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

Nature. 1997 Sep 25;389(6649):382-5. doi: 10.1038/38730.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / antagonists & inhibitors*
  • Analgesics / pharmacology
  • Animals
  • In Vitro Techniques
  • Male
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Raphe Nuclei / cytology
  • Raphe Nuclei / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / physiology*
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / physiology*


  • Analgesics
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu