 2004;16:159–72.

    Article  CAS  PubMed  Google Scholar 

  44. Cota D, Tschop MH, Horvath TL, Levine AS. Cannabinoids, opioids and eating behavior: the molecular face of hedonism? Brain Res Rev. 2006;51:85–107.

    Article  CAS  PubMed  Google Scholar 

  45. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7.

    Article  CAS  PubMed  Google Scholar 

  46. Csuhai E, Little SS, Hersh LB. Inactivation of neuropeptides. Prog Brain Res. 1995;104:131–42.

    Article  CAS  PubMed  Google Scholar 

  47. da Fonseca PD, Klein A, de Castro PA, da Fonseca Pacheco CM, de Francischi JN, Duarte ID. The mu-opioid receptor agonist morphine, but not agonists at delta- or kappa-opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors. Br J Pharmacol. 2008;154:1143–9.

    Article  CAS  Google Scholar 

  48. Dackis C, O’Brien C. Neurobiology of addiction: treatment and public policy ramifications. Nat Neurosci. 2005;8:1431–6.

    Article  CAS  PubMed  Google Scholar 

  49. Dale CS, Pagano Rde L, Rioli V. Hemopressin: a novel bioactive peptide derived from the alpha1-chain of hemoglobin. Mem Inst Oswaldo Cruz. 2005a;100(Suppl 1):105–6.

    Article  CAS  PubMed  Google Scholar 

  50. Dale CS, Pagano Rde L, Rioli V, Hyslop S, Giorgi R, Ferro ES. Antinociceptive action of hemopressin in experimental hyperalgesia. Peptides. 2005b;26:431–6.

    Article  CAS  PubMed  Google Scholar 

  51. Dassen H, Kamps R, Punyadeera C, Dijcks F, de Goeij A, Ederveen A, et al. Haemoglobin expression in human endometrium. Hum Reprod. 2008;23:635–41.

    Article  CAS  PubMed  Google Scholar 

  52. De Vries TJ, Homberg JR, Binnekade R, Raaso H, Schoffelmeer AN. Cannabinoid modulation of the reinforcing and motivational properties of heroin and heroin-associated cues in rats. Psychopharmacology. 2003;168:164–9.

    Article  PubMed  CAS  Google Scholar 

  53. Del Arco I, Navarro M, Bilbao A, Ferrer B, Piomelli D, De Fonseca FR. Attenuation of spontaneous opiate withdrawal in mice by the anandamide transport inhibitor AM404. Eur J Pharmacol. 2002;454:103–4.

    Article  PubMed  Google Scholar 

  54. den Boon FS, Chameau P, Schaafsma-Zhao Q, van Aken W, Bari M, Oddi S, et al. Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors. Proc Natl Acad Sci U S A. 2012;109:3534–9.

    Article  Google Scholar 

  55. Desroches J, Bouchard JF, Gendron L, Beaulieu P. Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia. Neuroscience. 2014;261:23–42.

    Article  CAS  PubMed  Google Scholar 

  56. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS, et al. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev. 1996;48:567–92.

    CAS  PubMed  Google Scholar 

  57. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC, et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372:686–91.

    Article  PubMed  Google Scholar 

  58. Dodd GT, Mancini G, Lutz B, Luckman SM. The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J Neurosci. 2010;30:7369–76.

    Article  CAS  PubMed  Google Scholar 

  59. Duan YL, Wang SY, Zeng QW, Su DS, Li W, Wang XR, et al. Astroglial reaction to delta opioid peptide [D-Ala2, D-Leu5] enkephalin confers neuroprotection against global ischemia in the adult rat hippocampus. Neuroscience. 2011;192:81–90.

    Article  CAS  PubMed  Google Scholar 

  60. Dupont A, Barden N, Cusan L, Merand Y, Labrie F, Vaudry H. beta-Endorphin and met-enkephalins: their distribution, modulation by estrogens and haloperidol, and role in neuroendocrine control. Fed Proc. 1980;39:2544–50.

    CAS  PubMed  Google Scholar 

  61. Edsall SA, Knapp RJ, Vanderah TW, Roeske WR, Consroe P, Yamamura HI. Antisense oligodeoxynucleotide treatment to the brain cannabinoid receptor inhibits antinociception. Neuroreport. 1996;7:593–6.

    Article  CAS  PubMed  Google Scholar 

  62. Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS, Bruchas MR, et al. Kappa opioid receptor-induced aversion requires p38 MAPK activation in VTA dopamine neurons. J Neurosci. 2015;35:12917–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eriksson PS, Hansson E, Ronnback L. Delta and kappa opiate receptors in primary astroglial cultures from rat cerebral cortex. Neurochem Res. 1990;15:1123–6.

    Article  CAS  PubMed  Google Scholar 

  64. Eriksson PS, Hansson E, Ronnback L. Mu and delta opiate receptors in neuronal and astroglial primary cultures from various regions of the brain–coupling with adenylate cyclase, localisation on the same neurones and association with dopamine (D1) receptor adenylate cyclase. Neuropharmacology. 1991;30:1233–9.

    Article  CAS  PubMed  Google Scholar 

  65. Evans CJ, Keith DE Jr, Morrison H, Magendzo K, Edwards RH. Cloning of a delta opioid receptor by functional expression. Science. 1992;258:1952–5.

    Article  CAS  PubMed  Google Scholar 

  66. Falcon E, Browne CA, Leon RM, Fleites VC, Sweeney R, Kirby LG, et al. Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology. 2016;41:2344–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fattore L, Vigano D, Fadda P, Rubino T, Fratta W, Parolaro D. Bidirectional regulation of mu-opioid and CB1-cannabinoid receptor in rats self-administering heroin or WIN 55,212-2. Eur J Neurosci. 2007;25:2191–200.

    Article  PubMed  Google Scholar 

  68. Ferrari LL, Agostinelli LJ, Krashes MJ, Lowell BB, Scammell TE, Arrigoni E. Dynorphin inhibits basal forebrain cholinergic neurons by pre- and postsynaptic mechanisms. J Physiol. 2016;594:1069–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ferre S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol. 2009;5:131–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fichna J, Dicay M, Lewellyn K, Janecka A, Zjawiony JK, MacNaughton WK, et al. Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors. Inflamm Bowel Dis. 2012;18:1137–45.

