GABAergic disinhibition through the STING-dependent autophagic pathway in the dorsal horn underlies diabetic neuropathic pain pathogenesis.

Our previous study demonstrated that STING/ATG5-mediated autophagy in the spinal dorsal horn contributes to diabetic neuropathic pain (DNP), although the underlying mechanisms remained unclear. In this study, we investigated how STING-driven autophagy leads to impaired spinal inhibition via lysosomal degradation of GABA receptors. In a rat model of DNP, spinal levels of STING and ATG5 were elevated, while P62, GABAA receptor, and GABAB receptor expression were reduced. Behavioral tests showed that intrathecal administration of a STING inhibitor increased mechanical pain thresholds and upregulated P62 and GABA receptors. Conversely, treatment with a STING agonist worsened hyperalgesia and further suppressed GABA receptor expression. Knockdown of ATG5 via siRNA similarly alleviated pain and restored GABA receptor levels. Interestingly, although the mTOR inhibitor rapamycin alleviated neuropathic pain, it unexpectedly increased spinal P62 expression compared to the DNP group. Administration of leupeptin, a lysosomal protease inhibitor, significantly increased paw withdrawal thresholds on days 1-3 and elevated GABA receptor expression, whereas the proteasomal inhibitor MG132 had no effect. These results demonstrate that STING/ATG5-mediated autophagy promotes DNP through autophagic-lysosomal degradation of GABA receptors, highlighting this pathway as a promising therapeutic target for treating diabetic neuropathic pain.