The μ-opioid receptor is an autoreceptor on hypothalamic β-endorphin neurons that when activated inhibits cell firing via increasing an inwardly rectifying potassium conductance. The membrane hyperpolarization to DAMGO ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin) in β-endorphin and other arcuate (ARC) neurons was investigated in hypothalamic slices from control and morphine-treated, ovariectomized guinea pigs. Chronic morphine treatment caused both a decreased potency (EC50: 220 ± 10 nM vs. 64 ± 3 nM in controls) and a decreased efficacy (V(max): -7.1 ± 1.1 mV vs. -10.7 ± 0.6 mV in controls) of DAMGO in a population of ARC neurons including β- endorphin neurons. In another population of ARC neurons from morphine- treated animals, DAMGO was less potent (EC50: 110 ± 4 nM) than in controls (EC50: 64 ± 3 nM), but there was not a significant change in the efficacy of DAMGO. Twenty percent of ARC neurons did not exhibit any signs of tolerance. The density of μ-opioid receptors labeled with the antagonist radioligand [3H]diprenorphine was found to be significantly decreased in the ARC and surrounding mediobasal hypothalamus after morphine treatment (B(max): 217 ± 9 vs. 276 ± 16 fmol/mg protein in controls), which is consistent with the altered response in β-endorphin neurons. In summary, chronic morphine treatment decreases μ-opioid receptor density and the functional coupling of μ-opioid receptors to K+ channels in ARC neurons. This expression of morphine tolerance by β-endorphin (ARC) neurons may serve as a homeostatic mechanism to maintain opioid control of a variety of systems ranging from reproduction to motivation and reward.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Apr 1 1996|
ASJC Scopus subject areas
- Molecular Medicine