Open AccessTumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy
Author(s) -
Lu ShuiChin,
Chang YingShuang,
Kan HungWei,
Hsieh YuLin
Publication year - 2018
Publication title -
the kaohsiung journal of medical sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.439
H-Index - 36
eISSN - 2410-8650
pISSN - 1607-551X
DOI - 10.1016/j.kjms.2018.04.008
Subject(s) - resiniferatoxin , medicine , allodynia , tumor necrosis factor alpha , tumor necrosis factor receptor 1 , hyperalgesia , trpv1 , neuropathic pain , inflammation , receptor , cytokine , capsaicin , nociception , endocrinology , anesthesia , transient receptor potential channel , tumor necrosis factor receptor
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 < 0.0001) but had no relationship with thermal latencies. This study confirmed that TNFα rather than TNFα mediated neuropathic manifestation through the Ret receptor, specifically mechanical allodynia in RTX neuropathy.