Tumor necrosis factor-α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

Abstract Neurogenic inflammation is an onset characteristic of small fiber neuropathy (SFN), which is attributed to neuropathic manifestations. Tumor necrosis factor-α (TNFα) is a cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1), and targeting TNFα/TNFR1 signaling is a direction toward treating inflammatory diseases and injury-induced neuropathy. However, the relationships between TNFα/TNFR1 signaling and Ret signaling, which mediates pain hypersensitivity, remains elusive. This study used resiniferatoxin (RTX), an ultrapotent analog of capsaicin, to generate a mouse model of SFN, leading to marked hindpaw edema ( p  = 0.013) and parallel the release of TNFα ( p  = 0.014), which was associated with the upregulation of Ret(+) neurons ( p  = 0.0043) and partial depletion of TNFR1 caused by colocalization with TRPV1 depleted by RTX. Pharmacological intervention of TNFα with etanercept (Enbrel ® , Wyeth), a clinical application of TNFα blockers, relieved neurogenic inflammation and caused a reduction in hindpaw thickness ( p  = 0.03) and TNFα releases ( p  = 0.01), which were determined to be associated with the normalization of mechanical allodynia ( p  = 0.22). The extraction of either TNFR1(+) or Ret(+) neurons from total of TNFR1(+):Ret(+) neurons indicated that TNFR1(−)/Ret(+) neurons correlated with the mechanical threshold in an antiparallel fashion (r = −0.84, p