Papers of the Week

Elevated excitability of primary afferent neurons underlies chronic pain in patients with functional or inflammatory bowel diseases. Recent studies have established an essential role for an enhanced transient receptor potential vanilloid subtype 1 (TRPV1) signaling in mediating peripheral hyperalgesia in inflammatory conditions. Since co-localization of Toll-like receptor 4 (TLR4) and TRPV1 has been observed in primary afferents including the trigeminal sensory neurons and the dorsal root ganglion (DRG) neurons, we test the hypothesis that TLR4 might regulate the expression and function of TRPV1 in primary afferent neurons in TNBS-induced colitis using the TLR4-deficient and the wild type (WT) C57 mice. Despite having a higher disease activity index following administration of TNBS, the TLR4 deficient mice showed less inflammatory infiltration in the colon than the WT mice. Increased expression of TLR4 and TRPV1 as well as increased density of capsaicin-induced TRPV1 current was observed in L4-S2 DRG neurons of WT colitis mice till two weeks post TNBS treatment. In comparison, TLR4 deficient colitis mice had lower TRPV1 expression and TRPV1 current density in DRG neurons with lower abdominal withdrawal response scores during noxious colonic distensions. In WT but not in TLR4-deficient DRG neurons, acute administration of the TLR4 agonist lipopolysacharide (LPS) increased the capsaicin-evoked TRPV1 current. In addition, we found that the canonical signaling downstream of TLR4 was activated in TNBS induced colitis in the WT but not in TLR4-deficient mice. These results indicate that TLR4 may play a major role in regulation of TRPV1 signaling and peripheral hyperalgesia in inflammatory conditions.