Up-regulation of microglial chemokine CXCL12 in anterior cingulate cortex mediates neuropathic pain in diabetic mice

Abstract

Diabetic patients frequently experience neuropathic pain, which currently lacks effective treatments. The mechanisms underlying diabetic neuropathic pain remain unclear. The anterior cingulate cortex (ACC) is well-known to participate in the processing and transformation of pain information derived from internal and external sensory stimulation. Accumulating evidence shows that dysfunction of microglia in the central nervous system contributes to many diseases, including chronic pain and neurodegenerative diseases. In this study, we investigated the role of microglial chemokine CXCL12 and its neuronal receptor CXCR4 in diabetic pain development in a mouse diabetic model established by injection of streptozotocin (STZ). Pain sensitization was assessed by the left hindpaw pain threshold in von Frey filament test. Iba1⁺ microglia in ACC was examined using combined immunohistochemistry and three-dimensional reconstruction. The activity of glutamatergic neurons in ACC (ACC^Glu) was detected by whole-cell recording in ACC slices from STZ mice, in vivo multi-tetrode electrophysiological and fiber photometric recordings. We showed that microglia in ACC was significantly activated and microglial CXCL12 expression was up-regulated at the 7-th week post-injection, resulting in hyperactivity of ACC^Glu and pain sensitization. Pharmacological inhibition of microglia or blockade of CXCR4 in ACC by infusing minocycline or AMD3100 significantly alleviated diabetic pain through preventing ACC^Glu hyperactivity in STZ mice. In addition, inhibition of microglia by infusing minocycline markedly decreased STZ-induced upregulation of microglial CXCL12. Together, this study demonstrated that microglia-mediated ACC^Glu hyperactivity drives the development of diabetic pain via the CXCL12/CXCR4 signaling, thus revealing viable therapeutic targets for the treatment of diabetic pain.

Keywords: AMD3100; CXCL12/CXCR4 signaling; anterior cingulate cortex; diabetic neuropathic pain; glutamatergic neurons; microglia; microglia-neuron communication; minocycline.