    Article  PubMed  Google Scholar 

  71. Fields H. State-dependent opioid control of pain. Nat Rev Neurosci. 2004;5:565–75.

    Article  CAS  PubMed  Google Scholar 

  72. Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, et al. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet. 2000;25:195–200.

    Article  CAS  PubMed  Google Scholar 

  73. Fitzgerald ML, Shobin E, Pickel VM. Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;38:21–9.

    Article  CAS  Google Scholar 

  74. Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, Gustafsdottir SM, et al. Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol. 2002;20:473–7.

    Article  CAS  PubMed  Google Scholar 

  75. Furuhashi M, Mizutani S, Kurauchi O, Kasugai M, Narita O, Tomoda Y. In vitro degradation of opioid peptides by human placental aminopeptidase M. Exp Clin Endocrinol. 1988;92:235–7.

    Article  CAS  PubMed  Google Scholar 

  76. Gallagher SK, Anglen JN, Mower JM, Vigh J. Dopaminergic amacrine cells express opioid receptors in the mouse retina. Vis Neurosci. 2012;29:203–9.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M, et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci. 2010;30:2017–24.

    Article  CAS  PubMed  Google Scholar 

  78. Garcia-Gutierrez MS, Garcia-Bueno B, Zoppi S, Leza JC, Manzanares J. Chronic blockade of cannabinoid CB2 receptors induces anxiolytic-like actions associated with alterations in GABA(A) receptors. Br J Pharmacol. 2012;165:951–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gardell LR, Ossipov MH, Vanderah TW, Lai J, Porreca F. Dynorphin-independent spinal cannabinoid antinociception. Pain. 2002;100:243–8.

    Article  CAS  PubMed  Google Scholar 

  80. Garzon J, de la Torre-Madrid E, Rodriguez-Munoz M, Vicente-Sanchez A, Sanchez-Blazquez P. Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine. Mol Pain. 2009;5:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Gaskell H, Derry S, Moore RA, McQuay HJ. Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009:CD002763.

    Google Scholar 

  82. Gaveriaux-Ruff C, Matthes HW, Peluso J, Kieffer BL. Abolition of morphine-immunosuppression in mice lacking the mu-opioid receptor gene. Proc Natl Acad Sci U S A. 1998;95:6326–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gaveriaux-Ruff C, Nozaki C, Nadal X, Hever XC, Weibel R, Matifas A, et al. Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain. 2011;152:1238–48.

    Article  CAS  PubMed  Google Scholar 

  84. Gaveriaux-Ruff C, Simonin F, Filliol D, Kieffer BL. Enhanced humoral response in kappa-opioid receptor knockout mice. J Neuroimmunol. 2003;134:72–81.

    Article  CAS  PubMed  Google Scholar 

  85. Gelman JS, Sironi J, Castro LM, Ferro ES, Fricker LD. Hemopressins and other hemoglobin-derived peptides in mouse brain: comparison between brain, blood, and heart peptidome and regulation in Cpefat/fat mice. J Neurochem. 2010;113:871–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Genazzani AR, Nappi G, Facchinetti F, Mazzella GL, Parrini D, Sinforiani E, et al. Central deficiency of beta-endorphin in alcohol addicts. J Clin Endocrinol Metab. 1982;55:583–6.

    Article  CAS  PubMed  Google Scholar 

  87. Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R. Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci. 2002;22:1146–54.

    CAS  PubMed  Google Scholar 

  88. Glass M, Felder CC. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci. 1997;17:5327–33.

    CAS  PubMed  Google Scholar 

  89. Glaum SR, Miller RJ, Hammond DL. Inhibitory actions of delta 1-, delta 2-, and mu-opioid receptor agonists on excitatory transmission in lamina II neurons of adult rat spinal cord. J Neurosci. 1994;14:4965–71.

    CAS  PubMed  Google Scholar 

  90. Gold MS, Levine JD. DAMGO inhibits prostaglandin E2-induced potentiation of a TTX-resistant Na+ current in rat sensory neurons in vitro. Neurosci Lett. 1996;212:83–6.

    Article  CAS  PubMed  Google Scholar 

  91. Gomes I, Ayoub MA, Fujita W, Jaeger WC, Pfleger KD, Devi LA. G protein-coupled receptor heteromers. Annu Rev Pharmacol Toxicol. 2016a;56:403–25.

    Article  CAS  PubMed  Google Scholar 

  92. Gomes I, Grushko JS, Golebiewska U, Hoogendoorn S, Gupta A, Heimann AS, et al. Novel endogenous peptide agonists of cannabinoid receptors. FASEB J. 2009;23:3020–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gomes I, Sierra S, Devi LA. Detection of receptor heteromerization using in situ proximity ligation assay. Curr Prot Pharmacol. 2016b;75:2 16 11–31.

    Google Scholar 

  94. Gomes I, Wardman JH, Stockton SDJ, Devi LA. Neuropeptide receptors, vol 4. New Jersey: Morgan & Claypool Life Sciences; 2013. P. 1–153.

    Google Scholar 

  95. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, et al. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071:10–23.

    Article  CAS  PubMed  Google Scholar 

  96. Gowrisankar YV, Clark MA. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures. J Neurochem. 2016;138:74–85.

    Article  CAS  PubMed  Google Scholar 

  97. Graf L, Paldi A, Patthy A. Action of neutral metalloendopeptidase (“enkephalinase”) on beta-endorphin. Neuropeptides. 1985;6:13–9.

    Article  CAS  PubMed  Google Scholar 

  98. Grueter BA, Brasnjo G, Malenka RC. Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens. Nat Neurosci. 2010;13:1519–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gu M, Wessendorf M. Endomorphin-2-immunoreactive fibers selectively appose serotonergic neuronal somata in the rostral ventral medial medulla. J Comp Neurol. 2007;502:701–13.

