23: Sex-dependent Analgesia by MIF Inhibition: ISO-1 Reduces Neuropathic Pain after Sciatic Nerve Injury

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, , , , , , , , , , Neuroimmunology, Pharmacological interventions, Electrophysiology

Background and Aims: Peripheral neuropathic pain markedly impairs quality of life and remains challenging to treat. After peripheral nerve injury, coordinated peripheral and central processes drive persistent hypersensitivity, shaped by bidirectional signaling between immune cells and nociceptive pathways. Macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine, has emerged as a contributor to these neuroimmune cascades. We investigated whether pharmacological MIF antagonism with ISO-1 modifies neuropathic pain in adult mice using chronic constriction injury (CCI) of the sciatic nerve. Outcomes were evaluated in both males and females to address potential sex-dependent differences.

Methods: Adult male and female C57BL/6J mice underwent CCI of the sciatic nerve and received intraperitoneal ISO-1 (20 mg/kg; 1 h pre-CCI, then daily through day 6) or vehicle. Mechanical allodynia and heat hyperalgesia were quantified (electronic von Frey, hot plate) over acute and extended time courses. Spinal dorsal horn synaptic transmission was assessed by whole-cell patch clamp (sEPSCs, sIPSCs, optogenetically evoked IPSCs), while macrophage accumulation (CD68, CD206) in DRGs/sciatic nerve and inflammatory transcripts (MIF, CD74, CCL2, CD68, CD206) were measured by immunohistochemistry and qPCR.

Results: ISO-1 attenuated CCI-induced mechanical allodynia and thermal hyperalgesia in males, with analgesic effects persisting after treatment cessation, but showed no behavioral efficacy in females. In male spinal cord slices, ISO-1 reduced injury-enhanced excitatory drive (lower sEPSC frequency) and restored impaired evoked inhibition (normalized light-evoked IPSC amplitude), indicating partial correction of the excitatory–inhibitory imbalance. ISO-1 decreased macrophage-associated signals (CD68/CD206 immunoreactivity in DRGs and selected sciatic nerve segments) and produced sex-dependent changes in expression of different mRNA in DRGs (MIF, CD74, CCL2, CD68, CD206).

Conclusions: Systemic inhibition of MIF with ISO-1 attenuated pain in the CCI model in a sex-dependent manner. In males, ISO-1 reduced behavioral hypersensitivity in parallel with dampened macrophage-associated responses in DRG and injured nerve, and partial normalization of dorsal horn synaptic processing consistent with reduced central sensitization. In contrast, females showed no analgesic benefit despite modulation of the MIF-related pathway, indicating divergent neuroimmune drivers of neuropathic pain. These data position MIF as a possible therapeutic target while suggesting that translation of MIF antagonism will require sex-stratified study designs and personalized treatment strategies for neuropathic pain. Supported by GACR 24-10712S.

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Presenting Author: Jiri Palecek MD, PhD
Submitting Author: Jiri Palecek

Senior Author: Jiri Palecek MD, PhD

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Monica Pontearso: PhD - Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
• Anirban Bhattacharyya: PhD - Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
• Daniel Vasconcelos: MSc - Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
• Pavel Adamek: PhD - Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
• Jakub Slepicka: MSc - Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
• Diana Spicarova: PhD - Laboratory of Pain Research, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic