Meningeal macrophages mask incision pain sensitization in male rats.

INTRODUCTION: Meninges surrounding the brain and spinal cord house a variety of immune cell types including macrophages that express the CD206 mannose receptor. Here, we investigated whether CD206(+) macrophages in the meninges play a role in regulating nociception and pain hypersensitivity. METHODS: We selectively depleted CD206(+) macrophages in the meninges around the lumbar spinal cord by intrathecal administration of anti-CD206 coupled to saporin, and determined the effects of CD206(+) macrophage depletion on responses in naïve rats and in those that had received a skin incision to the upper hindlimb. In addition, we used RNAseq to investigate transcriptional changes in lumbar meninges and dorsal root ganglia. Experiments were done in both male and female rats. RESULTS: Depleting CD206(+) meningeal macrophages did not alter basal responses in naïve animals of either sex. By contrast depleting these cells after skin injury induced mechanical hypersensitivity in male rats, without changes in thermal sensitivity but had no effect in females. In male rats with skin incision injury, we found that the mechanical hypersensitivity induced by depleting CD206(+) meningeal macrophages was reversed by administering the NMDAR antagonist, APV. In addition, the hypersensitivity was reversed by an enhancer of KCC2 function, CLP290. Unexpectedly, skin incision caused significant transcriptional changes in the meninges, but only in male rats. CONCLUSIONS: Taken together, our results indicate that while CD206(+) meningeal macrophages do not regulate basal nociception in naïve rats, after skin incision injury, these cells mask mechanical hypersensitivity in male rats only. Thus, we conclude that in a sex-dependent manner CD206(+) meningeal macrophages prevent the spread of pain hypersensitivity after a minor injury. Importantly, the skin incision we used was comparable to that used in "sham" controls in numerous rodent studies of neuropathic pain. Our findings have, therefore, potentially broad implications for re-interpreting results from previous neuropathic pain research.