Objective To observe the effects of PSD95 gene specific siRNAs on neuropathic pain relief

neuron viability

and postsynaptic calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) phosphorylation in vitro and in vivo. Methods Gene-specific siRNAs of rat PSD95 were synthesized chemically for transfection. Adult male Sprague-Dawley (SD) rats were randomly divided into 3 groups: naïve group (n=6)

sham group (n=6)

and sciatic nerve chronic constriction injury (CCI) group (n=24). The CCI group was further divided into 4 groups (n=6 in each group)

which were pretreated with normal saline

transfection vehicle

negative control siRNAs

and PSD95 gene specific siRNAs respectively. All the subgroups received corresponding agents intrathecally for 3 days

started one day before the CCI of sciatic nerve. Both mechanical allodynia and thermal hyperalgesia were measured on post-operative day 3 and 7. PSD95 gene silenced NG108-15 cells were further stimulated by glutamate

with the cell viability and the expression/phosphorylation of CaMKIIα measured by MTT cell proliferation assay and Western blot

respectively. Results The siRNAs decreased PSD95 mRNA level significantly both in vivo and in vitro. Neuropathic pain rats pretreated with PSD95 gene specific siRNAs exhibited significant elevation in the mechanical withdrawal threshold and paw withdrawal thermal latency

without affecting the baseline nociception. PSD95 gene silencing enhanced neuronal tolerance against the glutamate excitotoxicity

meanwhile the phosphorylation of CaMKIIα Thr286 was attenuated. Conclusion Pre-emptive administration of PSD95 gene specific siRNAs may attenuate the central sensitization CaMKIIα-related signaling cascades

leading to the relief of neuropathic pain.