    Article  PubMed  Google Scholar 

  100. Haber S, Elde R. The distribution of enkephalin immunoreactive neuronal cell bodies in the monkey brain: preliminary observations. Neurosci Lett. 1982;32:247–52.

    Article  CAS  PubMed  Google Scholar 

  101. Haller VL, Stevens DL, Welch SP. Modulation of opioids via protection of anandamide degradation by fatty acid amide hydrolase. Eur J Pharmacol. 2008;600:50–8.

    Article  CAS  PubMed  Google Scholar 

  102. Harris JA, Chang PC, Drake CT. Kappa opioid receptors in rat spinal cord: sex-linked distribution differences. Neuroscience. 2004;124:879–90.

    Article  CAS  PubMed  Google Scholar 

  103. Hayward MD, Pintar JE, Low MJ. Selective reward deficit in mice lacking beta-endorphin and enkephalin. J Neurosci. 2002;22:8251–8.

    CAS  PubMed  Google Scholar 

  104. Hegadoren KM, O’Donnell T, Lanius R, Coupland NJ, Lacaze-Masmonteil N. The role of beta-endorphin in the pathophysiology of major depression. Neuropeptides. 2009;43:341–53.

    Article  CAS  PubMed  Google Scholar 

  105. Heimann AS, Gomes I, Dale CS, Pagano RL, Gupta A, de Souza LL, et al. Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci U S A. 2007;104:20588–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Henstridge CM. Off-target cannabinoid effects mediated by GPR55. Pharmacology. 2012;89:179–87.

    Article  CAS  PubMed  Google Scholar 

  107. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11:563–83.

    CAS  PubMed  Google Scholar 

  108. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A. 1990;87:1932–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hofer SC, Ralvenius WT, Gachet MS, Fritschy JM, Zeilhofer HU, Gertsch J. Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla. Neuropharmacology. 2015;98:78–89.

    Article  CAS  PubMed  Google Scholar 

  110. Hohmann AG, Briley EM, Herkenham M. Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res. 1999;822:17–25.

    Article  CAS  PubMed  Google Scholar 

  111. Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, et al. mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharmacol Sci. 2008;108:308–19.

    Article  CAS  PubMed  Google Scholar 

  112. Honsek SD, Seal RP, Sandkuhler J. Presynaptic inhibition of optogenetically identified VGluT3+ sensory fibres by opioids and baclofen. Pain. 2015;156:243–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Houser SJ, Eads M, Embrey JP, Welch SP. Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP55,940, Delta(9)-THC and anandamide. Brain Res. 2000;857:337–42.

    Article  CAS  PubMed  Google Scholar 

  114. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202.

    Article  CAS  PubMed  Google Scholar 

  115. Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci. 2006;29:565–98.

    Article  CAS  PubMed  Google Scholar 

  116. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003;100:10529–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ibrahim MM, Rude ML, Stagg NJ, Mata HP, Lai J, Vanderah TW, et al. CB2 cannabinoid receptor mediation of antinociception. Pain. 2006;122:36–42.

    Article  CAS  PubMed  Google Scholar 

  118. Ingram SL, Williams JT. Opioid inhibition of Ih via adenylyl cyclase. Neuron. 1994;13:179–86.

    Article  CAS  PubMed  Google Scholar 

  119. Janecka A, Fichna J, Janecki T. Opioid receptors and their ligands. Curr Top Med Chem. 2004;4:1–17.

    Article  CAS  PubMed  Google Scholar 

  120. Ji RR, Zhang Q, Law PY, Low HH, Elde R, Hokfelt T. Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci. 1995;15:8156–66.

    CAS  PubMed  Google Scholar 

  121. Jutkiewicz EM, Rice KC, Traynor JR, Woods JH. Separation of the convulsions and antidepressant-like effects produced by the delta-opioid agonist SNC80 in rats. Psychopharmacology. 2005;182:588–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kaminski RM, Witkin JM, Shippenberg TS. Pharmacological and genetic manipulation of kappa opioid receptors: effects on cocaine- and pentylenetetrazol-induced convulsions and seizure kindling. Neuropharmacology. 2007;52:895–903.

    Article  CAS  PubMed  Google Scholar 

  123. Kang-Park M, Kieffer BL, Roberts AJ, Siggins GR, Moore SD. kappa-Opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. J Pharmacol Exp Ther. 2013;346:130–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89:309–80.

    Article  CAS  PubMed  Google Scholar 

  125. Kardon AP, Polgar E, Hachisuka J, Snyder LM, Cameron D, Savage S, et al. Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron. 2014;82:573–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedeberg’s Arch Pharmacol. 2006;372:354–61.

    Article  CAS  Google Scholar 

  127. Kato A, Punnakkal P, Pernia-Andrade AJ, von Schoultz C, Sharopov S, Nyilas R, et al. Endocannabinoid-dependent plasticity at spinal nociceptor synapses. J Physiol. 2012;590:4717–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Khajehali E, Malone DT, Glass M, Sexton PM, Christopoulos A, Leach K. Biased agonism and biased allosteric modulation at the CB1 cannabinoid receptor. Mol Pharmacol. 2015;88:368–79.

    Article  CAS  PubMed  Google Scholar 

  129. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc Natl Acad Sci U S A. 1992;89:12048–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Prog Neurobiol. 2002;66:285–306.

    Article  CAS  PubMed  Google Scholar 

  131. Kilpatrick DL, Eisen M, Ezra E, Udenfriend S. Processing of prodynorphin at single and paired basic residues in porcine neurointermediate lobe. Life Sci. 1983;33(Suppl 1):93–6.

    Article  CAS  PubMed  Google Scholar 

  132. Kim J, Li Y. Chronic activation of CB2 cannabinoid receptors in the hippocampus increases excitatory synaptic transmission. J Physiol. 2015;593:871–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kishimoto Y, Kano M. Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning. J Neurosci. 2006;26:8829–37.

    Article  CAS  PubMed  Google Scholar 

  134. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35:217–38.

    Article  PubMed  Google Scholar 

  135. Kovacs KM, Szakall I, O’Brien D, Wang R, Vinod KY, Saito M, et al. Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice. Alcohol Clin Exp Res. 2005;29:730–8.

