In what was initially designed as an unbiased exploratory study, the authors performed RNA sequencing on dorsal root ganglia (DRGs) from mice that had received a peripheral nerve injury. One of the RNA species that was greatly upregulated after the induction of neuropathic pain encodes colony-stimulating factor 1, or CSF1, a cytokine involved in the differentiation and proliferation of macrophages and microglia. Given that spinal microglia play a central role in the development of neuropathic pain and that CSF1 can be secreted, this initial observation suggested the possibility that CSF1 could be a trigger for microglial activation and the induction of chronic pain. Of course, this scenario would require that CSF1 be transported to the spinal cord and that microglia have the ability to perceive it. In a subsequent series of experiments, this is exactly what the authors showed. After ligation of the dorsal root between the DRG and the spinal cord, they observed an accumulation of CFS1 at the ligature sites, suggesting that, once expressed, the protein travels along the axons of the sensory neurons toward the spinal cord. In concert, the expression of the CSF1 receptor (CSF1R) increased in microglia in the dorsal horn of the spinal cord. Concomitantly, expression of CSF1 was also upregulated in motor neurons, but only those that had been damaged by the peripheral injury. As can be seen on the accompanying image, the motor neurons (blue) that were injured expressed CSF1 (magenta), and were in close proximity with many of the processes emerging from nearby microglia, which themselves expressed CSF1R (cyan).
Thus, all the elements required for CSF1 to act as a messenger between the peripheral nerves and the spinal cord are in place. But does CSF1 actually contribute to the development of pain? To answer this question, the authors used a two-pronged approach. They showed that deletion of the Csf1 gene from sensory neurons prevented the activation of spinal microglia that normally follows peripheral injury and the hypersensitivity to mechanical stimulation that is a hallmark of neuropathic pain. In addition, they found that intrathecal injection of CSF1 in uninjured mice was sufficient to both activate microglia and induce chronic pain.
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