Differential contribution of SNARE-dependent exocytosis to inflammatory potentiation of TRPV1 in nociceptors.
Potentiation of the pain-integrator ion channel transient receptor potential vanilloid type 1 (TRPV1) underlies thermal hyperalgesia mediated by a variety of proinflammatory factors. Two complementary mechanisms of TRPV1 inflammatory sensitization have been proposed, namely a decrease of its activation threshold and an increment of its surface expression in nociceptors. Here we investigated the involvement of regulated exocytosis to the inflammatory sensitization of TRPV1 in rat neonatal dorsal root ganglion neurons by proalgesic agents. The contribution of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent exocytosis was evaluated using a small peptide patterned after the synaptosomal-associated protein of 25 kDa (SNAP-25) protein that acts as a specific and potent inhibitor of neuronal exocytosis. We found that TRPV1 sensitization mediated by nerve growth factor, ATP, and IGF-I was accompanied by a higher channel expression in the neuronal plasma membrane, which was prevented by blockade of regulated exocytosis. In contrast, TRPV1 sensitization caused by bradykinin, IL-1beta, and artemin was insensitive to inhibition of SNARE-dependent vesicular fusion and was not due to an increase in TRPV1 surface expression. Therefore, it appears that some, but not all, proinflammatory agents sensitize rat nociceptors by promoting the recruitment of TRPV1 channels to the neuronal surface. These findings support the tenet that SNARE complex-mediated exocytosis of TRPV1 may be a valid therapeutic target to treat inflammatory pain.
Camprubí-Robles
M
M
Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Av de la Universidad s/n, 03202 Elche, Alicante, Spain.
Planells-Cases
R
R
Ferrer-Montiel
A
A
D000818:Animals; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D055666:Lipopeptides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D050600:SNARE Proteins / Q000502:physiology*; D050916:TRPV Cation Channels / Q000502:physiology*
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D055666:Lipopeptides; D050600:SNARE Proteins; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C545102:palmitoyl-glutamyl-glutamyl-methionyl-glutaminyl-arginyl-argininamide; D007334:Insulin-Like Growth Factor I