Capsaicin and nitric oxide synthase inhibitor interact to evoke a hypothermic synergy

The present study investigated the effect of a drug combination of capsaicin and l-NAME on hypothermia in rats. Capsaicin administration (0.1, 0.25, 0.5, 1 and 2 mg/kg, i.m.) caused a significant hypothermia. l-NAME (50 mg/kg, i.p.), a nonspecific nitric oxide synthase (NOS) inhibitor, was ineffective. For combined administration, progressively increasing doses of capsaicin (0.1, 0.25, 0.5, 1 and 2 mg/kg, i.p.) were given with a non-hypothermic dose of l-NAME (50 mg/kg, i.p.). Experiments revealed that l-NAME (50 mg/kg, i.p.) enhanced the hypothermic response to capsaicin (0.25, 0.5, 1, and 2 mg/kg, i.m.). Comparison of the graded dose–effect curves for capsaicin alone and capsaicin plus l-NAME revealed a significant difference (P < 0.05), thus indicating synergy for the drug interaction. To determine if l-NAME acted centrally, a fixed dose of l-NAME (1 mg/rat, i.c.v.) was given with graded doses of capsaicin (0.25, 0.5, 1, and 2 mg/kg, i.m.). l-NAME (1 mg/rat, i.c.v.) only enhanced the hypothermia at a single dose of capsaicin (0.5 mg/kg, i.m.). The super-additive hypothermia produced by the concurrent administration of capsaicin and l-NAME (50 mg/kg, i.p.) is the first evidence of synergy for a drug combination of capsaicin and a NOS inhibitor. The synergy is apparent only when l-NAME is given systemically, thus indicating that the inhibition of peripheral NO production enhances the hypothermic response to capsaicin.