Research on the thermoregulatory significance of MSH stems from the discovery that it reduces normal body temperature when given centrally in sufficient doses. This effect was discovered in a long-term screening of amino acids5 and peptides6 for effects on body temperature. In one examination of 16 peptides, 6 MSH(l-13) and adrenocorticotropin (ACTH)(l-24) were the only ones to reliably decrease temperature when injected into the cerebral ventricles (intracerebroventricularly, i.c.v.) of rabbits. Doses of 1.25 to 5.0 J..l-g of either peptides, doses since discovered to be very large relative to the amount required to reduce fever, evoked dose-related hypothermia in a thermoneutral environment. This was the first discovery that these two peptides can have direct actions on central temperature controls. A fragment common to the two peptides, ACTH(l-10), had no effect on temperature, and, in later studies, corticotropin-like intermediate lobe peptide (CLIP), ACTH(l839), was also inactive. Both MSH and ACTH(l-24) caused greater decreases in temperature when the experiments were done in a cold environment, 8 but they had no effect in a 30°C environment. These results indicate that large doses of MSH, and of ACTH, do not alter the central "set point" about which body temperature is regulated. If the set point were altered by MSH, the changes in body temperature should be approximately the same in all three ambient temperatures. The lack of effect in the hot environment is most likely due to the low level of endogenous heat production since the peptides inhibited both heat production and heat conservation when pitted against the hyperthermic effects of centrally administered PGE2 and peripheral amphetamine. Unknown to us before these experiments, ACTH-induced hypothermia had been observed in 1952 by Douglas and Paton. 9 These investigators administered ACTH i.v. during screening of peptide preparations for pyrogen contamination. Temperature began to fall within 15 min and decreased to a nadir within 90 min. It is unlikely that this effect was due to contamination with posterior pituitary hormones that were known to be present in small amounts in the ACTH samples because injections of posterior pituitary extract did not cause hypothermia.