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The Journal of Neuroscience, November 1, 1999, 19(21):9642-9653

Spinal Opioid Analgesia: How Critical Is the Regulation of Substance P Signaling?

Jodie A. Trafton¹, Catherine Abbadie¹, Serge Marchand², Patrick W. Mantyh³, and Allan I. Basbaum¹

¹ Departments of Anatomy and Physiology and W. M. Keck Foundation for Integrative Neuroscience, University of California San Francisco, San Francisco, California 94143, ² Department of Clinical Sciences, University of Quebec, Rouyn-Noranda, Quebec, Canada, J9X5E4, and ³ Molecular Neurobiology Laboratory, Veterans Administration Medical Center, Minneapolis, Minnesota 55417

Although opioids can reduce stimulus-evoked efflux of Substance P (SP) from nociceptive primary afferents, the consequences of this reduction on spinal cord nociceptive processing has not been studied. Rather than assaying SP release, in the present study we examined the effect of opioids on two postsynaptic measures of SP release, Fos expression and neurokinin-1 (NK-1) receptor internalization, in the rat. The functional significance of the latter was first established in in vitro studies that showed that SP-induced Ca²⁺ mobilization is highly correlated with the magnitude of SP-induced NK-1 receptor internalization in dorsal horn neurons. Using an in vivo analysis, we found that morphine had little effect on noxious stimulus-evoked internalization of the NK-1 receptor in lamina I neurons. However, internalization was reduced when we coadministered morphine with a dose of an NK-1 receptor antagonist that by itself was without effect. Thus, although opioids may modulate SP release, the residual release is sufficient to exert maximal effects on the target NK-1 receptors. Morphine significantly reduced noxious stimulus-induced Fos expression in lamina I, but the Fos inhibition was less pronounced in neurons that expressed the NK-1 receptor. Taken together, these results suggest that opioid analgesia predominantly involves postsynaptic inhibitory mechanisms and/or presynaptic control of non-SP-containing primary afferent nociceptors.

Key words: morphine; dorsal horn; tachykinin; nociception; internalization; intrathecal

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19219642-12$05.00/0

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