Peripheral Glial Cell Line-Derived Neurotrophic Factor Facilitates the Functional Recovery of Mechanical Nociception Following Inferior Alveolar Nerve Transection in Rats

Aims: To identify endogenous sources of glial cell line-derived neurotrophic factor (GDNF) at the injury site following inferior alveolar nerve transection (IANX) and to determine whether GDNF signaling promotes the recovery of orofacial pain sensation. Methods: Nociceptive mechanical sensitivity of the facial skin was assessed following IANX (n = 10) or sham operation (n = 7). GDNF-positive cells were identified and the amount of GDNF measured in the injured region of IANX rats (n = 10) and in sham rats (n = 10). The number of trigeminal ganglion neurons with regenerated axons and the nociceptive mechanical sensitivity after continuous GDNF administration at the injury site were also assessed in IANX (n = 28) and sham (n = 12) rats. The effect of GDNF neutralization on nociceptive mechanical sensitivity at the injury site was evaluated using a neutralizing antibody (GFRα1 Nab) in four groups: IANX + phosphate-buffered saline (PBS) (n = 6); sham (n = 12); IANX + GDNF (n = 12); and IANX + GDNF + GFRα1 Nab (n = 12). Statistical analyses included one-way and two-way repeated measures analysis of variance followed by post hoc tests or unpaired t tests. The threshold for statistical significance was set at P .05. Results: Nociceptive mechanical sensitivity was lost over the 5 days following IANX and was recovered by day 13. GDNF was expressed in infiltrating inflammatory cells and had enhanced expression. GDNF administration enhanced axonal regeneration and recovery of nociceptive mechanical sensitivity. GDNF neutralization inhibited the recovery of nociceptive mechanical sensitivity after IANX. Conclusion: GDNF signaling at the injury site facilitates the functional recovery of mechanical nociception following IANX and is an attractive therapeutic target for the functional disturbance of pain sensation. Keywords: GDNF family receptor alpha, glial cell line-derived neurotrophic factor, inferior alveolar nerve injury, mechanical nociception, nerve regeneration