Selective changes in mu opioid receptor properties induced by chronic morphine exposure.

Abstract

Chronic infusion of morphine to guinea pigs produced selective changes in Im agonist binding properties in cerebrocortical membrane preparations. Employing the pselective opioid agonist MePhe4, in direct binding studies and in competition of labeled antagonist binding, we found that the major changes were a decrease in the number of sites with high affnity for agonist, a small reduction in total receptor number, and a loss in the ability of guanosine 5'-[y-thio]triphosphate to regulate binding. A fraction of high-affinity p receptors appeared to retain their high affinity for agonist and their sensitivity to guanine nucleotide analogue after the induction of morphine tolerance, possibly because the morphine concentrations achieved in brain were insufficient to uncouple all p receptors from associated guanine nucleotide-binding regulatory proteins. Some membrane preparations were treated with pertussis toxin, which has been shown to functionally uncouple IL opioid receptors from their effector systems. In these preparations, a single agonist-affinity state of the receptor was observed. The apparent dissociation constant for this affinity state in pertussis toxin-treated membranes was similar to the lower-affinity state observed in preparations from morphinetolerant animals. In contrast to the changes observed at , opioid binding sites, no significant changes in agonist affinity or binding density were observed for selective 8 or K agonists, consistent with the development of selective tolerance at Ip receptors.The mechanisms by which opiate drugs induce tolerance and dependence are not clearly understood. A number of observations suggest that changes occur in the function of the receptors through which the tolerance-inducing drug acts to evoke its primary pharmacologic effect. A significant fraction of the receptors must be activated for tolerance and dependence to develop (1,2). In tissues where more than one type of opioid receptor is present, the occurrence of receptorselective tolerance (3-5) also suggests that receptor-specific mechanisms are critical in the tolerance process. Studies of the interaction of agonists with 8 opioid receptors in NG108-15 neuroblastoma-glioma hybrid cells in culture after chronic receptor activation have demonstrated that sustained agonist exposure leads initially to a loss of the ability of 8 agonists to regulate their effector system (in this case, to inhibit adenylate cyclase), followed later by a reduction in the number of 8 receptors detected by radiolabeled ligand binding (6). Recently, similar results have been reported in a study of the chronic activation by morphine of 1 opioid receptors in 7315c pituitary tumor cells maintained in primary culture (7). Thus, in these cell systems in which opioid receptors negatively regulate adenylate cyclase, sustained exposure to morphine resulted in an initial desensitization followed by receptor down-regulation.Early studies examining the binding of opioid receptors in brain membranes from small mammals following treatment wi...

Analgesic Tolerance to High-Efficacy Agonists But Not to Morphine Is Diminished in Phosphorylation-Deficient S375A μ-Opioid Receptor Knock-In Mice

“…In the present study, we clearly show that chronic morphine produces a significant upregulation rather than downregulation of -opioid receptors in vivo under conditions that induce profound cellular tolerance. This is in contrast to the majority of previous binding studies, which detected no change in functional -opioid receptor binding sites in morphine-tolerant mice (Law et al, 1983;Werling et al, 1989). Given that morphine blocks receptor internalization, it is possible that in the continuous presence of morphine nonfunctional mice were treated with the indicated doses of morphine or fentanyl.…”

Chronic morphine treatment up-regulates mu opioid receptor binding in cells lacking filamin A

“…The effects of chronic morphine administration on MOP binding site density have also been investigated in animal brain and brain regions. These studies produced all possible changes in MOP density, namely, up-regulation (Besse et al, 1992;Brady et al, 1989;Fabian et al, 2002;Fabian et al, 2003;Holaday et al, 1982;Ray et al, 2004;Rothman et al, 1991;Schmidt et al, 2003;Vigano et al, 2003), down-regulation (Bhargava and Gulati, 1990;Meuser et al, 2003;Werling et al, 1989) or no change (Polastron et al, 1994;Stafford et al, 2001;Turchan et al, 1999). Some of these results appear to be regional differences, but others, performed on whole brain or the same regions of the same animal, appear to be discrepancies between different laboratories.…”

Agonist‐Induced Phosphorylation of the κ‐Opioid Receptor

“…While the full description of each of these components will ultimately be required to understand the consequences of prolonged opioid exposure, the recent cloning of the ,a-, 6-, and K-opioid receptors (see Kieffer, 1995) has opened up the study of the molecular basis of opioid desensitization of the signaling process. Several studies have shown that opioid receptors desensitize by uncoupling from their G protein (Werling et al, 1989;Tao et al, 1993), and opioid agonist efficacy is reduced during the development of tolerance Goldstein, 1982, 1984;Porreca and Burks, 1983).…”