DAMGO stimulates the hypothalamo-pituitary-adrenal axis through a mu-2 opioid receptor
Journal of Pharmacology and Experimental Therapeutics 266(2): 985-991
DAMGO, a highly selective mu opioid agonist, is capable of stimulating the hypothalamo-pituitary-adrenal (HPA) axis to produce a dose-related elevation in plasma corticosterone (CS). The purpose of this study was to confirm that this action was mu receptor selective and to determine which of the mu receptors was involved using naloxonazine, a mu-1 receptor-selective antagonist. Experiments were done in male rats with chronic i.v. catheters and i.c.v. cannula guides. This enabled the withdrawal of serial blood samples in conscious unrestrained animals that were isolated in sound-attenuated one-way vision boxes. DAMGO, 8 and 16 mu-g administered i.c.v. caused significant and prolonged elevation of plasma CS. beta-funaltrexamine (beta-FNA) in progressively increasing doses (i.c.v.), antagonized the effect of DAMGO. The hormone response to DAMGO was unaffected by pretreatment with norbinaltorphimine or naltrindole (both i.c.v.). Naloxonazine, 50 mu-g, administered i.c.v. 18 hr before DAMGO did not antagonize the response to DAMGO. The same dose of naloxonazine given 2 hr before did reduce the response to DAMGO. Naloxonazine, 20 mg/kg i.v., given 18 hr before did not alter DAMGO's effect on plasma CS; however, the analgesic response to DAMGO in the same animals 24 hr later was antagonized by naloxonazine pretreatment. Pretreatment with beta-FNA or naloxonazine i.c.v. did not alter the plasma CS increase after exposure to ether vapor. These results suggest: 1) DAMGO stimulates the HPA axis via a mu opioid receptor in that the response was blocked by beta-FNA and early naloxonazine but not by norbinaltorphimine or naltrindole; 2) the action is probably at the mu-2 receptor because naloxonazine given 18 hr before i.v. or i.c.v. had no effect on the DAMGO stimulation of the HPA axis, however, i.v. naloxonazine was effective in blocking the analgesic effect of DAMGO and 3) blockade of DAMGO's effect on the HPA axis by beta-FNA or early naloxonazine suggests that DAMGO's effect is opioid selective as neither pretreatment altered the effect of ether vapor exposure on the HPA axis.