Abstract
BackgroundAccidental mandibular nerve injury may occur during tooth extraction or implant procedures, causing ectopic orofacial pain. The exact mechanisms underlying ectopic orofacial pain following mandibular nerve injury is still unknown. Here, we investigated the role of macrophages and tumor necrosis factor alpha (TNFα) in the trigeminal ganglion (TG) in ectopic orofacial pain following inferior alveolar nerve transection (IANX).MethodsIANX was performed and the mechanical head-withdrawal threshold (MHWT) in the whisker pad skin ipsilateral to IANX was measured for 15 days. Expression of Iba1 in the TG was examined on day 3 after IANX, and the MHWT in the whisker pad skin ipsilateral to IANX was measured following successive intra-ganglion administration of the macrophage depletion agent liposomal clodronate Clophosome-A (LCCA). TNFα expression in the TG and the MHWT in the whisker pad skin ipsilateral to IANX following successive intra-ganglion administration of the TNFα blocker etanercept were measured on day 3 after IANX, and tumor necrosis factor receptor-1 (TNFR1) immunoreactive (IR) cells in the TG were analyzed immunohistochemically on day 3.ResultsThe MHWT in the whisker pad skin was significantly decreased for 15 days, and the number of Iba1-IR cells was significantly increased in the TG on day 3 after IANX. Successive intra-ganglion administration of the macrophage depletion agent LCCA significantly reduced the increased number of Iba1-IR cells in the TG and reversed the IANX-induced decrease in MHWT in the whisker pad skin. TNFα expression was increased in the TG on day 3 after IANX and was reduced following successive intra-ganglion administration of the TNFα inhibitor etanercept. The decreased MHWT was also recovered by etanercept administration, and TNFR1-IR cells in the TG were increased on day 3 following IANX.ConclusionsThese findings suggest that signaling cascades resulting from the production of TNFα by infiltrated macrophages in the TG contributes to the development of ectopic mechanical allodynia in whisker pad skin following IANX.
Highlights
Accidental mandibular nerve injury may occur during tooth extraction or implant procedures, causing ectopic orofacial pain
Mechanical allodynia and Iba1 expression in trigeminal ganglion (TG) following Inferior alveolar nerve transection (IANX) The mechanical head-withdrawal threshold (MHWT) of the whisker pad skin ipsilateral to IANX was significantly decreased on day 1 following IANX, and this decrease persisted until day 15 when compared with sham-operated animals (Fig. 1a)
The Iba1 protein level was increased in TG ipsilateral to IANX on day 3 following IANX compared to shamoperated animals (Fig. 1e)
Summary
Accidental mandibular nerve injury may occur during tooth extraction or implant procedures, causing ectopic orofacial pain. We investigated the role of macrophages and tumor necrosis factor alpha (TNFα) in the trigeminal ganglion (TG) in ectopic orofacial pain following inferior alveolar nerve transection (IANX). Previous studies have indicated that pathological changes in the intra-trigeminal ganglion (TG) signaling mechanisms following trigeminal nerve injury are involved in the development of ectopic orofacial neuropathic pain. Nitric oxide released from the injured TG neurons and satellite glial activation via connexin 43 signaling modulates the excitability of intact TG neurons following inferior alveolar nerve injury (IANX) [4, 5]. The infiltration of activated macrophages into the dorsal root ganglion results in the development of behavioral hypersensitivity in rats which induced chemotherapy-induced peripheral neuropathy [11]
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