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The Journal of Neuroscience, August 9, 2006, 26(32):8332-8338; doi:10.1523/JNEUROSCI.1989-06.2006

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Neurobiology of Disease
Tissue Injury Regulates Serotonin 1D Receptor Expression: Implications for the Control of Migraine and Inflammatory Pain

Andrew H. Ahn^1,2 and Allan I. Basbaum^2,3,4

¹Departments of Neurology, ²Anatomy, and ³Physiology, and ⁴The W. M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, California 94158

Correspondence should be addressed to Andrew H. Ahn, University of California, San Francisco, Box 2722, 1550 Fourth Street, San Francisco, CA 94158-2722. Email: andrew.ahn{at}ucsf.edu

The anti-migraine action of "triptan" drugs involves the activation of serotonin subtype 1D (5-HT_1D) receptors expressed on "pain-responsive" trigeminal primary afferents. In the central terminals of these nociceptors, the receptor is concentrated on peptidergic dense core vesicles (DCVs) and is notably absent from the plasma membrane. Based on this arrangement, we hypothesized that in the resting state the receptor is not available for binding by a triptan, but that noxious stimulation of these afferents could trigger vesicular release of DCVs, thus externalizing the receptor. Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat, there is a significant increase of 5-HT_1D-immunoreactivity (IR) in the ipsilateral dorsal horn of the spinal cord. We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane, where it is more readily detected. We also observed divergent changes in 5-HT_1D-IR in inflammatory and nerve-injury models of persistent pain, occurring at least in part through the regulation of 5-HT_1D-receptor gene expression. Finally, we found that 5-HT_1D-IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide substance P. This result differs from that reported for the -opioid receptor, which is also sorted to DCVs, but is greatly reduced in preprotachykinin mutant mice. We suggest that a "pain"-triggered regulation of 5-HT_1D-receptor expression underlies the effectiveness of triptans for the treatment of migraine. Moreover, the widespread expression of 5-HT_1D receptor in somatic nociceptive afferents suggests that triptans could, in certain circumstances, treat pain in nontrigeminal regions of the body.

Key words: migraine; pain; serotonin receptor; opioid receptor; substance P; calcitonin-gene related peptide; trigeminal; dorsal root ganglion; spinal cord

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Received May 9, 2006; revised July 10, 2006; accepted July 10, 2006.

Correspondence should be addressed to Andrew H. Ahn, University of California, San Francisco, Box 2722, 1550 Fourth Street, San Francisco, CA 94158-2722. Email: andrew.ahn{at}ucsf.edu

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