Cellular mechanisms of opioid tolerance: Studies in single brain neurons

Intracellular recordings of membrane potassium current were made from rat locus coeruleus in vitro. The effects of agonists at μ-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-A-a², Mephe⁴, Gly⁵-ol]enkephalin: experiments with the irreversible receptor blocker β-chlornaltrexamine indicated that normophine 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 μ-receptors because both full and partial agonists at α₂-adrenoceptors, which couple to the same potassium conductance, were unchanged in their effectiveness; nor was it associated with any change in the affinity of μ-receptors for the antagonist naloxone. Naloxone had no effect on the neurons other than simple competitive reversal of the action of the μ-receptor agonists. These results demonstrate that 1) the mechanism responsible for tolerance in locus coeruleus neurons is specifically associated with μ-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.