Macrophage Migration Inhibitory Factor (MIF) Makes Complex Contributions to Pain-Related Hyperactivity ofNociceptors after Spinal Cord Injury

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms areoften assumed to be in the CNS, rodent studies have revealed mechanistic contributions from primary nociceptors. These neuronsbecome chronically hyperexcitable after SCI, generating ongoing electrical activity that promotes ongoing pain. A major question iswhether extrinsic chemical signals help to drive ongoing electrical activity after SCI. People living with SCI exhibit acute and chronicelevation of circulating levels of macrophage migration inhibitory factor (MIF), a cytokine implicated in preclinical pain models.Probable nociceptors isolated from male rats and exposed to an MIF concentration reported in human plasma (1 ng/ml) showed hyper-activity similar to that induced by SCI, although, surprisingly, a 10-fold higher concentration failed to increase excitability. Conditionedbehavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibi-tor, Iso-1, reversed SCI-induced hyperexcitability. Unlike chronic SCI-induced hyperexcitability, acute MIF-induced hyperexcitability wasonly partially abrogated by inhibiting ERK signaling. Unexpectedly, MIF concentrations that induced hyperactivity in nociceptors fromnaive 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. Treatment with conditioned medium from culturesof DRG cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from naive rats. Thus, changes in sys-temic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain.

Automated summary

Neuropathic pain is a major challenge for people with spinal cord injury, and the mechanisms behind it involve chronic hyperexcitability of primary nociceptors. This study found that the cytokine MIF, which is elevated in individuals with SCI, contributes to ongoing electrical activity and promotes pain. It also discovered that MIF concentrations can induce hyperactivity in nociceptors and that blocking MIF signaling can reverse hyperexcitability. Moreover, the study suggests that changes in systemic and DRG levels of MIF play a role in maintaining nociceptor hyperactivity after SCI.