Further examination found two essential participants in neuropathic pain in the inhibitory circuit of the central nervous system: GAD65 and KCC2 were increased in the spinal cord of CCI rats after HDAC2 knockdown.
Evidence suggests that rehabilitation using active exercise and mechanical stimulation can attenuate spasticity and neuropathic pain in animal models, likely due to the upregulation of KCC2 expression via the BDNF-TrkB pathway.
Up-regulation of KCC2 function by targeting 5-HT<sub>2A</sub> receptors, therefore, has therapeutic potential in the treatment of neuropathic pain induced by SCI but not by SNI.
These results support the notion that KCC2 and GABAA receptor γ2 subunit contribute to NP following peripheral nerve injury and extend the understanding of the analgesic effects of EA on NP.
In this review, the hypothesis that an alteration of KCC2 expression has a crucial influence on the initiation/development or maintenance of neuropathic pain is discussed.
Deficit in KCC2 expression and/or activity is associated with epilepsy and neuropathic pain, and effective strategies are required to search for novel drugs augmenting KCC2 function.
Our results suggest that A3AR-mediated reversal of neuropathic pain increases modulation of GABA inhibitory neurotransmission both directly and indirectly through protection of KCC2 function, underscoring the unique utility of A3AR agonists in chronic pain.