SEX-DEPENDENT ANALGESIC EFFECTS OF MIF INHIBITION BY ISO-1 IN A MOUSE MODEL OF NEUROPATHIC PAIN

Peripheral neuropathic pain profoundly affects quality of life and remains difficult to manage. Following nerve injury, complex peripheral and central mechanisms are activated, involving extensive neuroimmune interactions. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the pathogenesis of neuropathic pain. This study examined the effects of ISO-1, a pharmacological MIF antagonist, in a murine model of chronic constriction injury (CCI) of the sciatic nerve in adult males and females.
Behavioral, electrophysiological, immunohistochemical, and molecular analyses were performed to assess ISO-1 efficacy. CCI induced pronounced mechanical allodynia and thermal hyperalgesia, accompanied by enhanced excitatory and reduced inhibitory synaptic currents in neurons of the superficial dorsal horn. Moreover, CCI promoted macrophage accumulation within the sciatic nerve lesion and dorsal root ganglia (DRG). ISO-1 treatment markedly attenuated pain hypersensitivity, restored synaptic balance, and reduced immune cell infiltration in male mice, whereas these effects were absent in females. The DRG expression levels of MIF mRNA mirrored this sexual dimorphism.
Collectively, our findings identify MIF as a key mediator of neuropathic pain and demonstrate that pharmacological MIF inhibition by ISO-1 confers analgesic effects in a sex-dependent manner. These results highlight the therapeutic potential of MIF antagonism for neuropathic pain while underscoring the importance of sex-specific mechanisms in treatment response. Supported by GACR 24-10712S.