Elsevier

Peptides

Volume 19, Issue 9, 1998, Pages 1603-1630
Peptides

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

https://doi.org/10.1016/S0196-9781(98)00126-0Get rights and content

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.

Section snippets

The discovery of opiate binding sites

The stereospecificity of narcotic analgesics led to the hypothesis that they act at specific receptors in the central nervous system (CNS) 77, 202. However, early attempts to demonstrate the “opiate receptor” biochemically were unsuccessful. One early paper described uptake of [3H]dihydromorphine into synaptosomes, but this did not necessarily represent specific binding (96). That same year, Goldstein et al. (77) proposed a method for determining specific binding by use of radioactive and

Opioid peptides

The initial discovery of opiate binding sites in the brain led to the speculation that there must be an endogenous ligand which acts at these sites. A search for this endogenous morphine-like ligand ensued. Two different approaches were used to screen brain extracts for opiate activity: (a) displacement of opiate alkaloids in binding assays and (b) bioassays consisting of guinea pig myenteric plexus or mouse vas deferens preparations. For either assay, reversibility of the response by naloxone

Opiate receptor-effector coupling

Opiate receptors belong to the superfamily of G-protein-coupled receptors. Opiate ligands bind to a membrane receptor, which transduces this signal into the cell via activation of a guanosine triphosphate (GTP)-binding protein and effectors such as AC and ion channels. The coupling of receptor to G-protein is a possible locus of specificity of action for different receptor subtypes and of regulation during chronic ligand exposure.

The cycle of G-protein activation and deactivation was initially

Opiate receptor localization

The cloning of opiate receptors has allowed for the use of molecular biologic techniques to localize the receptors in the CNS. Such techniques extend the anatomic detail with which the receptors can be studied beyond that revealed by autoradiographic studies of binding sites, the method of choice before the cloning of the receptor. For example, in situ hybridization (ISH) and immunocytochemistry (ICC) offer better resolution than autoradiography, enabling examination of single cells. Also, the

Opiate tolerance

One of the major limitations of the clinical use of opiates is their tendency to induce tolerance and dependence. As such, the possible mechanisms for these phenomena have been intensively studied in an attempt to understand and prevent them. Early studies focused on the obvious mechanisms of receptor down-regulation and desensitization (TABLE 1, TABLE 2 , ref. 247, and below). Because these mechanisms cannot fully explain the phenomena, more recent studies have investigated a possible role

Summary and conclusions

The studies outlined above indicate that a wealth of information exists about opiate receptors and peptides. Also, there has been extensive investigation of the effects of chronic opiates. However, a clear picture of the correlation between biochemical effects and behavioral tolerance has yet to emerge. A simple blunting of the response to opiates does not seem to be the sole mechanism of tolerance. Rather, the induction of a compensatory response, in addition to a decrease in response to

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    Present Address: Department of Physiology and Pharmacology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland OR 97201.

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