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SUMMARY1. In rats and guinea-pigs a subcutaneous or intraperitoneal injection of capsaicin, the substance responsible for the pungency of red pepper, produces profound hypothermia associated with skin vasodilatation.2. After large doses of capsaicin rats and guinea-pigs become insensitive to the hypothermic action of capsaicin. This densensitization is apparently irreversible since it is present months after the capsaicin treatment.3. Capsaicin-desensitized animals are no longer able to protect themselves against overheating but respond with pronounced hyperthermia to high ambient temperatures (32-40(C). Temperature regulation against cold exposure, however, is not impaired.4. They also respond with an enhanced hyperthermia to painful stimuli such as repeated pinching of the tail or repeated introduction of the thermometer probe into the rectum.5. The enhanced hyperthermias are not due to increased heat production but to impairment of the heat dissipating mechanisms, which in rats and guinea-pigs acts mainly through evaporation of saliva, and skin vasodilatation.6. Acylamides with pungent action related to capsaicin such as piperine, caprinoyl-p-aminophenol and propionyl vanillylamide also cause hypothermia followed by desensitization and their efficacy is dependent on their pungency. The non-pungent nonenoyl benzylamide produces neither hypothermia nor desensitization.7. Capsaicin and its related pungent acylamides appear first to stimulate and then to desensitize the hypothalamic warmth detectors. By stimulating them the acylamides evoke reflexly the hypothermic response, whereas I7-2

1. In rats the injection of capsaicin into the pre-optic area of the anterior hypothalamus produces a prompt fall in body temperature and abolishes shivering. With repeated injections of capsaicin the hypothermic effect gradually diminishes and finally vanishes (local desensitization).2. Rats desensitized by hypothalamic injections exhibit a behaviour similar to rats pre-treated parenterally with capsaicin: put in a heat box at 37-39 degrees C they lose their ability to regulate against overheating of their bodies and respond with an enhanced hyperthermia to strong sensory stimuli such as repeated pinching of the tail.3. Parenteral desensitization strongly inhibits the effect of capsaicin given into the hypothalamus. On the other hand in intrahypothalamically desensitized rats the hypothermic response to subcutaneously given capsaicin is also reduced.4. The hypothermic response to local heating of the anterior hypothalamus by diathermy (from 1 to 4 degrees C above the initial temperature) was markedly reduced or even abolished in rats pre-treated parenterally with large doses of capsaicin.5. It is concluded that the hypothalamic warmth detectors are stimulated and subsequently desensitized by capsaicin. Thus, in the thermoregulatory disturbances caused by capsaicin the impairment of the hypothalamic warmth detectors plays an important role.6. Capsaicin is proposed as a tool in studying the function of the hypothalamic warmth detectors.