Cellular mechanism for anti-analgesic action of agonists of the κ-opioid receptor

The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through μ-opioid receptors1,2,3, but the function of the κ-receptor in opioid analgesia is unclear. Although κ-receptor agonists can produce analgesia4,5, behavioural studies indicate that κ agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia (see refs 4, 6 for reviews). As morphine, a primary μ agonist1, also binds to κ-receptors7 and the analgesic effectiveness of morphine decreases with repeated use (tolerance), it is important to understand the mechanism for the functional interaction between κ- and μ-opioid receptors in the central nervous system. Here we present in vitro electrophysiological and in vivo behavioural evidence that activation of the κ-receptor specifically antagonizes μ-receptor-mediated analgesia. We show that in slice preparations of a rat brainstem nucleus, which is critical for the action of opioids in controlling pain, functional κ- and μ-receptors are each localized on physiologically different types of neuron. Activation of the κ-receptor hyperpolarizes neurons that are activated indirectly by the μ-receptor. In rats, κ-receptor activation in this brainstem nucleus significantly attenuates local μ-receptor-mediated analgesia. Our findings suggest a new cellular mechanism for the potentially ubiquitous opposing interaction between μ- and κ-opioid receptors and may help in the design of treatments for pain.