Neurokinin-1 Receptor Enhances TRPV1 Activity in Primary Sensory Neurons via PKCε: A Novel Pathway for Heat Hyperalgesia

• Published in: The Journal of neuroscience 2007-10, Vol.27 (44), p.12067-12077
• Main Authors: Zhang, Hua, Cang, Chun-Lei, Kawasaki, Yasuhiko, Liang, Ling-Li, Zhang, Yu-Qiu, Ji, Ru-Rong, Zhao, Zhi-Qi
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0496-07.2007

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 [Sar 9 , Met(O 2 ) 11 ]–substance P (Sar-SP) significantly potentiated capsaicin-induced currents and increase of [Ca 2+ ] 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, PKCε inhibitor completely blocked both Sar-SP-induced TRPV1 potentiation and heat hyperalgesia. Sar-SP also induced membrane translocation of PKCε 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 PKCε-mediated potentiation of TRPV1.