    Article  CAS  PubMed  Google Scholar 

  136. Kraft B. Is there any clinically relevant cannabinoid-induced analgesia? Pharmacology. 2012;89:237–46.

    Article  CAS  PubMed  Google Scholar 

  137. Lai HW, Minami M, Satoh M, Wong YH. Gz coupling to the rat kappa-opioid receptor. FEBS Lett. 1995;360:97–9.

    Article  CAS  PubMed  Google Scholar 

  138. Law PY. Opioid receptor signal transduction mechanisms. In: Pasternak G (ed) The opiate receptors. Totowa: Humana Press; 2011. P. 195–238.

    Google Scholar 

  139. Law SF, Reisine T. Changes in the association of G protein subunits with the cloned mouse delta opioid receptor on agonist stimulation. J Pharmacol Exp Ther. 1997;281:1476–86.

    CAS  PubMed  Google Scholar 

  140. Le Naour M, Akgun E, Yekkirala A, Lunzer MM, Powers MD, Kalyuzhny AE, et al. Bivalent ligands that target mu opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. J Med Chem. 2013;56:5505–13.

    Article  PubMed  CAS  Google Scholar 

  141. Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science. 1999;283:401–4.

    Article  CAS  PubMed  Google Scholar 

  142. Leishman E, Mackie K, Luquet S, Bradshaw HB. Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain. Biochim Biophys Acta. 2016;1861:491–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Li Y, Kim J. Deletion of CB2 cannabinoid receptors reduces synaptic transmission and long-term potentiation in the mouse hippocampus. Hippocampus. 2016;26:275–81.

    Article  CAS  PubMed  Google Scholar 

  144. Lichtman AH, Sheikh SM, Loh HH, Martin BR. Opioid and cannabinoid modulation of precipitated withdrawal in delta(9)-tetrahydrocannabinol and morphine-dependent mice. J Pharmacol Exp Ther. 2001;298:1007–14.

    CAS  PubMed  Google Scholar 

  145. Lichtman AH, Shelton CC, Advani T, Cravatt BF. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain. 2004;109:319–27.

    Article  CAS  PubMed  Google Scholar 

  146. Lim G, Sung B, Ji RR, Mao J. Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of Win 55,212-2 on neuropathic pain behaviors in rats. Pain. 2003;105:275–83.

    Article  CAS  PubMed  Google Scholar 

  147. Lim G, Wang S, Mao J. Central glucocorticoid receptors modulate the expression of spinal cannabinoid receptors induced by chronic morphine exposure. Brain Res. 2005;1059:20–7.

    Article  CAS  PubMed  Google Scholar 

  148. Lindskog M, Svenningsson P, Fredholm B, Greengard P, Fisone G. Mu- and delta-opioid receptor agonists inhibit DARPP-32 phosphorylation in distinct populations of striatal projection neurons. Eur J Neurosci. 1999;11:2182–6.

    Article  CAS  PubMed  Google Scholar 

  149. Liu L, Zeng M, Stamler JS. Hemoglobin induction in mouse macrophages. Proc Natl Acad Sci U S A. 1999;96:6643–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lozovaya N, Min R, Tsintsadze V, Burnashev N. Dual modulation of CNS voltage-gated calcium channels by cannabinoids: focus on CB1 receptor-independent effects. Cell Calcium. 2009;46:154–62.

    Article  CAS  PubMed  Google Scholar 

  151. Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25.

    Article  CAS  PubMed  Google Scholar 

  152. Lukiw WJ. Endogenous signaling complexity in neuropeptides- leucine- and methionine-enkephalin. Cell Mol Neurobiol. 2006;26:1003–10.

    Article  CAS  PubMed  Google Scholar 

  153. Maguire DR, France CP. Impact of efficacy at the mu-opioid receptor on antinociceptive effects of combinations of mu-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther. 2014;351:383–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Mailleux P, Vanderhaeghen JJ. Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience. 1992;48:655–68.

    Article  CAS  PubMed  Google Scholar 

  155. Malan TP, Ossipov MH, Gardell LR, Ibrahim M, Bian D, Lai J, et al. Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats. Pain. 2000;86:185–94.

    Article  CAS  PubMed  Google Scholar 

  156. Maneuf YP, Brotchie JM. Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol. 1997;120:1397–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Mansour A, Fox CA, Burke S, Meng F, Thompson RC, Akil H, et al. Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J Comp Neurol. 1994;350:412–38.

    Article  CAS  PubMed  Google Scholar 

  158. Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA. Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain. Brain Res Mol Brain Res. 1998;55:126–32.

    Article  CAS  PubMed  Google Scholar 

  159. Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA. Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci. 1999;20:287–94.

    Article  CAS  PubMed  Google Scholar 

  160. Manzanares J, Ortiz S, Oliva JM, Perez-Rial S, Palomo T. Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects. Alcohol Alcohol. 2005;40:25–34.

    Article  CAS  PubMed  Google Scholar 

  161. Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem. 2005;95:437–45.

    Article  CAS  PubMed  Google Scholar 

  162. Margolis EB, Hjelmstad GO, Bonci A, Fields HL. Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons. J Neurophysiol. 2005;93:3086–93.

    Article  CAS  PubMed  Google Scholar 

  163. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O. Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci. 2000;12:4038–46.

    Article  CAS  PubMed  Google Scholar 

  164. Mas-Nieto M, Pommier B, Tzavara ET, Caneparo A, Da Nascimento S, Le Fur G, et al. Reduction of opioid dependence by the CB(1) antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction. Br J Pharmacol. 2001;132:1809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mascia MS, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A, et al. Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB(1) receptor knockout mice. Eur J Pharmacol. 1999;383:R1–2.

    Article  CAS  PubMed  Google Scholar 

  166. Massi P, Vaccani A, Romorini S, Parolaro D. Comparative characterization in the rat of the interaction between cannabinoids and opiates for their immunosuppressive and analgesic effects. J Neuroimmunol. 2001;117:116–24.

    Article  CAS  PubMed  Google Scholar 

  167. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–4.

    Article  CAS  PubMed  Google Scholar 

  168. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature. 1996;383:819–23.

    Article  CAS  PubMed  Google Scholar 

  169. McLaughlin JP, Marton-Popovici M, Chavkin C. Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J Neurosci. 2003;23:5674–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Melo I, Drews E, Zimmer A, Bilkei-Gorzo A. Enkephalin knockout male mice are resistant to chronic mild stress. Genes Brain Behav. 2014;13:550–8.

    Article  CAS  PubMed  Google Scholar 

  171. Mendez IA, Ostlund SB, Maidment NT, Murphy NP. Involvement of endogenous enkephalins and beta-endorphin in feeding and diet-induced obesity. Neuropsychopharmacology. 2015;40:2103–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Mendizabal V, Zimmer A, Maldonado R. Involvement of kappa/dynorphin system in WIN 55,212-2 self-administration in mice. Neuropsychopharmacology. 2006;31:1957–66.

    Article  CAS  PubMed  Google Scholar 

  173. Meng F, Xie GX, Thompson RC, Mansour A, Goldstein A, Watson SJ, et al. Cloning and pharmacological characterization of a rat kappa opioid receptor. Proc Natl Acad Sci U S A. 1993;90:9954–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Merighi S, Gessi S, Varani K, Fazzi D, Mirandola P, Borea PA. Cannabinoid CB(2) receptor attenuates morphine-induced inflammatory responses in activated microglial cells. Br J Pharmacol. 2012;166:2371–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Mika J, Popiolek-Barczyk K, Rojewska E, Makuch W, Starowicz K, Przewlocka B. Delta-opioid receptor analgesia is independent of microglial activation in a rat model of neuropathic pain. PLoS One. 2014;9.

    Google Scholar 

  176. Miyashita K, Oyama T, Sakuta T, Tokuda M, Torii M. Anandamide induces matrix metalloproteinase-2 production through cannabinoid-1 receptor and transient receptor potential vanilloid-1 in human dental pulp cells in culture. J Endod. 2012;38:786–90.

    Article  PubMed  Google Scholar 

  177. Muccioli GG. Endocannabinoid biosynthesis and inactivation, from simple to complex. Drug Discov Today. 2010;15:474–83.

    Article  CAS  PubMed  Google Scholar 

  178. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5.

    Article  CAS  PubMed  Google Scholar 

  179. Murataeva N, Straiker A, Mackie K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol. 2014;171:1379–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Navarrete M, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron. 2008;57:883–93.

    Article  CAS  PubMed  Google Scholar 

  181. Navarro M, Carrera MRA, Fratta W, Valverde O, Cossu G, Fattore L, et al. Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci. 2001;21:5344–50.

    CAS  PubMed  Google Scholar 

  182. Navarro M, Chowen J, Rocio ACM, del Arco I, Villanua MA, Martin Y, et al. CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport. 1998;9:3397–402.

    Article  CAS  PubMed  Google Scholar 

  183. Nguyen AT, Marquez P, Hamid A, Kieffer B, Friedman TC, Lutfy K. The rewarding action of acute cocaine is reduced in beta-endorphin deficient but not in mu opioid receptor knockout mice. Eur J Pharmacol. 2012;686:50–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Nishi H, Inagi R, Kato H, Tanemoto M, Kojima I, Son D, et al. Hemoglobin is expressed by mesangial cells and reduces oxidant stress. J Am Soc Nephrol. 2008;19:1500–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Nitsche JF, Schuller AG, King MA, Zengh M, Pasternak GW, Pintar JE. Genetic dissociation of opiate tolerance and physical dependence in delta-opioid receptor-1 and preproenkephalin knock-out mice. J Neurosci. 2002;22:10906–13.

    CAS  PubMed  Google Scholar 

  186. Nock B, Rajpara A, O’Connor LH, Cicero TJ. Autoradiography of [3H]U-69593 binding sites in rat brain: evidence for kappa opioid receptor subtypes. Eur J Pharmacol. 1988;154:27–34.

    Article  CAS  PubMed  Google Scholar 

  187. Nockemann D, Rouault M, Labuz D, Hublitz P, McKnelly K, Reis FC, et al. The K+ channel GIRK2 is both necessary and sufficient for peripheral opioid-mediated analgesia. EMBO Mol Med. 2013;5:1263–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. O’Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. 2007;152:576–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Okada-Ogawa A, Kurose M, Meng ID. Attenuation of cannabinoid-induced inhibition of medullary dorsal horn neurons by a kappa-opioid receptor antagonist. Brain Res. 2010;1359:81–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. OMIM®. OMIiM (Medicine M-NIOG, ed) Baltimore: Johns Hopkins University; n.d..

    Google Scholar 

  191. Pacheco Dda F, Klein A, Perez AC, Pacheco CM, de Francischi JN, Reis GM, et al. Central antinociception induced by mu-opioid receptor agonist morphine, but not delta- or kappa-, is mediated by cannabinoid CB1 receptor. Br J Pharmacol. 2009;158:225–31.

    Article  PubMed  CAS  Google Scholar 

  192. Palazuelos J, Aguado T, Pazos MR, Julien B, Carrasco C, Resel E, et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain. 2009;132:3152–64.

    Article  PubMed  Google Scholar 

  193. Paldyova E, Bereczki E, Santha M, Wenger T, Borsodi A, Benyhe S. Altered gene expression and functional activity of opioid receptors in the cerebellum of CB1 cannabinoid receptor knockout mice after acute treatments with cannabinoids. Acta Biol Hung. 2007;58(Suppl):113–29.

    Article  PubMed  Google Scholar 

  194. Pan B, Wang W, Zhong P, Blankman JL, Cravatt BF, Liu QS. Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice. J Neurosci. 2011;31:13420–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Peng J, Sarkar S, Chang SL. Opioid receptor expression in human brain and peripheral tissues using absolute quantitative real-time RT-PCR. Drug Alcohol Depend. 2012;124:223–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Pickel VM, Chan J, Kash TL, Rodriguez JJ, Mackie K. Compartment-specific localization of cannabinoid 1 (CB1) and mu-opioid receptors in rat nucleus accumbens. Neuroscience. 2004;127:101–12.

