Vol. 280, Issue 2, 1057-1064, 1997

Tolerance to µ-Opioid Receptor Agonists but not Cross-tolerance to -Aminobutyric Acid_B Receptor Agonists in Arcuate A₁₂ Dopamine Neurons with Chronic Morphine Treatment¹

Edward J. Wagner, Ge Zhang², Andre H. Lagrange, Oline K. Rønnekleiv and Martin J. Kelly

Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon

The present study examined the potential for cross-tolerance development between µ-opioid and -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 -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 -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.