Advanced glycation end products mediated diabetic neuropathic pain via activation protein tyrosine phosphatase 1B in the spinal cord dorsal horn.

AIMS: Diabetic neuropathic pain (DNP) is a debilitating complication of diabetes mellitus that significantly impairs patients' quality of life. In this study, we aimed to investigate whether much higher plasma advanced glycation end products (AGEs) concentrations discriminate between diabetes-affected individuals with pain and those without pain.

METHODS

We administered exogenous AGEs intravenously to C57BL/6J wild-type mice and assessed nociceptive behaviours, as well as anxiety- and depression-like behaviours. To explore the further mechanism, we knocked out the protein tyrosine phosphatase 1B (PTP1B) in the spinal dorsal horn by injecting the AAV viral construct encoding short-hairpin RNA (shRNA). Electrophysiological recordings were used to assay the N-methyl-D-aspartate receptor (NMDAR) function.

RESULTS

Our results demonstrated that elevated plasma AGEs levels led to significant hyperalgesia, which was alleviated by the specific knockout of PTP1B in the spinal dorsal horn. However, this knockout did not ameliorate AGEs-induced anxiety- and depression-like behaviours. Electrophysiological recordings revealed that AGEs enhanced NMDAR-mediated excitatory postsynaptic currents (eEPSCs) in spinal cord slices, an effect attenuated by PTP1B inhibition. Biochemical analyses showed that AGEs decreased phosphorylation at the Tyr529 site of Src kinase and increased phosphorylation at the Tyr1472 site of the NMDAR subunit 2B (GluN2B); these changes were reversed by PTP1B knockdown.

CONCLUSION

These findings suggest that elevated plasma AGEs contribute to hyperalgesia through a PTP1B-dependent mechanism involving Src/NMDAR signalling in the spinal dorsal horn. Targeting the AGEs-PTP1B-NMDAR pathway may offer new therapeutic strategies for managing DNP.