Tolerance of hypothalamic beta-endorphin neurons to mu-opioid receptor activation after chronic morphine.

Zhang G, Lagrange AH, R√łnnekleiv OK, Kelly MJ
J Pharmacol Exp Ther. 1996 277 (1): 551-8

PMID: 8613967

The mu-opioid receptor is an autoreceptor on hypothalamic beta-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 beta-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 (Vmax: -7.1 +/- 1.1 mV vs. -10.7 +/- 0.6 mV in controls) of DAMGO in a population of ARC neurons including beta-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 +/- 3nM), 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 mu-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 (Bmax: 217 +/- 9 vs. 276 +/- 16 fmol/mg protein in controls), which is consistent with the altered response in beta-endorphin neurons. In summary, chronic morphine treatment decreases mu-opioid receptor density and the functional coupling of mu-opioid receptors to K+ channels in ARC neurons. This expression of morphine tolerance by beta-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.

MeSH Terms (12)

Analgesics, Opioid Animals Arcuate Nucleus of Hypothalamus beta-Endorphin Drug Tolerance Enkephalin, Ala(2)-MePhe(4)-Gly(5)- Enkephalins Female Guinea Pigs Hypothalamus Morphine Receptors, Opioid, mu

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