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The Molecular Basis of Opioid Receptor Function

Molecular Pathophysiology Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health Bethesda, Maryland 20892

Correspondence: Address requests for reprints to: William F. Simonds, M.D., Molecular Pathophysiology Section, Metabolic Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, Building 10, Room 9C-101, National Institutes of Health, Bethesda, Maryland 20892.

Abstract

OPIOID receptors in the membranes of nerve cells are key elements in a regulatory system which allows opioids outside the cell to modify intracellular events and alter cell function. These receptors mediate the diverse effects of endogenous opioid peptides and opiate drugs. Activation of opioid receptors characteristically depresses neuronal firing and inhibits neurotransmitter and hormone release. Opioids inhibit central nervous system pathways from spinal cord to cerebral cortex, block hypothalamic and neurohypophyseal hormone release, and depress autonomic effector systems in the periphery. The pharmacological spectrum of opioid action comprises prominent analgesic, antiperistaltic, antitussive, and mood-altering effects, but opioids also cause hypotension and respiratory depression. While the last 15 yr has seen a volcanic growth in our understanding of this ancient class of drugs, we still lack the knowledge to harness the unique potential of opioids free of their addictive and often lethal side effects. More detailed knowledge of the molecular basis of opioid receptor multiplicity and function will allow the rational design of new opioids which may possess the requisite pharmacological selectivity to fully realize the opioids' clinical promise. This review will examine recent advances in our understanding of the molecular basis of opioid receptor structure and function. Particular emphasis will be given to biochemical and electrophysiological evidence for opioid receptor multiplicity and interaction with guanine nucleotide regulatory proteins. Only the acute effects of opioids will be considered. Comparisons to other hormonal systems will be drawn where structural or functional analogies appear likely. While this review is by no means comprehensive, the reader is directed to other recent reviews on the biochemical and pharmacological classification of opioid receptors (1–3), their affinity labeling (4), distribution (5, 6), and endocrinology (7, 8). Reviews of the endogenous opioid ligands and their precursors have appeared elsewhere (9,10). According to the convention of Hughes and Kosterlitz (11), "opiate" will refer only to alkaloid and related synthetic and semisynthetic drugs of this class, while the more encompassing term "opioid" will also include peptides which interact at the same receptors.

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