G protein-coupled opioid receptors

Peterson PK, Sharp BM, Gekker G, Jackson B, Balfour HH Jr (1991) Opiates, human peripheral blood mononuclear cells, and HIV. Adv Exp Med Biol 288 171-178 Peterson PK, Gekker G, Schut R, Hu S, Balfour HH Jr, Chao CC (1993) Enhancement of HlV-1 replication by opiates and cocaine the cytokine connection. Adv Exp Med Biol 335 181-188 Peterson PK, Gekker G, Hu S, Sheng WS, Molitor TW, Chao CC (1995) Morphine stimulates phagocytosis of Mycobacterium tuberculosis by human microglial cells involvement of a G protein-coupled opiate receptor. Adv Neuroimmunol 5 299-309 Peterson PK, Molitor TW, Chao CC (1998) The opioid-cytokine connection. J Neuroimmunol 83 63-69... 

Opioid receptors are seven transmembrane G-protein coupled inhibitory receptors (Bockaert, 1991), although an association to excitatory G-proteins has also been reported (Varga et al., 2003). Intracellular signaling by these receptors involves the inhibition of adenylate cyclase with a subsequent decrease in cAMP levels (Surprenant et al., 1990), regulation of intracellular calcium levels, modulation of potassium channels (Williams et al., 2001), and control of MAP-kinase and ERK activity (Eitan et al., 2003 Varga et al., 2003). 

There is also high sequence homology with opioid receptors in the intracellular loops, consistent with ORLl receptors coupling to the same G-proteins as opioid receptors. Splice variants of the ORLl gene have been reported (see Refs. 87,90 for reviews),and the results of some pharmacological studies have suggested receptor heterogeneity (see Ref 87), but the existence of subtypes of the ORLl receptor has not been firmly established. 

Receptor interactions clonidine interacts at the G protein-coupled alpha receptors with a greater affinity for the alpha-2 receptors. The activation of the alpha-2 receptors results in decreased cAMP, K efflux as well as Ca entry into the nerve terminals. Activation of receptors in the sympathetic nerve endings and in the noradrenergic neurons in the CNS inhibits release of norepinephrine and may release acetylcholine. The locus coeruleus is an important modulator of alertness and may be the major site for the hypnotic effects of clonidine. Additionally, the G protein pathway has a similar transduction pathway to the opioids, explaining some of the cross-tolerance and synergy between the two classes of drugs. 

Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (p, 8, k) have been cloned. Additional subtypes (e.g., pl3 p2, 81 82), possibly resulting from gene polymorphisms, splice variants or alternative processing have been proposed. Opioid receptors are localized and can be activated... 

Opioids G-protein coupled p-, 5-, k-receptors l cAMP l Ca2+ currents t K+ currents l Excitability of peripheral and central neurons l Release of excitatory neurotransmitters p, 5 sedation, nausea, euphoria/re-ward, respiratory depression, constipation k dysphoria/aversion, diuresis, sedation... 

Similar to endogenous opioids, opiates like morphine and other synthetic opioids activate G-protein-coupled receptors which couple to G-proteins of the Gi/0 family. 

Woody GE, Luborsky L, McLellan AT, et al Psychotherapy for opiate addicts does it help Arch Gen Psychiatry 40 639—645, 1983 Woody GE, McLellan AT, Luborsky L, et al Severity of psychiatric symptoms as a predictor of benefits from psychotherapy the Veterans Administration-Penn study. Am J Psychiatry 141 1172—1177, 1984 Woody GE, McLellan AT, Luborsky L, et al Twelve-month follow-up of psychotherapy for opiate dependence. Am J Psychiatry 144 590-596, 1987 Yabaluri N, Medzihradsky F Down-regulation of mu-opioid receptor by full but not partial agonists is independent of G protein coupling. Mol Pharmacol 52 896-902, 1997... 

Wetzel MA, Steele AD, Eisenstein TK, Adler MW, Henderson EE, Rogers TJ (2000) Mu-opioid induction of monocyte chemoattractant protein-1, RANTES, and IFN-gamma-inducible protein-10 expression in human peripheral blood mononuclear cells. J Immunol 165 6519-6524 Widmer U, Manogue KR, Cerami A, Sherry B (1993) Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines. J Immunol 150 4996-5012 Ye RD (2001) Regulation of nuclear factor kappaB activation by G-protein-coupled receptors. [Review] [136 refs]. J Leukoc Biol 70 839-848... 

Bohn LM, Dykstra LA, Lefkowitz RJ, Caron MG, Barak LS (2004) Relative opioid efficacy is determined by the complements of the G protein-coupled receptor desensitization machinery. Mol Pharmacol 66 106-112... 

Rogers TJ, Peterson PK (2003) Opioid G protein-coupled receptors signals at the crossroads of inflammation. Trends Immunol 24 116-121... 

Pei G, Kieffer BL, Lefkowitz RJ et al. Agonist-dependent phosphorylation of the mouse K-opioid receptor involvement of G protein-coupled receptor kinases but not protein kinase C. Mol Pharmacol 1995 48 173-177. 

Wang HL. A cluster of Ser/Thr residues at the C-terminus of mu-opioid receptor is required for G protein-coupled receptor kinase 2-mediated desensitization. Neuropharmacology 2000 353—363. 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

Filizola, M. and Weinstein, H. (2002) Structural models for dimerization of G protein coupled receptors the opioid receptor homodimers. Biopolymers (Peptide Sci.) 66, 317-325. 

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