Our findings suggest that O2(-) and NO mediate IR injury-induced chronic pain, and that ROS scavengers administered during the peri-reperfusion period have long-term analgesic effects.

BackgroundRecent studies indicate that reactive oxygen species (ROS) are involved in persistent pain, including neuropathic and inflammatory pain. Since the data suggest that ROS are involved in central sensitization, the present study examines the levels of activated N-methyl-D-aspartate (NMDA) receptors in the dorsal horn after an exogenous supply of three antioxidants in rats with chronic post-ischemia pain (CPIP). This serves as an animal model of complex regional pain syndrome type-I induced by hindpaw ischemia/reperfusion injury.MethodsThe application of tight-fitting O-rings for a period of three hours produced CPIP in male Sprague-Dawley rats. Allopurinol 4 mg/kg, allopurinol 40 mg/kg, superoxide dismutase (SOD) 4,000 U/kg, N-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg and SOD 4,000 U/kg plus L-NAME 10 mg/kg were administered intraperitoneally just after O-ring application and on the first and second days after reperfusion. Mechanical allodynia was measured, and activation of the NMDA receptor subunit 1 (pNR1) of the lumbar spinal cord (L4-L6) was analyzed by the Western blot three days after reperfusion.ResultsAllopurinol reduced mechanical allodynia and attenuated the enhancement of spinal pNR1 expression in CPIP rats. SOD and L-NAME also blocked spinal pNR1 in accordance with the reduced mechanical allodynia in rats with CPIP.ConclusionsThe present data suggest the contribution of superoxide, produced via xanthine oxidase, and the participation of superoxide and nitric oxide as a precursor of peroxynitrite in NMDA mediated central sensitization. Finally, the findings support a therapeutic potential for the manipulation of superoxide and nitric oxide in ischemia/reperfusion related pain conditions.

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Background: Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes including complex regional pain syndromes (CRPS). Underlying mechanisms for the development of such pain are still a matter of investigation. Several studies suggest that activation of the N-methyl-D-aspartate (NMDA) receptor is essential for central sensitization as a base for persistent pain. The aim is to assess whether alteration of NMDA receptor expression correlates with the contralateral allodynia in the chronic post-ischemia pain (CPIP) model rats representing CRPS-Type I.Methods: Application of a tight-fitting tourniquet for a period of 3 hours before reperfusion produced CPIP in male Sprague-Dawley rats. The mechanical paw withdrawal thresholds to von Frey stimuli (using a dynamic plantar aesthesiometer) were measured as pain indicators in ipsilateral and contralateral hindpaws. Phosphorylation of the NMDA receptor 1 subunit (pNR1), assessed with Western blot, was measured in the contralateral L4-6 spinal cord.Results: Ipsilateral and contralateral mechanical allodynia is present at 4 hours after reperfusion, peaked at 3 days, and continued for 7 days after reperfusion. The relative density of pNR1 of CPIP rats significantly decreased in the contralateral L4-6 spinal cord compared to baseline value (P ＜ 0.05). There was significant correlation between paw withdrawal threshold and the relative density of pNR1 (ipsilateral; R 2 = 0.75, P ＜ 0.01, contralateral; R 2 = 0.60, P ＜ 0.01).Conclusions: These data suggest that pNR1 is correlated to the contralateral mechanical allodynia in CPIP rats.

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