Is intracellular sodium involved in the mechanism of tolerance to opioid drugs?

Abstract

Recent studies indicate that one of the more likely mechanisms of opioid tolerance could involve a decrease in the efficiency with which agonists can induce coupling of their specific binding sites in neuronal membranes to the activation (or deactivation) of an effector system. Reports of sodium-induced decreases in opioid receptor agonist binding and in the size of ligand/receptor complexes, as well as modulation of opioid activity by manipulation of sodium in vivo, indicate that sodium might play a physiological role in modulating opioid receptor function. Reports of morphine-induced systemic sodium retention in animals, as well as morphine-induced increases in brain intracellular sodium and decreases in brain Na +, K +-ATPase activity, indicate that the development of tolerance may be accompanied by changes in the disposition of sodium. The direction of these sodium- and morphine-induced changes is consistent with the hypothesis that an increase in intracellular sodium could participate in the mechanism(s) of opioid tolerance development.