Effects of massive doses of alpha-MSH on thermoregulation in the rabbit

alpha-MSH-related compounds may prove to be clinically useful antipyretics since the parent peptide is extremely potent in reducing fever, it is effective when given orally, and it neither stimulates corticosteroid activity nor has marked melanotropic effects in man. To determine whether or in what doses alpha-MSH might cause harmful side-effects, we injected doses greatly exceeding those required to reduce fever into a lateral cerebral ventricle of afebrile rabbits. One hundred to seven hundred and fifty micrograms alpha-MSH caused large and prolonged reductions in body temperature and the dose-response relation was bell-shaped for both magnitude and duration. These doses caused no apparent injury to the animals. One mg alpha-MSH elicited hyperthermic responses that were variable in magnitude and duration. Animals that had previously received large doses of alpha-MSH (greater than or equal to 100 micrograms) did not develop hyperthermia, even when given 2 mg, indicating an acquired tolerance to this hyperthermic action of alpha-MSH. All animals, tolerant or previously uninjected, showed symptoms with doses greater than or equal to 1 mg alpha-MSH that included: increased salivation, agitation, ataxia, respiratory distress, and death (in 30% of the animals); those that recovered from these large doses resumed outwardly healthy appearance and behavior. Although alpha-MSH is toxic when given centrally in large doses, the 5000-fold difference between antipyretic and toxic doses indicates a wide safety margin should this peptide be used clinically as an antipyretic drug.