The role of histaminergic-noradrenergic axis in naloxone-induced withdrawal symptoms in mice

The effects of histamine antagonists on naloxone-precipitated withdrawal symptoms were studied in morphine-dependent mice. Chlorpheniramine (0.5–10 mg/kg), a H 1-blocker, given IP 30 min before naloxone challenge produced a dose-dependent potentiation of withdrawal body weight loss, burrowing, and hypothermia, but did not influence either jumping or wet-dog shakes. On the other hand, cimetidine (10–100 mg/kg), a H 2-blocker, produced dose-dependent potentiation of withdrawal hypothermia and jumping. Cimetidine was without effect on wet-dog shakes, burrowing, and body weight loss. The effect of Chlorpheniramine was investigated in mice injected with 6-hydroxydopamine (6-OHDA) intracerebrally to examine whether histamine-mediated effects are some-how linked to noradrenergic pathways. Intracerebral injection of 6-OHDA in 5-day-old mice pups resulted in hyperlocomotion by the end of 30 days before initiation of morphine dependence. Mice pretreated with 6-OHDA developed a higher degree of naloxone-induced withdrawal jumping than nontreated mice. 6-OHDA (50 μg) lesions completely blocked the potentiating effect of Chlorpheniramine on burrowing, hypothermia, and even reversed the effect on body weight loss. These findings suggest that both histamine H 1- and H 2-receptors may be involved in the expression of precipitated withdrawal in morphine-dependent mice and histamine receptors function as modulators of noradrenergic neurotransmission.