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The Journal of Neuroscience, October 31, 2007, 27(44):12067-12077; doi:10.1523/JNEUROSCI.0496-07.2007

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Cellular/Molecular
Neurokinin-1 Receptor Enhances TRPV1 Activity in Primary Sensory Neurons via PKC{varepsilon}: A Novel Pathway for Heat Hyperalgesia

Hua Zhang,1 Chun-Lei Cang,1 Yasuhiko Kawasaki,2 Ling-Li Liang,1 Yu-Qiu Zhang,1 Ru-Rong Ji,2 and Zhi-Qi Zhao1

1Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China, and 2Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Zhi-Qi Zhao at the above address. Email: zqzhao{at}fudan.edu.cn

The neuropeptide substance P (SP) is expressed in unmyelinated primary sensory neurons and represents the best known "pain" neurotransmitter. It is generally believed that SP regulates pain transmission and sensitization by acting on neurokinin-1 receptor (NK-1), which is expressed in postsynaptic dorsal horn neurons. However, the expression and role of NK-1 in primary sensory neurons are not clearly characterized. Our data showed that NK-1 was expressed in both intact and dissociated dorsal root ganglion (DRG) neurons. In particular, NK-1 was mainly coexpressed with the capsaicin receptor TRPV1 (transient receptor potential vanilloid subtype 1), a critical receptor for the generation of heat hyperalgesia. NK-1 agonist [Sar9, Met(O2)11]–substance P (Sar-SP) significantly potentiated capsaicin-induced currents and increase of [Ca2+]i in dissociated DRG neurons. NK-1 antagonist blocked not only the potentiation of TRPV1 currents but also heat hyperalgesia induced by intraplantar Sar-SP. NK-1 antagonist also inhibited capsaicin-induced spontaneous pain, and this inhibition was enhanced after inflammation. To analyze intracellular cross talking of NK-1 and TRPV1, we examined downstream signal pathways of G-protein-coupled NK-1 activation. Sar-SP-induced potentiation of TRPV1 was blocked by inhibition of G-protein, PLCβ (phospholipase C-β), or PKC but not by inhibition of PKA (protein kinase A). In particular, PKC{varepsilon} inhibitor completely blocked both Sar-SP-induced TRPV1 potentiation and heat hyperalgesia. Sar-SP also induced membrane translocation of PKC{varepsilon} in a portion of small DRG neurons. These results reveal a novel mechanism of NK-1 in primary sensory neurons via a possible autocrine and paracrine action of SP. Activation of NK-1 in these neurons induces heat hyperalgesia via PKC{varepsilon}-mediated potentiation of TRPV1.

Key words: transient receptor potential vanilloid subtype 1 (TRPV1); dorsal root ganglion; substance P; pain; neurokinin-1 receptor (NK-1); PKC; hyperalgesia

Received Feb. 5, 2007; revised July 31, 2007; accepted Sept. 3, 2007.

Correspondence should be addressed to Dr. Zhi-Qi Zhao at the above address. Email: zqzhao{at}fudan.edu.cn




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[Abstract] [Full Text] [PDF]


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