Unraveling the Role of SSH1 in Chronic Neuropathic Pain: A Focus on LIMK1 and Cofilin Dephosphorylation in the Prefrontal Cortex

Neuropathic pain, a debilitating condition stemming from nervous system injuries, has profound impacts on quality of life. The medial prefrontal cortex (mPFC) plays a crucial role in the modulation of pain perception and emotional response. This study explores the involvement of Slingshot Homolog 1 (SSH1) protein in neuropathic pain and related emotional and cognitive dysfunctions in a mouse model of spared nerve injury (SNI). SNI was induced in C57BL/6J mice. SSH1's role was investigated via its overexpression and knockdown using lentiviral vectors in the mPFC. Behavioral assays (thermal and mechanical allodynia, open field test, elevated plus maze, tail suspension test, Y-maze, and novel object recognition were conducted to assess pain sensitivity, anxiety, depression, and cognitive function. Tissue samples underwent Hematoxylin and Eosin staining, Western blotting, immunofluorescence, co-immunoprecipitation, and enzyme-linked immunosorbent assay for inflammatory markers. SNI mice displayed significant reductions in neuronal density and dendritic integrity in the mPFC, alongside heightened pain perception and emotional disturbances, as compared to sham controls. Overexpression of SSH1 ameliorated these alterations, improving mechanical and thermal thresholds, reducing anxiety and depressive behaviors, and enhancing cognitive performance. Conversely, SSH1 knockdown exacerbated these phenotypes. Molecular investigations revealed that SSH1 modulates pain processing and neuronal health in the mPFC partially through the dephosphorylation of Cofilin and LIM domain kinase 1 (LIMK1), as evidenced by changes in their phosphorylation states and interaction patterns. SSH1 plays a pivotal role in the modulation of neuropathic pain and associated neuropsychological disturbances in the mPFC of mice. Manipulating SSH1 expression can potentially reverse the neurophysiological and behavioral abnormalities induced by SNI, highlighting a promising therapeutic target for treating neuropathic pain and its complex comorbidities. •SSH1 is downregulated in the SNI model and plays a crucial role in modulating the sensory, emotional, and cognitive impairments as well as the neuropathological changes in the neurons of the mPFC induced by SNI surgery•SSH1 Mediates Cofilin Dephosphorylation in the mPFC of SNI Mice•SSH1 Modulates Neuropathic Pain in SNI Mice via Cofilin Dephosphorylation in the mPFC•SSH1 Modulates LIMK1 Dephosphorylation in the mPFC of SNI Mice•SSH1 Modulates Cofilin