Introduction

Complex Regional Pain Syndrome type I (CRPS-I) is a chronic pain condition marked by persistent pain disproportionate to the initial injury, with vasomotor, sudomotor, motor, and trophic disturbances, but no major nerve damage1. Although CRPS-I mechanisms remain unclear, vascular dysfunction likely contributes to its pathophysiology.

The Chronic Post-Ischemia Pain (CPIP) model replicates key CRPS-I features—mechanical hypersensitivity, cold allodynia, and autonomic dysfunction—making it useful to study links between vascular function and sensory changes2. Given the role of cold-sensitive TRP channels in vascular tone and sensory signaling, we evaluated whether CPIP alters vascular responses mediated by these channels.

Material and Methods

All experimental procedures were approved by the Animal Ethics Committee of the University of Valladolid and the Regional Government. CPIP was induced in male C57BL/6 mice aged 9–16 weeks using a 3-hour hind paw ischemia followed by reperfusion. Mechanical, cold and heat sensitivity were assessed using the von Frey, acetone and hot plate tests, respectively. Vascular function in isolated plantar arteries was assessed by pressure myography, one day after injury, comparing phenylephrine- and cold-induced constriction in CPIP and sham animals. TRP mRNA was analyzed by qPCR.

Results

Behavioral testing showed marked mechanical hypersensitivity in the ipsilateral paw of CPIP animals (n=10) vs. sham controls (n=9) from 3 hours to 90 days post-reperfusion (p < 0.001; von Frey test). Cold allodynia was present from 3 hours to 3 days post-induction in CPIP animals (p < 0.001; acetone test), but not at later time points. Thermal sensitivity (hot plate test) did not differ between groups.

In pressure myography, CPIP arteries showed increased sensitivity to phenylephrine than sham arteries (EC50 0.37 vs 1.02 μM; n=5) and a reduced vasoconstrictor response to cold. Accordingly, the cold-to-phenylephrine response ratio was lower in CPIP mice than in sham mice (0.86 ± 0.16 vs 1.41 ± 0.09; n=3). The contribution of TRPM8 and TRPA1 to cold-induced vasoconstriction in CPIP was analyzed with selective agonist and blockers of the channels.

Conclusions

The CPIP model reproduces key CRPS-I sensory features and causes early plantar artery changes, including enhanced phenylephrine sensitivity (increased adrenergic responsiveness) and reduced cold-induced vasoconstriction. These findings suggest that vascular dysfunction and sensory abnormalities interact to contribute to post-ischemic pain, pointing to potential vascular targets for treating CRPS-I and related chronic pain disorders.