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Cellular mechanisms of opioid tolerance: studies in single brain neurons
M J Christie1, J T Williams, R A North
1Vollum Institute, Oregon Health Sciences University, Portland 97201.
Abstract:
Intracellular recordings of membrane potassium current were made from rat locus coeruleus in vitro. The effects of agonists at mu-opioid receptors were studied on neurons from rats that had been chronically treated with morphine; these were compared with actions on neurons from control rats. Tolerance to the opioid-induced increase in potassium conductance was observed, and this was more pronounced for normorphine than for [Met5]enkephalin and [D-Ala2, Mephe4, Gly5-ol]enkephalin: experiments with the irreversible receptor blocker beta-chlornaltrexamine indicated that normorphine had lower intrinsic efficacy than [Met5]enkephalin and [D-Ala2 MePhe4, Gly5-ol]enkephalin. This adaptation was not due to any change of the properties of the potassium conductance activated by mu-receptors because both full and partial agonists at alpha 2-adrenoceptors, which couple to the same potassium conductance, were unchanged in their effectiveness; nor was it associated with any change in the affinity of mu-receptors for the antagonist naloxone. Naloxone had no effect on the neurons other than simple competitive reversal of the action of the mu-receptor agonists. These results demonstrate that 1) the mechanism responsible for tolerance in locus coeruleus neurons is specifically associated with mu-receptors and/or their coupling to potassium channels, 2) the intrinsic efficacy of an opioid determines the degree of tolerance observed, and 3) tolerance and physical dependence can be dissociated at the cellular level.
Insights
Opioid tolerance in rat locus coeruleus neurons is linked to mu-opioid receptor changes, not alpha 2-adrenoceptors. Opioid efficacy influences tolerance development, dissociating it from physical dependence at the cellular level.
Area of Science:
- Neuroscience
- Pharmacology
- Cellular Biology
Background:
- Opioid medications are widely used for pain management.
- Understanding the cellular mechanisms of opioid tolerance is crucial for optimizing pain therapy and minimizing adverse effects.
- The locus coeruleus is a key brainstem region involved in opioid dependence and withdrawal.
Purpose of the Study:
- To investigate the cellular mechanisms underlying opioid tolerance in rat locus coeruleus neurons.
- To compare the development of tolerance to different mu-opioid receptor agonists.
- To determine if tolerance is specific to mu-opioid receptor pathways or involves broader adaptive changes.
Main Methods:
- Intracellular recordings of membrane potassium current in rat locus coeruleus neurons in vitro.
- Chronic morphine treatment in rats to induce tolerance.
- Application of mu-opioid receptor agonists and alpha 2-adrenoceptor agonists.
- Use of irreversible receptor blocker beta-chlornaltrexamine and antagonist naloxone.
Main Results:
- Tolerance to opioid-induced potassium current increase was observed in chronically treated rats.
- Tolerance was more pronounced for normorphine than for enkephalins, indicating differences in intrinsic efficacy.
- The adaptive mechanism was specific to mu-opioid receptors, as alpha 2-adrenoceptor agonists' effectiveness remained unchanged.
- Receptor affinity for naloxone was not altered, and naloxone acted as a competitive antagonist.
Conclusions:
- Tolerance in locus coeruleus neurons is specifically associated with mu-opioid receptors and their coupling to potassium channels.
- The intrinsic efficacy of an opioid agonist directly influences the degree of tolerance developed.
- Tolerance and physical dependence can be dissociated at the cellular level, suggesting distinct underlying mechanisms.