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Spontaneous Withdrawal from Long‐Term Treatment with Morphine Accelerates the Turnover of α 2 ‐Adrenoceptors in the Rat Brain: Up‐Regulation of Receptors Associated with Increased Receptor Appearance
Author(s) -
Gabilondo Ane M.,
GarcíaSevilla Jesús A.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64062590.x
Subject(s) - morphine , endocrinology , agonist , chemistry , medicine , receptor , clonidine , opiate , turnover , physical dependence , management , economics
The aim of this study was to quantify and compare the turnover of brain α 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 [ 3 H]clonidine in the cerebral cortex. However, spontaneous opiate withdrawal (24 h) significantly increased the density of cortical α 2 ‐adrenoceptors ( B max for [ 3 H]clonidine was 21% greater). The recovery of [ 3 H]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by N ‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (1.6 mg/kg) was assessed in naive, morphine‐dependent, and morphine‐withdrawn rats to study the process of α 2 ‐adrenoceptor repopulation and to calculate receptor turnover parameters. The simultaneous analysis of receptor recovery curves revealed that the turnover of brain α 2 ‐adrenoceptors in morphine‐withdrawn rats was accelerated [appearance rate constant ( r ) = 21 fmol/mg of protein/day; disappearance rate constant ( k ) = 0.25 day −1 ] compared with those in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 α 2 ‐adrenoceptors observed during morphine withdrawal was due to a significantly higher receptor appearance (Δ r = 37–57%) and not to a decreased receptor disappearance, which in fact showed also an increase (Δ k = 56–79%). It is proposed that the increased rate of α 2 ‐adrenoceptor production in the brain of morphine‐dependent rats during spontaneous withdrawal is most probably mediated by the overactivity of the adenylyl cyclase/cyclic AMP system induced by opiate addiction.