Regulation of nociceptor excitability by macrophage migration inhibitory factor (MIF) as a therapeutic strategy for chronic pain treatment after spinal cord injury - Project summary Affecting over half of people living with spinal cord injury (SCI), chronic neuropathic pain can have a disastrous impact on quality of life. Despite recent advances in understanding neuropathic pain, its mechanisms remain elusive and it is still largely resistant to available treatments, including opioids. Increasing evidence indicates that mechanisms important for chronic SCI pain are located within the cell bodies of nociceptive sensory neurons and their sensory terminals. After moderate contusive injury at the thoracic level in rodents, a nociceptor hyperactive state exhibiting ongoing, apparently spontaneous, firing of action potentials can drive chronic pain. Dorsal root ganglia (DRGs) receive circulating influences from the blood and cerebrospinal fluid due to DRGs’ rich vascularization, lack of an effective vascular permeability barrier, and intrathecal location. Thus, circulating factors (e.g., hormones, cytokines) and their downstream signaling pathways that drive nociceptor hyperactivity may be logical therapeutic targets for relieving SCI pain. We recently showed that macrophage migration inhibitory factor (MIF), a key pro-inflammatory cytokine that has been understudied in preclinical models of inflammatory and neuropathic pain, induces a hyperactive state in dissociated nociceptor cell bodies comparable to that produced by SCI. MIF is effective when delivered at concentrations reported acutely and chronically in the plasma of SCI patients. Nociceptors from SCI rats exhibit a higher sensitivity to MIF, a MIF inhibitor suppresses this hyperactive state in vitro, and injections of MIF in naïve rats trigger an affective pain state assessed by operant behavioral tests. Preliminary findings reveal that i) CXCR2 receptors contribution to MIF hyperexcitability, ii) isolated human nociceptors are hyperexcitable upon MIF treatment, and iii) nociceptors from naïve rats show hyperexcitability when exposed to plasma from SCI rats, providing direct evidence for circulating excitatory factors released after injury. This multidisciplinary and highly collaborative project will define the contribution of MIF and its downstream signaling to SCI-induced neuropathic pain. The guiding hypothesis is that after SCI, MIF stimulates a nociceptor hyperactive state in a CXCR2/CXCR4-dependent manner, and that pharmacological inhibition of MIF and/or its receptors will alleviate chronic ongoing pain by reducing nociceptor hyperactivity. This hypothesis will be tested using nociceptors from rodents and humans. Aim 1 will determine the MIF signaling driving the nociceptor hyperactive state. Aim 2 will test the prediction that inhibition of MIF and/or its signaling can reduce chronic pain behavior after SCI. Aim 3 will validate MIF and/or its signaling as a promising therapeutic target by characterizing the effects of MIF and its signaling on isolated human nociceptors. A novel in vitro electrophysiological assay using rodent nociceptors will be used to test plasma from SCI patients for contributions of increased circulating MIF to nociceptor hyperactivity, and potentially for many other circulating factors helping to drive chronic pain.
