Abstract
BackgroundReactive oxygen and nitrogen species are key molecules that mediate neuropathic pain. Although hydrogen is an established antioxidant, its effect on chronic pain has not been characterized. This study was to investigate the efficacy and mechanisms of hydrogen-rich normal saline induced analgesia.Methodology/Principal findingsIn a rat model of neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), intrathecal injection of hydrogen-rich normal saline relieved L5 SNL-induced mechanical allodynia and thermal hyperalgesia. Importantly, repeated administration of hydrogen-rich normal saline did not lead to tolerance. Preemptive treatment with hydrogen-rich normal saline prevented development of neuropathic pain behavior. Immunofluorochrome analysis revealed that hydrogen-rich normal saline treatment significantly attenuated L5 SNL-induced increase of 8-hydroxyguanosine immunoreactive cells in the ipsilateral spinal dorsal horn. Western blot analysis of SDS/PAGE-fractionated tyrosine-nitrated proteins showed that L5 SNL led to increased expression of tyrosine-nitrated Mn-containing superoxide dismutase (MnSOD) in the spinal cord, and hydrogen-rich normal saline administration reversed the tyrosine-nitrated MnSOD overexpression. We also showed that the analgesic effect of hydrogen-rich normal saline was associated with decreased activation of astrocytes and microglia, attenuated expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord.Conclusion/SignificanceIntrathecal injection of hydrogen-rich normal saline produced analgesic effect in neuropathic rat. Hydrogen-rich normal saline-induced analgesia in neuropathic rats is mediated by reducing the activation of spinal astrocytes and microglia, which is induced by overproduction of hydroxyl and peroxynitrite.
Highlights
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are key factors in the pathogenesis of central nervous system (CNS) disorders
L5 spinal nerve ligation (L5 SNL) was performed on 10 rats, a procedure that resulted in marked reduction in mechanical thresholds
Note that mechanical thresholds were markedly reduced after nerve ligation, and administration of hydrogenrich normal saline (HRS) raised these thresholds for about 8 hrs before the thresholds declined to the level of the normal saline (NS) group
Summary
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are key factors in the pathogenesis of central nervous system (CNS) disorders. Studies have shown that ROS and the superoxide byproduct peroxynitrite (ONOO2) are involved in neuropathic pain [1, 2]. Free radical scavengers such as TEMPOL, phenyl-Ntert-butylnitrone (PBN) and vitamin E, could alleviate neuropathic pain [3,4,5,6], delivery these agents directly to the sub-arachnoid space produced more potent effects, suggesting that antioxidants exert their anti-allodynic action mainly at the spinal levels [7]. Leakage of high energy electrons along the mitochondria electron transport chain causes the formation of superoxide (O22), hydrogen peroxide (H2O2) and peroxynitrite [8,9,10,11]. This study was to investigate the efficacy and mechanisms of hydrogen-rich normal saline induced analgesia
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