Cholecystokinin-octapeptide-induced hypothermia in rats: dose-effect and structure-effect relationships, effect of ambient temperature, pharmacological interactions and tolerance.
Subcutaneous injection of cholecystokinin octapeptide (CCK-8) (0.005-1.25 mg/kg) elicited dose-dependent hypothermia in rats. The threshold of the response was between 0.01 and 0.05 mg/kg and the dose-response curve levelled off at doses larger than 0.2-0.5 mg/kg. Warm and cold ambient temperatures decreased and increased the response, respectively. Pretreatment with capsaicin, morphine, naloxone, atropine, haloperidol or propranolol did not affect the response to CCK-8, whereas pretreatment with phenoxybenzamine and a large dose of proglumide, an antagonist for CCK-receptors, attenuated the hypothermia. It seems that neither capsaicin-sensitive thermal and non-thermal afferents, nor opiate mechanisms are involved in the response, but alpha-adrenoceptors might be of some importance in the hypothermia. Non-sulphated-CCK-8, the C-terminal tetrapeptide and hexapeptide, [D-Ala4]-CCK-8 and [D-Met6]-CCK-8 were ineffective. Chronic treatment with CCK-8 resulted in the development of tolerance to the thermoregulatory effect, while the hypothermic responses to apomorphine and capsaicin were not affected. It seems that the tolerance cannot be attributed to conditioned homeostatic reactions.