Reactive oxygen species contribute to neuropathic pain and locomotor dysfunction via activation of CamKII in remote segments following spinal cord contusion injury in rats

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Abstract

Summary

We report that reactive oxygen species (ROS)–mediated activation of CaMKII (phosphorylated, pCAMKII) contributes to below-level neuropathic pain following thoracic spinal cord contusion injury. Following thoracic SCI, increased intensity of pCamKII and Dhet, a ROS marker, was produced in the lumbar spinal dorsal horn neurons, respectively, and was suppressed by ROS scavenger treatment. Mechanical allodynia in hind paws and neuronal hyperexcitability in the lumbar spinal dorsal horn neurons induced by spinal cord injuries were attenuated by ROS scavenger treatment. To demonstrate causality, ROS donor treatment produced mechanical allodynia and increased intensity of pCamKII. In addition, treatment with KN-93, which prevents CaMKII activation, significantly decreased mechanical allodynia induced by spinal cord injuries. In addition, blocking ROS and its overproduction improved recovery of locomotion. This is the first evidence that ROS contribute to neuropathic pain via activation of CamKII in the spinal dorsal horn neurons. Furthermore, targeting key intracellular signaling is a novel and useful therapeutic strategy for treating central neuropathic pain.

In this study, we examined whether blocking spinal cord injury (SCI)-induced increases in reactive oxygen species (ROS) by a ROS scavenger would attenuate below-level central neuropathic pain and promote recovery of locomotion. Rats with T10 SCI developed mechanical allodynia in both hind paws and overproduction of ROS, as assayed by Dhet intensity, in neurons in the lumbar 4/5 dorsal horn (*P < 0.05). To scavenge ROS, phenyl-N-tert-butylnitrone (PBN, a ROS scavenger) was administered immediately after SCI and for 7 consecutive days (early treatment) by either intrathecal (it; 1 and 3 mg) or systemic (ip; 10, 50 and 100 mg) injections. In addition, the high doses of it (3 mg) or ip (100 mg) injections were performed at 35 days (delayed treatment) after SCI. High doses of PBN (ip, 100 mg, and it, 3 mg) significantly attenuated mechanical allodynia in both hind paws at both early and delayed treatments, respectively (*P < 0.05). The abnormal hyperexcitability of wide dynamic range neurons after SCI was significantly attenuated by both early and delayed PBN treatment (*P < 0.05). Early PBN treatment (100 mg, ip, and 3 mg, it) attenuated overproduction of ROS in neurons in the lumbar 4/5 dorsal horn. In addition, it and ip t-BOOH (ROS donor) treatment dose-dependently produced mechanical allodynia in both hind paws (*P < 0.05). Both SCI and t-BOOH treatment groups showed significantly increased phospho-CamKII (pCamKII) expression in neurons and KN-93 (an inhibitor of pCamKII) significantly attenuated mechanical allodynia (*P < 0.05). In addition, high doses of PBN significantly promoted the recovery of locomotion (*P < 0.05). In conclusion, the present data suggest that overproduction of ROS contribute to sensory and motor abnormalities in remote segments below the lesion after thoracic SCI.

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