Modulation of brain alpha 2-adrenoceptor and mu-opioid receptor densities during morphine dependence and spontaneous withdrawal in rats.
The densities of brain alpha 2-adrenoceptors and mu-opioid receptors, quantitated by means of the binding of the agonists [3H]clonidine and [3H]dihydromorphine, respectively, were studied during the development of morphine dependence and spontaneous withdrawal in the rat. The oral administration of morphine (12-130 mg/kg for 3-21 days) led to inconsistent changes in alpha 2-adrenoceptor density while the density of mu-opioid receptors was down-regulated. In contrast, spontaneous opiate withdrawal (3-72 h) significantly increased the density of alpha 2-adrenoceptors while the density of mu-opioid receptors was rapidly up-regulated to control values. In the hypothalamus, but not in other brain regions, the increase in alpha 2-adrenoceptor density after withdrawal followed a time course (3-72 h) related to the severity of the abstinence syndrome. Thus, there was a positive and significant correlation between the severity of withdrawal and the density of alpha 2-adrenoceptors in the hypothalamus. Short-term treatment with clonidine (2 x 0.5 mg/kg, i.p.) prevented the morphine withdrawal-induced increases in alpha 2-adrenoceptor density in various brain regions, but not in the hypothalamus. The main results suggest that modulation of hypothalamic alpha 2-adrenoceptor density during morphine withdrawal is a relevant physiological mechanism by which the opiate abstinence syndrome is counteracted.
Ulibarri
I
I
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad del País Vasco, Bizkaia, Spain.
García-Sevilla
J A
JA
Ugedo
L
L
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004090:Dihydromorphine / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D011942:Receptors, Adrenergic, alpha; D011957:Receptors, Opioid; D009020:Morphine; D004090:Dihydromorphine; D003000:Clonidine