THE ROLE OF HISTAMINERGIC-NORADRENERGIC AXIS IN NALOXONE-INDUCED WITHDRAWAL SYMPTOMS IN MICE

The effects of histamine antagonists on naloxone-precipitated withdraw al symptoms were studied in morphine-dependent mice. Chlorpheniramine (0.5-10 mg/kg), a H-1-blocker, given IP 30 min before naloxone challen ge produced a dose-dependent potentiation of withdrawal body weight lo ss, burrowing, and hypothermia, but did not influence either jumping o r wet-dog shakes. On the other hand, cimetidine (10-100 mg/kg), a H-2- blocker, produced dose-dependent potentiation of withdrawal hypothermi a and jumping. Cimetidine was without effect on wet-dog shakes, burrow ing, and body weight loss. The effect of chlorpheniramine was investig ated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether histamine-mediated effects are somehow linked to no radrenergic pathways. Intracerebral injection of 6-OHDA in 5-day-old m ice pups resulted in hyperlocomotion by the end of 30 days before init iation of morphine dependence. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than nontreated mice. 6-OHDA (50 mu g) lesions completely blocked the potentiating eff ect of chlorpheniramine on burrowing, hypothermia, and even reversed t he effect on body weight loss. These findings suggest that both histam ine H-1- and H-2-receptors may be involved in the expression of precip itated withdrawal in morphine-dependent mice and histamine receptors f unction as modulators of noradrenergic neurotransmission.