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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.

We have previously shown that some substances which produce inflammation exert their effect by a mechanism which is dependent on the presence of intact sensory nerves. Examples of such substances are capsaicin and related acyl amides, mustard oil, xylene and o-chloroacetophenone. In experiments with animals, an inflammatory response to the administration of these substances could be prevented by chronic denervation or by capsaicin desensitization (Jancs6, 1960;Jancso, Jancso-Gabor & Szolcsanyi, 1967).In this paper we report experiments in which the effect of local anaesthesia on the inflammation induced by these irritants was investigated in rats and on human skin. Furthermore, inflammatory effects were investigated on denervated and normal skin areas of two subjects with peripheral nerve injuries.Part of this work was communicated at the Pain Symposium of the Third International Pharmacological Congress, Sao Paulo, 1966. METHODSInduction of inflammation in normal and anaesthetized eyes and paws of the rat In the eyes and the skin of the paws of rats, inflammation was induced with irritants which, according to our previous experiments, exert their effect by the neurogenic route (Jancs6, 1960; Jancs6 et al., 1967). Solutions of capsaicin (50 jug/ml.), w-chloroacetophenone (1 mg/ml.) or a saturated aqueous solution of mustard oil were instilled into the eye. The skin of the paw was painted with xylene or 5% mustard oil in liquid paraffin. The inflammatory reaction was made visible by injecting, before the irritants, Evans blue dye 50 mg/kg into the tail vein. Ten minutes after the application of the irritant the animals were killed by bleeding and the amount of dye in the conjunctivae or skin of the paws was determined quantitatively by the suramin extraction method (Jancs6-Gabor, Szolcsdnyi & Jancs6, 1967).In experiments with local anaesthetics, Cornecain (3%) or Psicain-Neu (1%) were instilled two or three times into the conjunctival sac. Five minutes later the corneal reflex could no longer be elicited. Evans blue was then injected intravenously and the local anaesthetics applied once again. The local anaesthetic by itself did not cause any appreciable exudation of the dye. Five minutes later the irritant was instilled. After this instillation the animal was held firmly so that it could not scratch or wipe its eyes. To reduce the possibility that the irritant was rinsed out with the tears, the instillation of the irritant was repeated. SENSOR Y NERVE ENDINGS AND INFLAMMA TIONThe dorsal skin of the paws was anaesthetized with 0.1 ml. of a 1°' procaine solution, injected subcutaneously. Five minutes later the Evans blue dye was given intravenously. Procaine by itself caused some dye exudation which could be prevented by injecting the 5-hydroxytryptamine antagonist methysergide (0.75 mg/kg) subcutaneously 30 min before procaine.Inflammatory reactions induced by irritants in the normal, anaesthetized or denervated human skin Inflammation in the skin of the forearm was induced by capsaicin, mustard oil, histamine, ...

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