Neuropeptides 5: 117-120, 1984 ACUTE SYSTEMIC ADMINISTRATION OF MORPHINE SELECTIVELY INCREASES MU OPIOID RECEPTOR BINDING IN THE RAT BRAIN James W. Lewis, Michael E. Lewis, Deborah J. Loomus, and Huda Akil. Mental Health Research Institute and Department of Psychiatry, University of Michigan, Ann Arbor, MI, 48109, U.S.A. (reprint requests to JWL). Opioid receptor binding, including the mu, delta, and kappa receptor subtypes, was compared in morphine-injected and control rats. Brain tissues were homogenized and centrifuged either one or two times prior to receptor binding assay. In brain membranes from morphine-injected rats centrifuged once, there was a decrease in mu, but not delta or kappa, binding compared to controls, perhaps indicating occupation of these sites by morphine. By contrast, homogenates from morphine-injected rats centrifuged twice manifested an increase in mu, but not delta or kappa, binding sites. These results suggest that pharmacological stimulation of central opioid receptors with morphine causes a rapid, selective increase in the number of available mu binding sites. INTRODUCTION It is now widely held that multiple subtypes of opioid receptors mediate the various physiological and behavioral effects of endogenous and exogenous opioids (for recent reviews see 1,210 A common theme in the description of multiple receptor subtypes is the attempt to ascribe particular functions to specific receptors (e-g. 3,4). Converging lines of evidence, from a variety of in vitro bioassays, receptor binding assays, and -- in vivo pharmacological studies, points to an important role for the mu -- receptor in mediation of analgesia (e.g. 5-7). There are, however, reports that kappa and delta selective agents can also induce analgesia depending upon variables such as the route of administration and the type of pain inhibited (e.g. 7). In the present study, we have shown that morphine, the prototypic opiate analgesic and mu receptor agonist, selectively occupies mu opioid receptors in vivo following administration of pharmacologically relevant doses. Interestingly, following systemic administration of analgesic doses of morphine, a pronounced increase in the number of mu, but not delta or kappa, binding sites was observed. ME'IHODS Subjects were male Sprague-Dawley rats (200-25Og; Charles River Laboratories, Worcester,MA). Rats were injected subcutaneously with either morphine sulfate (5 mg/kg) or 0.9% saline 20 min prior to sacrifice by decapitation. Brains (minus cerebellum) were rapidly removed, placed in ice cold Tris buffer (50 mM, pB 7.4), and homogenized with a Brinkmsn Polytron. 117