carbon monoxide reduces neuropathic pain and spinal microglial activation by inhibiting nitric oxide synthesis in mice一氧化碳可以减少神经性疼痛和脊髓小胶质激活通过抑制一氧化氮合成在老鼠身上.pdfVIP

Carbon Monoxide Reduces Neuropathic Pain and Spinal Microglial Activation by Inhibiting Nitric Oxide Synthesis in Mice 1 ´ 1 1 2 1 Arnau Hervera , Sergi Leanez , Roger Negrete , Roberto Motterlini , Olga Pol * ´ ` ` ` 1 Grup de Neurofarmacologia Molecular, Institut d’Investigacio Biomedica Sant Pau Institut de Neurociencies, Universitat Autonoma de Barcelona, Barcelona, Spain, 2 INSERM U955, Equipe 3, Faculty of Medicine, University Paris-Est, Creteil, France Abstract Background: 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. Methodology/Principal Findings: We 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 treatm