| Abstract |
Physical disuse is a major risk factor for complex regional pain syndrome type I. Using a rat chronic post-cast pain model, we investigated how oxidative stress modulates pain processing across the neuraxis and evaluated sex as a biological variable. Following immobilization, both sexes developed widespread mechanical hyperalgesia, which was markedly attenuated by the antioxidant Tempol. However, we uncovered a striking phenotypic dissociation: whereas male rats also developed tactile and cold allodynia, female rats completely lacked tactile allodynia. Peripherally, Tempol reduced neurogenic inflammation and suppressed p38 MAPK phosphorylation in peptidergic and nonpeptidergic dorsal root ganglion nociceptors, demonstrating a conserved reactive oxygen species-dependent "hardware" for mechanical pain. Centrally, Tempol inhibited plasticity-related pERK expression in neurokinin1 receptor-positive projection neurons and stimulus-evoked c-Fos in the lumbar (L5) and sacral (S2) dorsal horn. Crucially, the sex-specific behavioral divergence correlated with distinct neuroimmune profiles. Quantitative polymerase chain reaction revealed that while male rats exhibited a robust pro-inflammatory cytokine upregulation (C-C motif chemokine ligand 2, interleukin-1beta, interleukin-6) in the soleus muscle, this inflammatory cascade was markedly blunted in female rats. Consistent with this lack of peripheral inflammatory amplification, optogenetic stimulation of nonnociceptive Aβ fibers failed to induce c-Fos in the female spinal cord and central amygdala-a maladaptive sensory processing shift that Tempol successfully reversed in male rats. These findings demonstrate that disuse-induced oxidative stress initiates sensitization across the neuraxis. Importantly, our study reveals that while reactive oxygen species drives mechanical pain uniformly, the development of tactile allodynia requires a sexually dimorphic inflammatory amplification, underscoring the critical need for personalized, sex-specific therapeutic strategies in pain management.
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