Spontaneous Withdrawal from Long‐Term Treatment with Morphine Accelerates the Turnover of α2‐Adrenoceptors in the Rat Brain: Up‐Regulation of Receptors Associated with Increased Receptor Appearance

Abstract

The aim of this study was to quantify and compare the turnover of brain alpha 2-adrenoceptors during chronic morphine treatment and after spontaneous morphine withdrawal in rats. The oral administration of increasing doses of morphine (10-90 mg/kg) for 20 days did not alter the specific binding of the agonist [3H]-clonidine in the cerebral cortex. However, spontaneous opiate withdrawal (24 h) significantly increased the density of cortical alpha 2-adrenoceptors (Bmax for [3H]clonidine was 21% greater). The recovery of [3H]clonidine binding after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (1.6 mg/kg) was assessed in naive, morphine-dependent, and morphine-withdrawn rats to study the process of alpha 2-adrenoceptor repopulation and to calculate receptor turnover parameters. The simultaneous analysis of receptor recovery curves revealed that the turnover of brain alpha 2-adrenoceptors in morphine-withdrawn rats was accelerated [appearance rate constant (r) = 21 fmol/mg of protein/day; disappearance rate constant (k) = 0.25 day-1] compared with those in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 significantly higher receptor appearance (delta r = 37-57%) and not to a decreased receptor disappearance, which in fact showed also an increase (delta k = 56-79%).(ABSTRACT TRUNCATED AT 250 WORDS)