![]() ![]() Available treatments, including opioids, remain inadequate. ![]() Pain can drastically impair quality of life, and produces substantial economic and social burdens. SIGNIFICANCE STATEMENT Chronic neuropathic pain is a major challenge for people with spinal cord injury (SCI). Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain. Treatment with conditioned medium from cultures of DRG cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from naive rats. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors from naive animals, after SCI induced a long-lasting conversion from a highly excitable nonaccommodating type to a rapidly accommodating, hypoexcitable type, possibly as a homeostatic response to prolonged depolarization. Unlike chronic SCI-induced hyperexcitability, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. Probable nociceptors isolated from male rats and exposed to an MIF concentration reported in human plasma (1 ng/ml) showed hyperactivity similar to that induced by SCI, although, surprisingly, a 10-fold higher concentration failed to increase excitability. People living with SCI exhibit acute and chronic elevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models. A major question is whether extrinsic chemical signals help to drive ongoing electrical activity after SCI. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity that promotes ongoing pain. ![]() While SCI pain mechanisms are often assumed to be in the CNS, rodent studies have revealed mechanistic contributions from primary nociceptors. Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). ![]()
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