Distinct role of tumor necrosis factor receptor subtypes 1 and 2 in the red nucleus in the development of neuropathic pain

Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-α) in the red nucleus (RN) plays a facilitated role in the development of neuropathic pain. Here, the protein levels and roles of two different TNF receptors, p55 type 1 (TNFR1) and p75 type 2 (TNFR2), in the RN of rats with spared nerve injury (SNI) were investigated. Immunohistochemistry demonstrated that both TNFR1 and TNFR2 were significantly increased in the RN of rats with SNI compared with sham-operated and normal rats. The up-regulation of TNFR1 occurred at two weeks after SNI, while TNFR2 had markedly increased already at one week and began to decrease at two weeks after SNI. Microinjection of different doses (500, 250 and 100 ng) of anti-TNFR1 antibody (anti-TNFR1-Ab) or anti-TNFR2-Ab into the RN contralateral to the nerve injury side dose-dependently increased the paw withdrawal threshold of rats, as assessed using von Frey filaments. The analgesic effects produced by anti-TNFR1-Ab at one week and two weeks after SNI did not show significant difference. However, the analgesic effect produced by anti-TNFR2-Ab at two weeks after SNI was significantly lower and shorter than that produced at one week after SNI. Combined injection of anti-TNFR1-Ab and anti-TNFR2-Ab (500 ng for each antibody) into the RN generated a relatively faster and longer analgesic effect compared with single using of anti-TNFR1-Ab or anti-TNFR2-Ab. These results support that TNF-α in the RN plays a crucial role in regulating neuropathic pain, and suggest that the algesic effect of TNF-α is transmitted through both TNFR1 and TNFR2. TNFR1 has equally important role in the early development and later maintenance of neuropathic pain, while TNFR2 is more inclined to play a role in the early development of neuropathic pain.