Opiate tolerance and dependence: receptors, G-proteins, and antiopiates

Opiate tolerance and dependence: receptors, G-proteins, and antiopiates Despite the existence of a large body of information on the subject, the mechanisms of opiate tolerance and dependence are not yet fully understood. Although the traditional mechanisms of receptor down-regulation and desensitization seem to play a role, they cannot entirely explain the phenomena of tolerance and dependence. Therefore, other mechanisms, such as the presence of antiopiate systems and the coupling of opiate receptors to alternative G-proteins, should be considered. A further complication of studies of opiate tolerance and dependence is the multiplicity of endogenous opiate receptors and peptides. This review will focus on the endogenous opioid system—peptides, receptors, and coupling of receptors to intracellular signaling via G-proteins—in the context of their roles in tolerance and dependence. Opioid peptides include the recently discovered endomorphins and those encoded by three known genes—pro-opiomelanocortin, pro-enkephalin, and pro-dynorphin. They bind to three types of receptors—mu, delta, and kappa. Each of the receptor types is further divided into multiple subtypes. These receptors are widely known to be coupled to G-proteins of the G i and G o subtypes, but an increasing body of results suggests coupling to other G-proteins, such as G s . The coupling of opiate receptors to G s , in particular, has implications for tolerance and dependence. Alterations at the receptor and transduction level have been the focus of many studies of opiate tolerance and dependence. In these studies, both receptor down-regulation and desensitization have been demonstrated in vivo and in vitro. Receptor down-regulation has been more easily observed in vitro, especially in response to morphine, a phenomenon which suggests that some factor which is missing in vitro prevents receptors from down-regulating in vivo and may play a critical role in tolerance and dependence. We suggest that antiopiate peptides may operate in vivo in this capacity, and we outline the evidence for the antiopiate properties of three peptides: neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1. In addition, we provide new results suggesting that Tyr-W-MIF-1 may act as an antiopiate at the cellular level by inhibiting basal G-protein activation, in contrast to the activation of G-proteins by opiate agonists. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Peptides Elsevier

Opiate tolerance and dependence: receptors, G-proteins, and antiopiates

Peptides, Volume 19 (9) – Jan 1, 1998

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Publisher
Elsevier
Copyright
Copyright © 1998 Elsevier Science Inc.
ISSN
0196-9781
D.O.I.
10.1016/S0196-9781(98)00126-0
Publisher site
See Article on Publisher Site

Abstract

Despite the existence of a large body of information on the subject, the mechanisms of opiate tolerance and dependence are not yet fully understood. Although the traditional mechanisms of receptor down-regulation and desensitization seem to play a role, they cannot entirely explain the phenomena of tolerance and dependence. Therefore, other mechanisms, such as the presence of antiopiate systems and the coupling of opiate receptors to alternative G-proteins, should be considered. A further complication of studies of opiate tolerance and dependence is the multiplicity of endogenous opiate receptors and peptides. This review will focus on the endogenous opioid system—peptides, receptors, and coupling of receptors to intracellular signaling via G-proteins—in the context of their roles in tolerance and dependence. Opioid peptides include the recently discovered endomorphins and those encoded by three known genes—pro-opiomelanocortin, pro-enkephalin, and pro-dynorphin. They bind to three types of receptors—mu, delta, and kappa. Each of the receptor types is further divided into multiple subtypes. These receptors are widely known to be coupled to G-proteins of the G i and G o subtypes, but an increasing body of results suggests coupling to other G-proteins, such as G s . The coupling of opiate receptors to G s , in particular, has implications for tolerance and dependence. Alterations at the receptor and transduction level have been the focus of many studies of opiate tolerance and dependence. In these studies, both receptor down-regulation and desensitization have been demonstrated in vivo and in vitro. Receptor down-regulation has been more easily observed in vitro, especially in response to morphine, a phenomenon which suggests that some factor which is missing in vitro prevents receptors from down-regulating in vivo and may play a critical role in tolerance and dependence. We suggest that antiopiate peptides may operate in vivo in this capacity, and we outline the evidence for the antiopiate properties of three peptides: neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1. In addition, we provide new results suggesting that Tyr-W-MIF-1 may act as an antiopiate at the cellular level by inhibiting basal G-protein activation, in contrast to the activation of G-proteins by opiate agonists.

Journal

PeptidesElsevier

Published: Jan 1, 1998

References

  • Neuropeptide FF in the VTA blocks the analgesic effects of both intra-VTA morphine and exposure to stress
    Altier, N; Stewart, J
  • Opioid inhibition of adenylate cyclase in the striatum and vas deferens of the rat
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  • Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors
    Childers, S.R; Snyder, S.H
  • The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion
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    Harrison, L.M; Kastin, A.J; Zadina, J.E
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    Kest, B; Jenab, S; Brodsky, M; Elliot, K; Inturrisi, C.E
  • Demonstration and characterization of opiate inhibition of the striatal adenylate cyclase
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    Yoburn, B.C; Billings, B; Duttaroy, A

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