Neuropathic pain, a debilitating
chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. One hallmark is abnormal
pain hypersensitivity to innocuous stimuli (
tactile allodynia), for which effective
therapy is lacking, and the underlying mechanisms of which remain to be determined. Here we show that Lyn, a member of the
Src family kinases (SFKs), plays an important role in the pathogenesis of
neuropathic pain. Nerve injury, but not peripheral
inflammation, increased immunoreactivity for active SFKs that were autophosphorylated in the
kinase domain (phospho-SFK-IR) in spinal microglia. In spinally derived microglial cells, we identified Lyn as the predominant SFK among the five members (Src, Fyn, Yes, Lck, and Lyn) known to be expressed in the CNS. Lyn expression in the spinal cord was highly restricted to microglia, and its level was increased after nerve injury. We found that mice lacking lyn (lyn(-/-)) exhibit a striking reduction in the levels of phospho-SFK-IR and
tactile allodynia after nerve injury, without any change in basal mechanical sensitivity or inflammatory
pain. Importantly, lyn(-/-) mice displayed impaired upregulation of the ionotropic
ATP receptor subtype P2X(4) receptors (P2X(4)R) in the spinal cord after nerve injury, which is crucial for
tactile allodynia. Microglial cells from lyn(-/-) mice showed a deficit in their ability to increase P2X(4)R expression in response to
fibronectin,
a factor implicated as a microglial P2X(4)R upregulator in
allodynia. Together, our findings suggest that Lyn may be a critical
kinase mediating nerve injury-induced P2X(4)R upregulation and
neuropathic pain.