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The Journal of Neuroscience, April 6, 2005, 25(14):3651-3660; doi:10.1523/JNEUROSCI.0252-05.2005

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Behavioral/Systems/Cognitive
Inhibition by Spinal µ- and -Opioid Agonists of Afferent-Evoked Substance P Release

Ichiro Kondo,¹ Juan Carlos G. Marvizon,³ Bingbing Song,³ Frances Salgado,¹ Simone Codeluppi,^2,4 Xiao-Ying Hua,¹ and Tony L. Yaksh¹

Departments of ¹Anesthesiology and ²Pathology, University of California-San Diego, La Jolla, California 92093, ³Center for Neurovisceral Sciences and Women's Health, Department of Medicine, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073, and ⁴The Burnham Institute, La Jolla, California 92037

Opioid µ- and -receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the µ agonist [D-Ala², N-Me-Phe⁴, Gly-ol⁵]-enkephalin (DAMGO) (1 µM) and decreased by the agonist [D-Phe^2,5]-enkephalin (DPDPE) (1 µM). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the µ and agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Key words: C-fibers; dorsal horn; internalization; neurokinin; morphine; spinal cord

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Received Aug 12, 2004; revised February 24, 2005; accepted February 24, 2005.

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