Abstract
The present study examined the potential for cross-tolerance development between μ-opioid and γ-aminobutyric acidBreceptor 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 agonistd-Ala2,N-Me-Phe4,Gly-ol5-enkephalin and the γ-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 ofd-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, ofd-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 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.
Footnotes
-
Send reprint requests to: Edward J. Wagner, Ph.D., Department of Physiology and Pharmacology, L334, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201.
-
↵1 The experiments described in this study were supported by United States Public Health Service Grants DA05158 and DA00192 (Research Scientist Development Award to M.J.K.). E.J.W. was supported by National Institute on Drug Abuse Training Grant 5T32-DA07262.
-
↵2 Present address: Vollum Institute, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201.
- Abbreviations:
- aCSF
- artificial cerebrospinal fluid
- ARC
- arcuate
- cAMP
- cyclic adenosine monophosphate
- DAMGO
- D-Ala2,N-Me-Phe4,Gly-ol5-enkephalin
- GABA
- γ-aminobutyric acid
- M3G
- morphine-3-β-glucuronide
- M6G
- morphine-6-β-glucuronide
- Rin
- input resistance
- TH
- tyrosine hydroxylase
- TTX
- tetrodotoxin
- V/I
- voltage-current
- Vm
- membrane potential
- ΔVmax
- maximal steady-state hyperpolarization
- Received August 5, 1996.
- Accepted October 21, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|