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 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by N-ethoxycarbonyl-2-ethoxy-1,2- dihydroquinoline (1.6 mg/kg) was assessed in naive, morphine-dependent, and morphine-withdrawn rats to study the process of alpha 2-adrenoceptor repopulation and to calculate receptor turnover parameters.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simultaneous analysis of receptor recovery curves revealed that the turnover of brain alpha 2-adrenoceptors in morphine-withdrawn rats was accelerated [appearance rate constant (r) = 21 fmol/mg of protein/day; disappearance rate constant (k) = 0.25 day-1] compared with those in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)
Gabilondo
A M
AM
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, Leioa, Bizkaia.
García-Sevilla
J A
JA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D003000:Clonidine / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D000317:Adrenergic alpha-Antagonists; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; C000470:EEDQ; D009020:Morphine; D003000:Clonidine