1) Peripheral nerve injury often leads to neuropathic pain, which is characterized by tactile allodynia (a painful response to usually innocuous mechanical stimuli) and involves hyperexcitability in the primary somatosensory cortex (S1).
However, structural remodeling of cortical circuits following nerve injury has been believed to take months or years, which is not temporally correlated with rapid development of allodynia and S1 hyperexcitability. In this study, we used long-term in vivo two-photon imaging to longitudinally trace the dynamics of postsynaptic dendritic spines in the S1 of living adult mice with neuropathic pain induced by the partial sciatic nerve ligation injury, a well-characterized animal models. We report here that synaptic connections in the S1 are rapidly rewired within days following sciatic nerve ligation through phase-specific and size-dependent spine survival/growth. Spine turnover (formation and elimination) in the S1 area corresponding to the injured paw markedly increased during early development phase of allodynia and restored in later maintenance phase, which was prevented by immediate local blockade of the injured nerve throughout development phase. New spines that generated just before nerve injury showed volume decrease after injury, whereas more new spines that formed in development phase became persistent and substantially increased their volume during maintenance phase.
Further, pre-existing stable spines survived less following injury than controls and such lost persistent spines were smaller in size than the survived ones that displayed long-term potentiation-like enlargement over weeks. These results not only show the structural and temporal correlates of neuropathic pain, but also propose a close connection between pain and memory at single spine levels in the cortex, providing a potential therapeutic target in chronic pain.

2) Structural and functional plastic changes in the primary somatosensory cortex (S1) have been observed following peripheral nerve injury that often leads to neuropathic pain, characterized by tactile allodynia. However, remodeling of cortical connections following injury has been believed to take months or years, which is not temporally correlated with the rapid development of allodynia and S1 hyperexcitability. Here we first report, by using long-term two-photon imaging of postsynaptic dendritic spines in living adult mice, that synaptic connections in the S1 are rewired within days following sciatic nerve ligation through phase-specific and size-dependent spine survival/growth. Spine turnover in the S1 area corresponding to the injured paw markedly increased during an early phase of neuropathic pain and restored in a late phase of neuropathic pain, which was prevented by immediate local blockade of the injured nerve throughout the early phase. New spines that generated before nerve injury showed volume decrease after injury, whereas more new spines that formed in the early phase of neuropathic pain became persistent and substantially increased their volume during the late phase. Further, pre-existing stable spines survived less following injury than controls and such lost persistent spines were smaller in size than the survived ones that displayed long-term potentiation (LTP)-like enlargement over weeks. These results suggest that peripheral nerve injury induce rapid and selective remodeling of cortical synapses, which is associated with neuropathic pain development, probably underlying, at least partially, long-lasting sensory changes in neuropathic subjects.