Upregulation of synapse-associated protein 97 in the spinal dorsal horn exacerbates inflammatory pain through mediating GluA1-containing AMPARs membrane trafficking

Brain Res. 2026 Mar 29:150291. doi: 10.1016/j.brainres.2026.150291. Online ahead of print.

ABSTRACT

Molecules involved in trafficking and organization of glutamate receptors at the synapses between primary afferents and spinal dorsal horn neurons play an important role in the regulation of pain-related synaptic transmission. Synapse-associated protein 97 (SAP97) interacts directly with the AMPARs subunit GluA1 and drives GluA1-containing AMPARs trafficking from the Golgi network to the plasma membrane. However, the role of SAP97 in inflammatory pain remains unclear. In this study we found that intraplantar injection of complete Freund's adjuvant (CFA) in male and female rats led to increase in the production of SAP97 protein in the ipsilateral spinal dorsal horn neurons. Knockdown of SAP97 expression with microinjection of AAV-EGFP-SAP97 shRNA into lumbar 5 spinal dorsal horn alleviated mechanical allodynia and thermal hyperalgesia after CFA injection. Moreover, the association of SAP97 with GluA1 and the membrane insertion of GluA1-containing AMPARs in postsynaptic density (PSD) were also inhibited by the treatment. In addition, overexpression of SAP97 by microinjection of AAV-EGFP-SAP97 into lumbar 5 spinal dorsal horn in naïve rats resulted in abnormal pain, and caused enhanced-interaction of SAP97 with GluA1 and increased-membrane trafficking of GluA1-containing AMPARs in PSD fraction. The established inflammatory pain was partially attenuated by intrathecal injection of NASPM, an antagonist of GluA1-containing AMPARs, on day 7 after CFA injection. Collectively, our results indicate that the CFA-induced upregulation of SAP97 contributes to the pathogenesis of inflammatory pain via promoting GluA1-containing AMPARs membrane trafficking in the spinal dorsal horn. Targeting spinal SAP97 might be a promising therapeutic strategy to treat inflammatory pain.

PMID:41916464 | DOI:10.1016/j.brainres.2026.150291