Pharmacological studies on the role of histamine in thermoregulation.

Abstract

A possible involvement of histamine (HA) in thermoregulation mechanisms is suggested by several observations: (a) hypothalamus is the richest brain region both in HA and histidine decarboxylase [1]; (b) cold stress accelerates hypothalamic HA turnover [2]; (c) stereotaxic injection of HA in rostral hypothalamus [3] produces a marked hypothermia. This hypothesis has been further explored by studying the effects on body temperature of intraventricular injections of HA, and some derivatives, agonists and antagonists as well as of treatments known to affect either synthesis or catabolism of brain HA. Intraventricular injection of HA (1-10 [zg) produced in mice a dose dependent decrease in colonic temperature the dose dependence being more apparent on the duration of hypothermia than on the amplitude. Methylation is the main catabolic pathway of brain HA; intraventricular injection of methylhistamine (5 ~zg) did not produce the hypothermia observed with the same dose of HA. In addition administration of amodiaquine (30 rag/ kg, i.p.) an inhibitor of HA methylation before intraventricular HA (2 ~g) produced a significant potentiation of the latter. N'-Methyl and N',N'dimethyl derivatives of HA had approximately the same hypothermic activity than HA, and betazole has been found ten times less active. In order to characterize the nature of the implicated receptors we have used antihistamines specific for H1 or H2 receptors. But with mepyramine (15 mg/kg, i.p.) or burimamide (50 mg/ kg, i.p.) either alone or in combination we could not block HA hypothermia. Among treatments modifying central metabolism of HA we have recently shown [4] that loading mice with L-histidine in doses (850 mg/kg) able to double brain HA level was without effect on temperature; furthermore, inhibitors ofhistidine decarboxylase such as brocresine and hydrazino-histidine unexpectedly induced a very marked hypothermia. These last results do not support the hypothesis of an involvement of endogenous HA in thermoregulation. However, on the other hand, the observation that amodiaquine and several antihistamines, which are inhibitors of HA methylation, produce a dose dependent hypothermia is in agreement with this hypothesis.