The modulatory effects of MU and Kappa opioid agonists on 5-HT release from hippocampal and hypothalamic slices of euthermic and hibernating ground squirrels

To elucidate the role of opioids in regulating hibernation, the modulatory effects of different opioids on 35 mM K⁺-stimulated [³H]-5-HT release from brain slices were examined in the Richardson's ground squirrels. DAGO ([D-Ala²,N-Me-Phe⁴,Gly-ol⁵]-enkephalin), a specific μ agonist, evoked a significant dose-dependent (10^-7-10^-5 M) inhibition of K⁺-stimulated 5-HT release from hippocampal slices of the non-hibernating squirrels. The inhibitory effect of DAGO was attenuated by either the opioid antagonist naloxone (10^-6 M) or the voltage dependent sodium channel blocker tetrodotoxin (TTX, 10^-6 M). The inhibitory effect of DAGO persisted in the hibernating squirrels; however, a ten fold higher concentration of DAGO (10^-6-10^-5 M) was required to elicit a significant inhibition. In contrast, κ agonist U50488 (10^-5 M) exerted a significant enhancement of K⁺-stimulated 5-HT release from hippocampal slices of the non-hibernating squirrels. This enhancement was blocked by either the specific κ antagonist nor-binaltorphimine (10^-6 M) or TTX (10^-6 M). However, in the hibernating squirrels, the stimulatory effect of U50488 (10^-5 M) on 5-HT release was absent. DAGO and U50488 had no modulatory effects on K⁺-stimulated 5-HT release from the hypothalamic slices of either the non-hibernating or hibernating squirrels. These results demonstrate that the modulatory effects of opioids on 5-HT release are receptor-specific and state-dependent, indicating the complex nature of the roles of different opioids in regulating hibernation.