title: Cellular mechanism for anti-analgesic action of agonists of the kappa-opioid receptor.
abstract: The analgesic effect of clinically used exogenous opioids, such as morphine, is mediated primarily through mu-opioid receptors, but the function of the kappa-receptor in opioid analgesia is unclear. Although kappa-receptor agonists can produce analgesia, behavioural studies indicate that kappa agonists applied intravenously or locally into the spinal cord antagonize morphine analgesia. As morphine, a primary mu agonist, also binds to kappa-receptors and the analgesic effectiveness of morphine decreases with repeated 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 electrophysiological and in vivo behavioural evidence that activation of the kappa-receptor specifically antagonizes mu-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 kappa- and mu-receptors are each localized on physiologically different types of 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 mechanism for the potentially ubiquitous opposing interaction between mu- and kappa-opioid receptors and may help in the design of treatments for pain.
authors.affiliation: Department of Neurology, University of California, San Francisco 94143, USA. zzp@itsa.ucsf.edu
authors.forename: Z Z
authors.initials: ZZ
authors.lastname: Pan
authors.forename: S A
authors.initials: SA
authors.lastname: Tershner
authors.forename: H L
authors.initials: HL
authors.lastname: Fields
mesh_terms: D000700:Analgesics / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D000700:Analgesics; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu