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

Abstract

Neuropathic pain is a major, inadequately treated challenge for people with spinal cord injury (SCI). While SCI pain mechanisms are often assumed to be in the CNS, rodent studies have revealed mechanistic contributions from primary nociceptors. These neurons become chronically hyperexcitable after SCI, generating ongoing electrical activity that promotes ongoing pain. A major question is whether extrinsic chemical signals help to drive ongoing electrical activity after SCI. 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. 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. Conditioned behavioral aversion to a chamber associated with peripheral MIF injection suggested that MIF stimulates affective pain. A MIF inhibitor, Iso-1, reversed SCI-induced hyperexcitability. Unlike chronic SCI-induced hyperexcitability, acute MIF-induced hyperexcitability was only partially abrogated by inhibiting ERK signaling. 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. Treatment with conditioned medium from cultures of DRG cells obtained after SCI was sufficient to induce MIF-dependent hyperactivity in neurons from naive rats. Thus, changes in systemic and DRG levels of MIF may help to maintain SCI-induced nociceptor hyperactivity that persistently promotes pain.

Macrophage Migration Inhibitory Factor Promotes Expression of Matrix Metalloproteinases 1 and 3 in Spinal Cord Astrocytes following Gecko Tail Amputation

“…MIF is recognized as an important DAMPs molecule following CNS insults. It is immediately elevated after SCI by inducibly expressed in multiple cells including the neurons, oligodendrocytes, microglia, astrocytes and vascular endothelial cells, in association with neuronal apoptosis and demyelination [35,65]. Also, MIF is able to interact with membrane surface receptor CD74 in microglia and astrocytes to activate inflammatory and chemotactic responses [38,66].…”

“…Injury to the CNS elicits a severe inflammation, resulting in activation of MMPs [33]. As a critical proinflammatory cytokines of injured spinal cord, macrophage migration inhibitory factor (MIF) is inducibly expressed within neurons, microglia, astrocytes, ependymal cells, and epithelial cells of the choroid plexus [34][35][36]. The upregulation of MIF at lesion site of cord has been shown to mediate neuronal apoptosis and promote the production of inflammatory mediators from astrocytes, suggesting a key role of MIF in the neuropathogenesis of the injured spinal cord [37,38].…”

Bradykinin receptor expression and bradykinin-mediated sensitization of human sensory neurons

“…Cells that fired no more than one action potential in response to depolarizing current steps from 50 pA to 2 nA (D50 pA) and at 2-3x rheobase were categorized as "single spiking," similar to the "rapidly adapting" clusters described in rat DRG. 3,48 Cells which fired more than one action potential across multiple stepwise current injections were categorized as "repetitive-spiking" neurons, similar to the "nonadapting" clusters identified in rat DRG. 3,48 Repetitive-spiking neurons were further categorized into adapting and nonadapting clusters based on the presence of spike frequency adaptation.…”

“…3,48 Cells which fired more than one action potential across multiple stepwise current injections were categorized as "repetitive-spiking" neurons, similar to the "nonadapting" clusters identified in rat DRG. 3,48 Repetitive-spiking neurons were further categorized into adapting and nonadapting clusters based on the presence of spike frequency adaptation. A cell was classified as "repetitive adapting" if the cell displayed an inverse U-shaped input-output curve of spike number vs current injected, whereas cells displaying a linearly increasing input-output curve with no spike frequency adaptation were classified as "repetitive nonadapting.…”

“…12 In addition, recent work has suggested that both rodent and human sensory neurons exist in distinct physiological phenotypes that can be distinguished by single-or repetitively firing discharge pattern in response to a stepwise current injection. 3,48,53 Therefore, we tested whether acute BK-induced hyperexcitability is consistent across small-diameter neurons with different physiological phenotypes.…”