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

Abstract

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.

• Authors: G Zhang, A H Lagrange, O K Rønnekleiv, M J Kelly
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 277 Issue 1 Pg. 551-8 (Apr 1996) ISSN: 0022-3565 [Print] United States
• PMID: 8613967 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Analgesics, Opioid
• Enkephalins
• Receptors, Opioid, mu
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• beta-Endorphin
• Morphine

Topics

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