Tolerance to μ-opioid receptor agonists but not cross-tolerance to γ- aminobutyric acid(B) receptor agonists in arcuate A12 dopamine neurons with chronic morphine treatment

Edward J. Wagner, Ge Zhang, Andre H. Lagrange, Oline K. Rønnekleiv, Martin J. Kelly

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The present study examined the potential for cross-tolerance development between μ-opioid and γ-aminobutyric acid(B) receptor agonists, in hypothalamic arcuate neurons, resulting from chronic morphine treatment. Intracellular recordings were made in hypothalamic slices prepared from ovariectomized female guinea pigs. The μ-opioid receptor agonist D-Ala2,N- Me-Phe4,Gly-ol5-enkephalin and the γ-aminobutyric acid(B) receptor agonist baclofen produced dose-dependent membrane hyperpolarizations of arcuate neurons. The reversal potential for both agonist-induced hyperpolarizations was near -95 mV, indicative of the activation of an underlying K+ conductance. Coadministration of maximally effective concentrations of D- Ala2,N-Me-Phe4,Gly-ol5-enkephalin and baclofen produced a response that was not additive, indicating a convergence onto a common K+ channel. In arcuate neurons, including a subset that was immunopositive for tyrosine hydroxylase, chronic morphine treatment for 4 to 7 days produced a 3.2-fold reduction in the potency, with no change in the efficacy, of D-Ala2,N-Me- Phe4,Gly-ol5-enkephalin. In contrast, it affected neither the potency nor the efficacy of baclofen. Therefore, chronic morphine exposure does not produce cross-tolerance between μ-opioid and γ-aminobutyric acid(B) receptor agonists in A12 dopamine neurons, suggesting that convergence upon a common effector is not a sufficient criterion for the development of cross- tolerance between receptor systems.

Original languageEnglish (US)
Pages (from-to)1057-1064
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - May 3 1997


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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