CELLULAR MECHANISM FOR ANTIANALGESIC ACTION OF AGONISTS OF THE KAPPA-OPIOID RECEPTOR

The analgesic effect of clinically used exogenous opioids, such as mor phine, is mediated primarily through mu-opioid receptors(1-3), but the function of the kappa-receptor in opioid analgesia is unclear. Althou gh kappa-receptor agonists can produce analgesia(4,5), behavioural stu dies indicate that kappa agonists applied intravenously or locally int o the spinal cord antagonize morphine analgesia (see refs 4, 6 for rev iews). As morphine, a primary mu agonist(1), also binds to kappa-recep tors(7) and the analgesic effectiveness of morphine decreases with rep eated use (tolerance), it is important to understand the mechanism for the functional interaction between kappa- and mu-opioid receptors in the central nervous system. Here we present in vitro electrophysiologi cal and in vivo behavioural evidence that activation of the kappa-rece ptor specifically antagonizes mu-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critic al for the action of opioids in controlling pain, functional kappa- an d mu-receptors are each localized on physiologically different types o f neuron. Activation of the kappa-receptor hyperpolarizes neurons that are activated indirectly by the mu-receptor. In rats, kappa-receptor activation in this brainstem nucleus significantly attenuates local mu -receptor-mediated analgesia. Our findings suggest a new cellular mech anism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments fo r pain.