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Opiate tolerance and dependence: receptors, G-proteins, and antiopiates
L M Harrison1, A J Kastin, J E Zadina
1Tulane University School of Medicine and Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
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 Gi and Go subtypes, but an increasing body of results suggests coupling to other G-proteins, such as Gs. The coupling of opiate receptors to Gs, 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.
Insights
Opiate tolerance and dependence mechanisms are complex, involving more than just receptor changes. Antiopiate systems and novel G-protein couplings may explain these phenomena, offering new research avenues.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opiate tolerance and dependence mechanisms remain incompletely understood despite extensive research.
- Traditional models involving receptor down-regulation and desensitization do not fully account for these phenomena.
- The complexity is further increased by the diversity of endogenous opioid receptors and peptides.
Purpose of the Study:
- To review the endogenous opioid system, including peptides, receptors, and G-protein signaling, in the context of tolerance and dependence.
- To explore alternative mechanisms, such as antiopiate systems and novel G-protein couplings, contributing to opiate tolerance and dependence.
- To present new findings on the antiopiate activity of Tyr-W-MIF-1 at the cellular level.
Main Methods:
- Review of existing literature on endogenous opioid peptides (endomorphins, pro-opiomelanocortin, pro-enkephalin, pro-dynorphin) and their receptors (mu, delta, kappa).
- Analysis of G-protein coupling of opiate receptors, including Gi, Go, and potentially Gs subtypes.
- In vitro and in vivo studies examining receptor down-regulation and desensitization.
- Investigation of the antiopiate properties of neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1.
Main Results:
- Receptor down-regulation is more readily observed in vitro than in vivo, suggesting a missing in vivo regulatory factor.
- Evidence supports the role of antiopiate peptides, such as neuropeptide FF, orphanin FQ/nociceptin, and Tyr-W-MIF-1, in modulating opiate effects.
- New data indicate Tyr-W-MIF-1 inhibits basal G-protein activation, acting as an antiopiate at the cellular level.
Conclusions:
- Antiopiate systems likely play a crucial role in vivo, potentially explaining the discrepancy in receptor down-regulation between in vitro and in vivo studies.
- The coupling of opiate receptors to G-proteins beyond Gi/Go, particularly Gs, may contribute significantly to tolerance and dependence.
- Further research into antiopiate peptides and alternative G-protein signaling pathways is warranted for a comprehensive understanding of opiate tolerance and dependence.