Involvement of integrin β1/FAK signaling in the analgesic effects induced by glial cell line-derived neurotrophic factor in neuropathic pain

Treatment of neuropathic pain (NP) continues to be a clinical challenge and the underlying mechanisms of NP remain elusive. More evidence suggests that glial cell line-derived neurotrophic factor (GDNF) has potent anti-nociceptive effects on NP, but the underlying mechanisms are still largely unknown. Recent data have shown that integrin β1 plays an important part in NP induction, and that the activity of integrin β1 signaling is associated with the phosphorylation of the conserved threonines in the cytoplasmic domain and recruitment of focal adhesion kinase (FAK) to the integrin β1 tail and phosphorylation. We assessed the effect of GDNF on integrinβ1/FAK signaling in NP states. Immunostaining results showed that integrin β1 was mainly observed in the superficial dorsal horn in the spinal cord of rats, and was mostly expressed in intrinsic neurons. Expression of p-integrin β1 and the phosphorylation of integrin β1-associated FAK, but not integrin β1 itself, was up-regulated after chronic constriction injury (CCI), which could be reversed by GDNF, and the effect of GDNF on integrin β1/FAK signaling was inhibited by pre-treatment with RET function-blocking antibody (RET Ab). Moreover, pre-treatment with RET Ab could antagonize the effect of GDNF on inhibiting the NP induced by CCI. These data suggest that GDNF can regulate integrin β1 activity via a RET-related mechanism.