ANTISENSE CONFIRMATION OF MU-OPIOID AND KAPPA-OPIOID RECEPTOR MEDIATION OF MORPHINES EFFECTS ON BODY-TEMPERATURE IN RATS

Previous studies showed that parenterally administered morphine at 4-1 6 mg/kg markedly increased body temperature in the rat, but higher dos es of morphine (greater than or equal to 30 mg/kg, subcutaneously, sc) caused a profound decrease in body temperature. Based on the use of s elective opioid agonists and antagonists, we postulated that these eff ects were due to morphine's actions on mu and kappa receptors, respect ively. In the present study, we sought to determine whether an antisen se (AS) oligodeoxynucleotide (oligo) against cloned mu or kappa opioid receptors could affect morphine-induced body temperature changes. AS oligos were directed against nucleotides 1-18 of the coding region of the mu receptor and 4-21 of the coding region of the Ic receptor. Male SD rats were surgically implanted with intracerebroventricular (icy) cannulae. Rats received icy injections of vehicle or oligo in the anim al colony room on days 1, 3 and 5. Either AS oligo or missense (MS) ol igo was infused in a volume of 5 mu l over 30 s to freely moving anima ls. On day 6, the rats were tested. The results showed that icy treatm ent with an AS oligo against mu opioid receptors, but not an MS oligo against the mu opioid receptor or an AS oligo against the kappa opioid receptor, significantly attenuated the hyperthermia normally produced by a relatively low dose of morphine administered sc. In addition, tr eatment with an AS oligo against kappa receptors, but not an MS oligo against re opioid receptor or an AS oligo against the mu opioid recept or, significantly blocked the hypothermia induced by a high dose of mo rphine. This study confirms our earlier postulate that morphine at 4 m g/kg, sc, induces an increase in body temperature primarily via mu opi oid receptors in the brain and a high dose (30 mg/kg) of morphine admi nistered sc produces a decrease primarily through kappa opioid recepto rs in the brain.