Neurokinin release produced by capsaicin acting on the central terminals and axons of primary afferents: relationship with N-methyl-D-aspartate and GABA(B) receptors.
Capsaicin stimulates neurokinin release in the spinal cord when applied both centrally and peripherally. To determine whether these two actions have different mechanisms, we measured neurokinin 1 receptor (NK1R) internalization in rat spinal cord slices elicited by incubating the whole slice or just the dorsal root with capsaicin. NK1R internalization produced by incubating the slices with capsaicin was abolished by the NK1R antagonist RP-67580, by the vanilloid receptor 1 (VR1) antagonist capsazepine, and by eliminating Ca(2+) from the medium, but was not affected by the Na(+) channel blocker lidocaine. Therefore, the internalization was due to neurokinin release mediated by Ca(2+) entry through VR1 receptors, but did not require the firing of action potentials. Incubating the root with capsaicin produced NK1R internalization in the ipsilateral dorsal horn that was abolished when capsazepine or lidocaine was included in, or when Ca(2+) was omitted from, the medium surrounding the root. Therefore, the internalization was mediated by Ca(2+) entry in the axons through VR1, and required firing of action potentials. The efficacy of capsaicin when applied to the root (36+/-3%) was lower than when applied to the slice (91+/-3%), but its potency was the same (0.49 microM and 0.37 microM, respectively). We also investigated whether presynaptic N-methyl-D-aspartate (NMDA) and GABA(B) receptors modulate these two actions of capsaicin. Neither the NMDA receptor blocker MK-801 nor the GABA(B) agonist baclofen decreased NK1R internalization produced by 1 microM capsaicin applied to the slices, but they inhibited the internalization produced by 0.3 microM capsaicin applied to the slices or 1 microM capsaicin applied to the root. Therefore, capsaicin can produce neurokinin release from primary afferents 1) by a direct action on their central terminals and 2) by increasing the firing of action potentials on their axons. The first effect largely bypasses other modulatory mechanism, but the second does not.
Center for Neurovisceral Sciences and Women's Health, CURE: Digestive Diseases Research Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, 90095, USA.
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D000344:Afferent Pathways / Q000187:drug effects; D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D001418:Baclofen / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007839:Functional Laterality; D018755:GABA Agonists / Q000494:pharmacology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008012:Lidocaine / Q000494:pharmacology; D018613:Microscopy, Confocal; D064729:Neurokinin-1 Receptor Antagonists; D017729:Presynaptic Terminals / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology; D013126:Spinal Nerve Roots / Q000187:drug effects; D013997:Time Factors
D000779:Anesthetics, Local; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; D018040:Receptors, Neurokinin-1; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D016291:Dizocilpine Maleate; D008012:Lidocaine; D001418:Baclofen; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium