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

Nature volume 389, pages 382–385 (1997)Cite this article

Abstract

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.

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Figure 1: Agonists of the κ-receptor hyperpolarize a subpopulation of NRM neurons by increasing potassium conductance.
Figure 2: Activation of κ- and μ-receptors inhibit two distinct types of NRM cell respectively.
Figure 3: Activation of κ-receptor in the NRM antagonizes the analgesia induced by DAMGO microinjected into the periaqueductal grey (PAG).
Figure 4: Model for the opposing interaction between agonists of μ- and κ-opioid receptor in the NRM.

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Acknowledgements

We thank R. Nicoll for reviewing the manuscript. This work was supported by the National Institute of Drug Abuse.

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  1. Departments of Neurology and Physiology, the W. M. Keck Center for Integrative Neuroscience, Box 0114, University of California, San Francisco, 94143, California, USA

    Z. Z. Pan, S. A. Tershner & H. L. Fields

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  3. H. L. Fields
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Correspondence to Z. Z. Pan.

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Pan, Z., Tershner, S. & Fields, H. Cellular mechanism for anti-analgesic action of agonists of the κ-opioid receptor. Nature 389, 382–385 (1997). https://doi.org/10.1038/38730

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