    Article  CAS  PubMed  Google Scholar 

  197. Pleuvry BJ. Opioid receptors and their ligands – natural and unnatural. Br J Anaesth. 1991;66:370–80.

    Article  CAS  PubMed  Google Scholar 

  198. Ponterio G, Tassone A, Sciamanna G, Riahi E, Vanni V, Bonsi P, et al. Powerful inhibitory action of mu opioid receptors (MOR) on cholinergic interneuron excitability in the dorsal striatum. Neuropharmacology. 2013;75:78–85.

    Article  CAS  PubMed  Google Scholar 

  199. Powers MS, Breit KR, Chester JA. Genetic versus pharmacological assessment of the role of cannabinoid type 2 receptors in alcohol reward-related behaviors. Alcohol Clin Exp Res. 2015;39:2438–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Pritchard LE, White A. Neuropeptide processing and its impact on melanocortin pathways. Endocrinology. 2007;148:4201–7.

    Article  CAS  PubMed  Google Scholar 

  201. Qiu C, Sora I, Ren K, Uhl G, Dubner R. Enhanced delta-opioid receptor-mediated antinociception in mu-opioid receptor-deficient mice. Eur J Pharmacol. 2000;387:163–9.

    Article  CAS  PubMed  Google Scholar 

  202. Qu CL, Huo FQ, Huang FS, Tang JS. Activation of mu-opioid receptors in the ventrolateral orbital cortex inhibits the GABAergic miniature inhibitory postsynaptic currents in rats. Neurosci Lett. 2015;592:64–9.

    Article  CAS  PubMed  Google Scholar 

  203. Reed B, Bidlack JM, Chait BT, Kreek MJ. Extracellular biotransformation of beta-endorphin in rat striatum and cerebrospinal fluid. J Neuroendocrinol. 2008;20:606–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Reibaud M, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A. Enhancement of memory in cannabinoid CB1 receptor knock-out mice. Eur J Pharmacol. 1999;379:R1–2.

    Article  CAS  PubMed  Google Scholar 

  205. Richter F, Meurers BH, Zhu CN, Medvedeva VP, Chesselet MF. Neurons express hemoglobin alpha- and beta-chains in rat and human brains. J Comp Neurol. 2009;515:538–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Rioli V, Gozzo FC, Heimann AS, Linardi A, Krieger JE, Shida CS, et al. Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme. J Biol Chem. 2003;278:8547–55.

    Article  CAS  PubMed  Google Scholar 

  207. Rios C, Gomes I, Devi LA. mu opioid and CB1 cannabinoid receptor interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol. 2006;148:387–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Rios CD, Jordan BA, Gomes I, Devi LA. G-protein-coupled receptor dimerization: modulation of receptor function. Pharmacol Ther. 2001;92:71–87.

    Article  CAS  PubMed  Google Scholar 

  209. Roberts AJ, Gold LH, Polis I, McDonald JS, Filliol D, Kieffer BL, et al. Increased ethanol self-administration in delta-opioid receptor knockout mice. Alcohol Clin Exp Res. 2001;25:1249–56.

    CAS  PubMed  Google Scholar 

  210. Robledo P, Berrendero F, Ozaita A, Maldonado R. Advances in the field of cannabinoid-opioid cross-talk. Addict Biol. 2008;13:213–24.

    Article  CAS  PubMed  Google Scholar 

  211. Rodrigues LCM, Gobira PH, de Oliveira AC, Pelicao R, Teixeira AL, Moreira FA, et al. Neuroinflammation as a possible link between cannabinoids and addiction. Acta Neuropsychiatrica. 2014;26:334–46.

    Article  PubMed  Google Scholar 

  212. Rodriguez JJ, Mackie K, Pickel VM. Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci. 2001;21:823–33.

    CAS  PubMed  Google Scholar 

  213. Roques BP, Fournie-Zaluski MC, Wurm M. Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nat Rev Drug Discov. 2012;11:292–310.

    Article  CAS  PubMed  Google Scholar 

  214. Rozenfeld R, Bushlin I, Gomes I, Tzavaras N, Gupta A, Neves S, et al. Receptor heteromerization expands the repertoire of cannabinoid signaling in rodent neurons. PLoS One. 2012;7:e29239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Rubino T, Massi P, Vigano D, Fuzio D, Parolaro D. Long-term treatment with SR141716A, the CB1 receptor antagonist, influences morphine withdrawal syndrome. Life Sci. 2000;66:2213–9.

    Article  CAS  PubMed  Google Scholar 

  216. Rubino T, Tizzoni L, Vigano D, Massi P, Parolaro D. Modulation of rat brain cannabinoid receptors after chronic morphine treatment. Neuroreport. 1997;8:3219–23.

    Article  CAS  PubMed  Google Scholar 

  217. Rubinstein M, Mogil JS, Japon M, Chan EC, Allen RG, Low MJ. Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis. Proc Natl Acad Sci U S A. 1996;93:3995–4000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25.

    Article  CAS  PubMed  Google Scholar 

  219. Salio C, Fischer J, Franzoni MF, Mackie K, Kaneko T, Conrath M. CB1-cannabinoid and mu-opioid receptor co-localization on postsynaptic target in the rat dorsal horn. Neuroreport. 2001;12:3689–92.

    Article  CAS  PubMed  Google Scholar 

  220. Scavone JL, Mackie K, Van Bockstaele EJ. Characterization of cannabinoid-1 receptors in the locus coeruleus: relationship with mu-opioid receptors. Brain Res. 2010;1312:18–31.

    Article  CAS  PubMed  Google Scholar 

  221. Scavone JL, Sterling RC, Van Bockstaele EJ. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience. 2013;248:637–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F, O’Donnell D, et al. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell. 2009;137:1148–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Shapira M, Gafni M, Sarne Y. Independence of, and interactions between, cannabinoid and opioid signal transduction pathways in N18TG2 cells. Brain Res. 1998;806:26–35.

    Article  CAS  PubMed  Google Scholar 

  224. Shin EJ, Jang CG, Bing G, Park DH, Oh CH, Koo KH, et al. Prodynorphin gene deficiency potentiates nalbuphine-induced behavioral sensitization and withdrawal syndrome in mice. Drug Alcohol Depend. 2009;104:175–84.

    Article  CAS  PubMed  Google Scholar 

  225. Sierra S, Luquin N, Rico AJ, Gomez-Bautista V, Roda E, Dopeso-Reyes IG, et al. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct Funct. 2015;220:2721–38.

    Article  CAS  PubMed  Google Scholar 

  226. Simkins TJ, Janis KL, McClure AK, Behrouz B, Pappas SS, Lehner A, et al. Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice. J Neuroimmune Pharmacol. 2012;7:533–8.

    Article  PubMed  PubMed Central  Google Scholar 

  227. Singh ME, Verty AN, McGregor IS, Mallet PE. A cannabinoid receptor antagonist attenuates conditioned place preference but not behavioural sensitization to morphine. Brain Res. 2004;1026:244–53.

    Article  CAS  PubMed  Google Scholar 

  228. Smith MA, Hall R, Fisher K, Haake SM, Khalil F, Schabath MB, Vuaroqueaux V, Fiebig HH, Altiok S, Chen YA, Haura EB. Annotation of human cancers with EGFR signaling-associated protein complexes using proximity ligation assays. Sci Signal. 2015;8:ra4.

    Google Scholar 

  229. Spahn V, Fischer O, Endres-Becker J, Schafer M, Stein C, Zollner C. Opioid withdrawal increases transient receptor potential vanilloid 1 activity in a protein kinase A-dependent manner. Pain. 2013;154:598–608.

    Article  CAS  PubMed  Google Scholar 

  230. Sprouse-Blum AS, Smith G, Sugai D, Parsa FD. Understanding endorphins and their importance in pain management. Hawaii Med J. 2010;69:70–1.

    PubMed  PubMed Central  Google Scholar 

  231. Stein C. Opioid receptors. Annu Rev Med. 2016;67:433–51.

    Article  CAS  PubMed  Google Scholar 

  232. Subbanna S, Shivakumar M, Psychoyos D, Xie S, Basavarajappa BS. Anandamide-CB1 receptor signaling contributes to postnatal ethanol-induced neonatal neurodegeneration, adult synaptic, and memory deficits. J Neurosci. 2013;33:6350–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Sugiura T, Kondo S, Kishimoto S, Miyashita T, Nakane S, Kodaka T, et al. Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor – comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem. 2000;275:605–12.

    Article  CAS  PubMed  Google Scholar 

  234. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89–97.

    Article  CAS  PubMed  Google Scholar 

  235. Tanaka K, Shimizu T, Yanagita T, Nemoto T, Nakamura K, Taniuchi K, et al. Brain RVD-haemopressin, a haemoglobin-derived peptide, inhibits bombesin-induced central activation of adrenomedullary outflow in the rat. Br J Pharmacol. 2014;171:202–13.

    Article  CAS  PubMed  Google Scholar 

  236. Tejeda HA, Shippenberg TS, Henriksson R. The dynorphin/kappa-opioid receptor system and its role in psychiatric disorders. Cell Mol Life Sci. 2012;69:857–96.

    Article  CAS  PubMed  Google Scholar 

  237. Thibault K, Carrel D, Bonnard D, Gallatz K, Simon A, Biard M, et al. Activation-dependent subcellular distribution patterns of CB1 cannabinoid receptors in the rat forebrain. Cereb Cortex. 2013;23:2581–91.

    Article  PubMed  Google Scholar 

  238. Thorat SN, Bhargava HN. Evidence for a bidirectional cross-tolerance between morphine and delta 9-tetrahydrocannabinol in mice. Eur J Pharmacol. 1994;260:5–13.

    Article  CAS  PubMed  Google Scholar 

  239. Trigo JM, Martin-Garcia E, Berrendero F, Robledo P, Maldonado R. The endogenous opioid system: a common substrate in drug addiction. Drug Alcohol Depend. 2010;108:183–94.

    Article  CAS  PubMed  Google Scholar 

  240. Valverde O, Ledent C, Beslot F, Parmentier M, Roques BP. Reduction of stress-induced analgesia but not of exogenous opioid effects in mice lacking CB1 receptors. Eur J Neurosci. 2000a;12:533–9.

    Article  CAS  PubMed  Google Scholar 

  241. Valverde O, Maldonado R, Valjent E, Zimmer AM, Zimmer A. Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice. J Neurosci. 2000b;20:9284–9.

    CAS  PubMed  Google Scholar 

  242. Valverde O, Noble F, Beslot F, Dauge V, Fournie-Zaluski MC, Roques BP. Delta9-tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect. Eur J Neurosci. 2001;13:1816–24.

    Article  CAS  PubMed  Google Scholar 

  243. Van Bockstaele EJ, Colago EE, Moriwaki A, Uhl GR. Mu-opioid receptor is located on the plasma membrane of dendrites that receive asymmetric synapses from axon terminals containing leucine-enkephalin in the rat nucleus locus coeruleus. J Comp Neurol. 1996;376:65–74.

    Article  PubMed  Google Scholar 

  244. Varvel SA, Cravatt BF, Engram AE, Lichtman AH. Fatty acid amide hydrolase (–/–) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task. J Pharmacol Exp Ther. 2006;317:251–7.

    Article  CAS  PubMed  Google Scholar 

  245. Vaysse PJJ, Gardner EL, Zukin RS. Modulation of rat-brain opioid receptors by cannabinoids. J Pharmacol Exp Ther. 1987;241:534–9.

    CAS  PubMed  Google Scholar 

  246. Vela G, Ruiz-Gayo M, Fuentes JA. Anandamide decreases naloxone-precipitated withdrawal signs in mice chronically treated with morphine. Neuropharmacology. 1995;34:665–8.

