The role of 5-HT in the expression of morphine withdrawal in mice.

The effects of methysergide and cyproheptadine on naloxone-precipitated withdrawal symptoms were studied in morphine-dependent mice. The effects of these drugs were investigated both in normal mice and also mice injected with 6-OHDA intracerebrally to destroy the central noradrenergic neurones and examine whether 5-HT mediated effects are somehow linked to noradrenergic pathways. Methysergide given 30 min before naloxone attenuated withdrawal jumping, "wet dog" shakes, burrowing and body weight loss but aggravated hypothermia. Similar effects were produced by cyproheptadine on withdrawal "wet dog" shakes and hypothermia. Jumping was aggravated by low doses and attenuated by higher doses of cyproheptadine. Intracerebral injection of 6-OHDA in 5 days old mice pups resulted in hyperlocomotion by the end of 30 days before initiation of morphine dependence. When they were made morphine-dependent, mice pretreated with 6-OHDA developed higher degree of naloxone-induced withdrawal jumping than non-treated mice. Methysergide further aggravated jumping but its effect on both "wet dog" shakes and burrowing was lost in mice exposed to 6-OHDA. These findings suggest that 5-HT receptors are involved in the expression of withdrawal symptoms and the functional responsiveness of these receptors is dependent on intact nonadrenergic pathways.