title: Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia.
abstract: 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(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, PLCbeta (phospholipase C-beta), or PKC but not by inhibition of PKA (protein kinase A). In particular, PKCepsilon inhibitor completely blocked both Sar-SP-induced TRPV1 potentiation and heat hyperalgesia. Sar-SP also induced membrane translocation of PKCepsilon 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 PKCepsilon-mediated potentiation of TRPV1.
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Cang
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Ling-Li
authors.initials: LL
authors.lastname: Liang
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Zhao
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D051744:Protein Kinase C-epsilon; D002118:Calcium