Potentiation of TRPV4 signalling by histamine and serotonin: an important mechanism for visceral hypersensitivity

Background Although evidence points to a role for histamine and serotonin in visceral hypersensitivity, activation of calcium channels such as transient receptor potential vanilloid 4 (TRPV4) also causes visceral hypersensitivity. We hypothesised that TRPV4 is important for the generation of hypersensitivity, mediating histamine-and serotonin-induced visceral hypersensitivity. Methods In response to histamine, serotonin and/or TRPV4 agonist (4 alpha PDD), calcium signals and TRPV4 localisation studies were performed on dorsal root ganglia (DRG) neurons projecting from the colon. To evaluate visceral nociception, colorectal distension (CRD) was performed in mice treated with serotonin or histamine and with 4 alpha PDD. Intrathecal injection of TRPV4 silencer RNA (SiRNA) or mismatch SiRNA was used to target TRPV4 expression. Results Pre-exposure of DRG neurons projecting from the colon, to histamine or serotonin, increased Ca2+ responses induced by 4 alpha PDD by a protein kinase C (PKC), phospholipase C beta (PLC beta), mitogen-activated protein kinase kinase (MAPKK) and phospholipase A(2) (PLA(2))-dependent mechanisms. Serotonin or histamine treatments enhanced TRPV4 expression at the plasma membrane by a MAPKK mechanism. Hypersensitivity induced by serotonin or histamine were both significantly inhibited by TRPV4 SiRNA intrathecal injection. Administration of sub-nociceptive doses of serotonin or histamine potentiated 4 alpha PDD-induced hypersensitivity in response to CRD. Conclusions Serotonin and histamine sensitise TRPV4 response to 4 alpha PDD both in vivo (increased visceral hypersensitivity) and in vitro, in sensory neurons, by a PKC, PLA(2), PLC beta and MAPKK-dependent mechanism. Serotonin and histamine caused a MAPKK-dependent increase in TRPV4 expression in colonic sensory neurons plasma membranes. Further, histamine-or serotonin-mediated visceral hypersensitivity depend on TRPV4 expression in sensory neurons. TRPV4 appears as a common mechanism to several known mediators of visceral hypersensitivity.