Antisense confirmation of μ- and κ-opioid receptor mediation of morphine's effects on body temperature in rats

Abstract

Previous studies showed that parenterally administered morphine at 4–16 mg/kg markedly increased body temperature in the rat, but higher doses of morphine (>- 30 mg/kg, subcutaneously, sc) caused a profound decrease in body temperature. Based on the use of selective opioid agonists and antagonists, we postulated that these effects were due to morphine's actions on μ and κ receptors, respectively. In the present study, we sought to determine whether an antisense (AS) oligodeoxynucleotide (oligo) against cloned μ or κ opioid receptors could affect morphine-induced body temperature changes. AS oligos were directed against nucleotides 1–18 of the coding region of the μ receptor and 4–21 of the coding region of the κ receptor. Male SD rats were surgically implanted with intracerebroventricular (icv) cannulae. Rats received icv injections of vehicle or oligo in the animal colony room on days 1, 3 and 5. Either AS oligo or missense (MS) oligo was infused in a volume of 5 μl over 30 s to freely moving animals. On day 6, the rats were tested. The results showed that icv treatment with an AS oligo against μ opioid receptors, but not an MS oligo against the μ opioid receptor or an AS oligo against the κ opioid receptor, significantly attenuated the hyperthermia normally produced by a relatively low dose of morphine administered sc. In addition, treatment with an AS oligo against κ receptors, but not an MS oligo against κ opioid receptor or an AS oligo against the μ opioid receptor, significantly blocked the hypothermia induced by a high dose of morphine. This study confirms our earlier postulate that morphine at 4 mg/kg, sc, induces an increase in body temperature primarily via μ opioid receptors in the brain and a high dose (30 mg/kg) of morphine administered sc produces a decrease primarily through κ opioid receptors in the brain.