Tolerance to mu-opioid receptor agonists but not cross-tolerance to gamma-aminobutyric acid(B) receptor agonists in arcuate A12 dopamine neurons with chronic morphine treatment.
The present study examined the potential for cross-tolerance development between mu-opioid and gamma-aminobutyric acidB 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 mu-opioid receptor agonist D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin and the gamma-aminobutyric acidB 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 mu-opioid and gamma-aminobutyric acidB 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.
Wagner
E J
EJ
Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland 97201, USA.
Zhang
G
G
Lagrange
A H
AH
Rønnekleiv
O K
OK
Kelly
M J
MJ
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000502:physiology*; D001418:Baclofen / Q000494:pharmacology*; D004361:Drug Tolerance; D004594:Electrophysiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology*; D005260:Female; D058786:GABA-B Receptor Agonists; D006168:Guinea Pigs; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009020:Morphine / Q000097:blood / Q000494:pharmacology*; D009021:Morphine Dependence / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013779:Tetrodotoxin / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D004745:Enkephalins; D058786:GABA-B Receptor Agonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013779:Tetrodotoxin; D009020:Morphine; D014446:Tyrosine 3-Monooxygenase; D001418:Baclofen