    Article  CAS  PubMed  Google Scholar 

  247. Viader A, Blankman JL, Zhong P, Liu XJ, Schlosburg JE, Joslyn CM, et al. Metabolic Interplay between astrocytes and neurons regulates endocannabinoid action. Cell Rep. 2015;12:798–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Vigano D, Rubino T, Vaccani A, Bianchessi S, Marmorato P, Castiglioni C, et al. Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems. Psychopharmacology. 2005;182:527–36.

    Article  CAS  PubMed  Google Scholar 

  249. Vigano D, Valenti M, Cascio MG, Di Marzo V, Parolaro D, Rubino T. Changes in endocannabinoid levels in a rat model of behavioural sensitization to morphine. Eur J Neurosci. 2004;20:1849–57.

    Article  PubMed  Google Scholar 

  250. Vincent SR, Hokfelt T, Christensson I, Terenius L. Dynorphin-immunoreactive neurons in the central nervous system of the rat. Neurosci Lett. 1982;33:185–90.

    Article  CAS  PubMed  Google Scholar 

  251. Wahlert A, Funkelstein L, Fitzsimmons B, Yaksh T, Hook V. Spinal astrocytes produce and secrete dynorphin neuropeptides. Neuropeptides. 2013;47:109–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Watson SJ, Akil H, Ghazarossian VE, Goldstein A. Dynorphin immunocytochemical localization in brain and peripheral nervous system: preliminary studies. Proc Natl Acad Sci U S A. 1981;78:1260–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Welch SP. Interaction of the cannabinoid and opioid systems in the modulation of nociception. Int Rev Psychiatry. 2009;21:143–51.

    Article  PubMed  Google Scholar 

  254. Welch SP, Stevens DL. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther. 1992;262:10–8.

    CAS  PubMed  Google Scholar 

  255. Wise LE, Shelton CC, Cravatt BF, Martin BR, Lichtman AH. Assessment of anandamide’s pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CB1 receptors. Eur J Pharmacol. 2007;557:44–8.

    Article  CAS  PubMed  Google Scholar 

  256. Won JS, Suh HW. The comparative analysis of proenkephalin mRNA expression induced by cholera toxin and pertussis toxin in primary cultured rat cortical astrocytes. Brain Res Mol Brain Res. 2001;88:83–93.

    Article  CAS  PubMed  Google Scholar 

  257. Woodward DF, Liang Y, Krauss AH. Prostamides (prostaglandin-ethanolamides) and their pharmacology. Br J Pharmacol. 2008;153:410–9.

    Article  CAS  PubMed  Google Scholar 

  258. Wride MA, Mansergh FC, Adams S, Everitt R, Minnema SE, Rancourt DE, et al. Expression profiling and gene discovery in the mouse lens. Mol Vis. 2003;9:360–96.

    CAS  PubMed  Google Scholar 

  259. Yasuda K, Raynor K, Kong H, Breder CD, Takeda J, Reisine T, et al. Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. Proc Natl Acad Sci U S A. 1993;90:6736–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Yoo JH, Yang EM, Lee SY, Loh HH, Ho IK, Jang CG. Differential effects of morphine and cocaine on locomotor activity and sensitization in mu-opioid receptor knockout mice. Neurosci Lett. 2003;344:37–40.

    Article  CAS  PubMed  Google Scholar 

  261. Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A. 2014;111:E5007–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O’Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003;17:2750–4.

    Article  PubMed  Google Scholar 

  263. Zhang M, Wang K, Ma M, Tian S, Wei N, Wang G. Low-dose cannabinoid type 2 receptor agonist attenuates tolerance to repeated morphine administration via regulating mu-opioid receptor expression in walker 256 tumor-bearing rats. Anesth Analg. 2016;122:1031–7.

    Article  CAS  PubMed  Google Scholar 

  264. Zhang X, Bao L, Arvidsson U, Elde R, Hokfelt T. 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. 1998;82:1225–42.

    Article  CAS  PubMed  Google Scholar 

  265. Zheng T, Zhang T, Zhang R, Wang ZL, Han ZL, Li N, Li XH, Zhang MN, Xu B, Yang XL, Fang Q, Wang R. Pharmacological characterization of rat VD-hemopressin(alpha), an alpha-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice. Neuropeptides. 2016.

    Google Scholar 

  266. Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP, et al. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron. 1999;24:243–52.

    Article  CAS  PubMed  Google Scholar 

  267. Zimmer A, Valjent E, Konig M, Zimmer AM, Robledo P, Hahn H, et al. Absence of delta -9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J Neurosci. 2001;21:9499–505.

    CAS  PubMed  Google Scholar 

  268. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funding: This work was supported by NIH awards DA008863 and NS026880 to L.A.D. S.S. is supported by a grant from Alfonso Martin Escudero Foundation.

Competing Interests

The authors declare that they have no competing interests.

Figures 7.1 and 7.2 were composed using the Motifolio.com PPT Drawing Toolkits Biology Bundle. We thank Jill K Gregory, MFA, CMI for designing illustrations 3 and 4.

Author information

Authors and Affiliations

  1. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, 19-84 Annenberg Building, 1468 Madison Avenue, New York, NY, 10029, USA

    Salvador Sierra M.D., Ph.D., Ivone Gomes Ph.D. & Lakshmi A. Devi Ph.D.

Authors
  1. Salvador Sierra M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ivone Gomes Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lakshmi A. Devi Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lakshmi A. Devi Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York, USA

    Katharine Herrick-Davis

  2. Centre for Translational Pharmacology, Institute of Molecular Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom

    Graeme Milligan

  3. Department of Physiology and Biochemistry, University of Malta, Msida, Malta

    Giuseppe Di Giovanni

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Sierra, S., Gomes, I., Devi, L.A. (2017). Class A GPCRs: Cannabinoid and Opioid Receptor Heteromers. In: Herrick-Davis, K., Milligan, G., Di Giovanni, G. (eds) G-Protein-Coupled Receptor Dimers. The Receptors, vol 33. Humana Press, Cham. https://doi.org/10.1007/978-3-319-60174-8_7

Download citation

Publish with us

Policies and ethics

Search

Navigation