Extreme hyperthermia induced in cats by the enkephalin analog FK 33-824 ☆

Abstract FK 33-824 [H 2 N-Tyr- D -Ala-Gly-MePhe-Met(O)-OH] was injected into the third cerebral ventricle of unrestrained cats. Doses of 0.25–4 μg induced dose-related increases in body temperature. Hyperthermic responses to 1 μg of the peptide were greater the warmer the environment. Naloxone given intraventricularly 1 hr after FK 33-824 (1 μg) reduced the hyperthermia. In 12 tests with six cats FK 33-824 (1–25 μg) increased temperature 4.2–4.7°C. These marked responses were also inhibited by naloxone, but two cats died when administration of antagonist was delayed for 80 min to 3 hr after attainment of maximal body temperature. Larger doses of FK 33-824 (50–250 μg) evoked little increase in temperature, indicative of a separate action to depress thermoregulation. Although responses to FK 33-824 were antagonized by naloxone, this peptide, like another enkephalin analog D -Ala 2 -Met-enkephalinamide, must act on receptors which are not affected by morphine since (1) the hyperthermic response to FK 33-824 varied with environmental temperature, whereas the response to morphine does not, and (2) high doses of FK 33-824 depressed thermoregulation, an activity not shared by morphine in the cat. Furthermore, the maximal increases in temperature after FK 33-824 injection were greater than those evoked by either morphine or D -Ala 2 -Met-enkephalinamide. This observation provides evidence for an additional subset of naloxone-sensitive, ν, receptors, stimulation of which can influence thermoregulation in the cat.