Abstract
BackgroundCarbon monoxide (CO) synthesized by heme oxygenase 1 (HO-1) exerts antinociceptive effects during inflammation but its role during neuropathic pain remains unknown. Our objective is to investigate the exact contribution of CO derived from HO-1 in the modulation of neuropathic pain and the mechanisms implicated.Methodology/Principal FindingsWe evaluated the antiallodynic and antihyperalgesic effects of CO following sciatic nerve injury in wild type (WT) or inducible nitric oxide synthase knockout (NOS2-KO) mice using two carbon monoxide-releasing molecules (CORM-2 and CORM-3) and an HO-1 inducer (cobalt protoporphyrin IX, CoPP) daily administered from days 10 to 20 after injury. The effects of CORM-2 and CoPP on the expression of HO-1, heme oxygenase 2 (HO-2), neuronal nitric oxide synthase (NOS1) and NOS2 as well as a microglial marker (CD11b/c) were also assessed at day 20 after surgery in WT and NOS2-KO mice. In WT mice, the main neuropathic pain symptoms induced by nerve injury were significantly reduced in a time-dependent manner by treatment with CO-RMs or CoPP. Both CORM-2 and CoPP treatments increased HO-1 expression in WT mice, but only CoPP stimulated HO-1 in NOS2-KO animals. The increased expression of HO-2 induced by nerve injury in WT, but not in NOS2-KO mice, remains unaltered by CORM-2 or CoPP treatments. In contrast, the over-expression of CD11b/c, NOS1 and NOS2 induced by nerve injury in WT, but not in NOS2-KO mice, were significantly decreased by both CORM-2 and CoPP treatments. These data indicate that CO alleviates neuropathic pain through the reduction of spinal microglial activation and NOS1/NOS2 over-expression.Conclusions/SignificanceThis study reports that an interaction between the CO and nitric oxide (NO) systems is taking place following sciatic nerve injury and reveals that increasing the exogenous (CO-RMs) or endogenous (CoPP) production of CO may represent a novel strategy for the treatment of neuropathic pain.
Highlights
Neuropathic pain is a clinical manifestation characterized by the presence of allodynia and hyperalgesia and it is difficult to treat with the most potent analgesic compounds
In sham-operated wild type (WT) mice CORM-2, CORM-3 and cobalt protoporphyrin IX (CoPP) treatments did not produce any effect as compared to sham-operated vehicle treated WT mice for the whole duration of the experiment
In the present study we demonstrated, for first time, that the repeated intraperitoneal administration of CORM-2, CORM-3 or CoPP significantly reduced the mechanical allodynia, thermal hyperalgesia and thermal allodynia induced by the chronic constriction of sciatic nerve in WT mice
Summary
Neuropathic pain is a clinical manifestation characterized by the presence of allodynia and hyperalgesia and it is difficult to treat with the most potent analgesic compounds. Nitric oxide (NO) synthesized either by neuronal (NOS1) or inducible (NOS2) nitric oxide synthase mediates numerous neuropathic pain symptoms via cGMP-PKG pathway activation [2,3,4]. The expression of both enzymes is up-regulated in the spinal cord and dorsal root ganglia of animals with neuropathic pain [5,6,7]. The intraperitoneal administration of a NO donor potentiates the mechanical and thermal hypersensitivity induced by neuropathic pain [10]. Carbon monoxide (CO) synthesized by heme oxygenase 1 (HO-1) exerts antinociceptive effects during inflammation but its role during neuropathic pain remains unknown. Our objective is to investigate the exact contribution of CO derived from HO-1 in the modulation of neuropathic pain and the mechanisms implicated
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