Effect of superoxide on the development and maintenance of mechanical allodynia in a rat model of chronic post-ischemia pain

Abstract

BackgroundReactive oxygen species and inflammatory responses contribute to the development of neuropathic pain. Superoxide serves to mediate cell signaling processes and tissue injury during inflammation. We examined the effects of superoxide on the development and maintenance of mechanical allodynia, as well as its contribution to central sensitization in a superoxide-rich animal model of neuropathic pain.MethodsChronic post-ischemia pain (CPIP) was induced via the left hindpaw ischemia for 3 h, followed by reperfusion. Superoxide dismutase (4,000 U/kg, i.p.) was administered either 5 min before ischemia (BI), 5 min before reperfusion (BR), or 3 days after reperfusion (3AR). Withdrawal thresholds of the four paws were measured to assess the mechanical allodynia and the effects of circulating xanthine oxidase (XO)-mediated superoxide production. In addition, we measured the levels of N-methyl D-aspartate receptor subunit 1 phosphorylation (p-NR1) in the ipsilateral and contralateral spinal cord (L4-6), by Western blotting, to examine the superoxide-mediated central sensitization. Superoxide production was assessed by allopurinol-sensitive, XO-mediated lipid peroxidation of the spinal cord and gastrocnemius muscles.ResultsWithdrawal thresholds of forepaws did not vary across the 7 days of testing. In the hindpaws, both ipsilateral and contralateral mechanical allodynia was most attenuated in the BR group, followed by the BI and 3AR groups. The degree of NR1 activation was in contrast to the changes in the withdrawal thresholds.ConclusionsThese data suggest that superoxide is involved in the development and maintenance of mechanical allodynia, particularly via central sensitization in the spinal cord.

Inhibition of reactive oxygen species downregulates the MAPK pathway in rat spinal cord after limb ischemia reperfusion injury

“…There is accumulating evidence that the interaction between MAPK activation and ROS is linked to diverse pathologic conditions including IR injury, neuropathic pain [28], and inflammatory disease [29]. In a previous study, we found that ROS led to mechanical allodynia through central sensitization by N-methyl-D-aspartate (NMDA) receptor activation in the spinal cord [30]. This prompted us to hypothesize that ROS may activate intracellular signaling pathways in the spinal cord.…”

Electroacupuncture Alleviates Mechanical Allodynia in a Rat Model of Complex Regional Pain Syndrome Type-I via Suppressing Spinal CXCL12/CXCR4 Signaling

“…The mechanical allodynia of CPIP rat B A L1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 model can fully develop within 3 days and maintain thereafter. 8,14 Thus we waited 4 days after the model establishment and applied 2/100 Hz EA to rats on day 4. We found that EA can still produce robust antiallodynic effect on both ipsilateral and contralateral hind paw of CPIP model rats (Supplement Fig 1).…”

Comparative Study of Chronic Postischemic Pain Models in Mice: O-Ring Versus Tie Method

“…Future research should examine prolonged hind limb ischemia-reperfusion, which is known to induce inflammatory cascades and contribute to the formation of reactive oxygen species (1,7,(40)(41)(42)(43).…”