Effect of alpha 2-adrenoceptor agonists on the expression of morphine-withdrawal in rats.

Previous studies using clonidine indicate that alpha 2-adrenoceptors are involved in suppressing opiate-withdrawal symptoms. However, clonidine may act as a partial agonist at alpha 2-adrenoceptors and it also possesses significant alpha 1-receptor agonist activity. The aim of this study was to determine the role of alpha 2-adrenoceptors in the expression of opiate withdrawal signs using morphine-dependent rats. A range of agonists were selected for study on the basis of their differential preferences for alpha-adrenoceptors. Hooded Wistar rats were made physically dependent on morphine (s.c. injection of an emulsion releasing a total of 250 mg/kg of morphine base over 48 h). Test drugs were injected s.c. followed by naloxone (10 mg/kg i.p.) 20 min later. The incidence of 5 selected withdrawal signs was recorded during the following 20 min. The alpha 2-adrenoceptor agonists displayed different profiles of activity. Azepexole (1-10 mg/kg) reduced all signs. Clonidine (80-800 micrograms/kg) reduced all signs except paw shakes while guanfacine (25-250 micrograms/kg) reduced all except jumping and diarrhoea. Talipexole (0.1-1 mg/kg) reduced all signs except diarrhoea which was not affected and jumping which was markedly enhanced. UK 14,304 (80-800 micrograms/kg) reduced jumps, potentiated paw shakes but did not affect body shakes, teeth chattering or diarrhoea. The results suggest that there are subpopulations of alpha 2-adrenoceptors that modulate the expression of opiate withdrawal signs and/or that some of the drugs used affect receptors other than alpha 2-adrenoceptors.