SPONTANEOUS WITHDRAWAL FROM LONG-TERM TREATMENT WITH MORPHINE ACCELERATES THE TURNOVER OF ALPHA(2)-ADRENOCEPTORS IN THE RAT-BRAIN - UP-REGULATION OF RECEPTORS ASSOCIATED WITH INCREASED RECEPTOR APPEARANCE

The aim of this study was to quantify and compare the turnover of brai n alpha(2)-adrenoceptors during chronic morphine treatment and after s pontaneous morphine withdrawal in rats. The oral administration of inc reasing doses of morphine (10-90 mg/kg) for 20 days did not alter the specific binding of the agonist [H-3]-clonidine in the cerebral cortex . However, spontaneous opiate withdrawal (24 h) significantly increase d the density of cortical alpha(2)-adrenoceptors (B-max for [H-3] clon idine was 21% greater). The recovery of [H-3] clonidine binding after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquin oline (1.6 mg/kg) was assessed in naive, morphine-dependent, and morph ine-withdrawn rats to study the process of alpha(2)-adrenoceptor repop ulation and to calculate receptor turnover parameters. The simultaneou s analysis of receptor recovery curves revealed that the turnover of b rain alpha(2)-adrenoceptors in morphine-withdrawn rats was accelerated [appearance rate constant (r) = 21 fmol/mg of protein/day; disappeara nce rate constant (k) = 0.25 day(-1)] compared with those in morphine- dependent (r = 13 fmol/mg of protein/day; k = 0.14 day(-1)) and naive (r = 15 fmol/mg of protein/day; k = 0.16 day(-1)) rats. Moreover, this analysis also indicated that the increased density of cortical alpha( 2)-adrenoceptors observed during morphine withdrawal was due to a sign ificantly higher receptor appearance Delta r = 37-57%) and not to a de creased receptor disappearance, which in fact showed also an increase (Delta k = 56-79%). It is proposed that the increased rate of alpha(2) -adrenoceptor production in the brain of morphine-dependent rats durin g spontaneous withdrawal is most probably mediated by the overactivity of the adenylyl cyclase/cyclic AMP system induced by opiate addiction .