title: TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation.
abstract: The anti-hyperalgesic effects of TRPV1 receptor antagonists are well documented in animal models of pain, however, the precise site of their action is not known. Here we have examined the effects of the selective TRPV1 antagonist SB-366791 on glutamatergic synaptic transmission in substantia gelatinosa using spinal cord slices from either control rats or animals that had undergone a peripheral inflammation induced by intraplantar injection of Freund's complete adjuvant (FCA). In control animals, SB-366791 (30 microM) had no effect on spontaneous excitatory post-synaptic currents (sEPSC) or evoked EPSCs. In slices from FCA-inflamed animals, SB-366791 decreased sEPSC frequency to 66+/-8% of control in 5/10 neurones, and decreased miniature glutamatergic EPSCs (mEPSC) frequency to 63+/-4% of control, in 6/7 neurones; with no significant effect on sEPSC or mEPSC amplitude. Dorsal root evoked EPSCs at C-fibre intensity were reduced to 72+/-6% of control by SB-366791 (30 microM) in 3/4 neurones from FCA-treated animals. In conclusion, SB-366791 inhibited glutamatergic transmission in a subset of neurones via a pre-synaptic mechanism following peripheral inflammation. We hypothesise that during peripheral inflammation spinal TRPV1 becomes tonically active, promoting the synaptic release of glutamate. These results provide evidence for a mechanism by which TRPV1 contributes to inflammatory pain and provides a basis for the understanding of the efficacy of TRPV1 antagonists.
authors.affiliation: Neurology and GI CEDD, GlaxoSmithKline, New Frontiers Science Park North, Third Avenue, Harlow, Essex, CM19 5AW, UK. Sarah.C.Lappin@gsk.com
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Lappin
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Gunthorpe
authors.forename: Valerie
authors.initials: V
authors.lastname: Morisset
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000633:toxicity; D005971:Glutamates / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D008954:Models, Biological; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000813:Anilides; D002934:Cinnamates; D005971:Glutamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005620:Freund's Adjuvant