Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCε:: A novel pathway for heat hyperalgesia

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 [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, PLC beta( phospholipase C-beta), or PKC but not by inhibition of PKA ( protein kinase A). In particular, PKC epsilon inhibitor completely blocked both Sar-SP-induced TRPV1 potentiation and heat hyperalgesia. Sar-SP also induced membrane translocation of PKC epsilon 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 epsilon-mediated potentiation of TRPV1.