The Effects of Cobalt Protoporphyrin IX and Tricarbonyldichlororuthenium (II) Dimer Treatments and Its Interaction with Nitric Oxide in the Locus Coeruleus of Mice with Peripheral Inflammation

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund’s adjuvant (CFA), we assessed: (1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; (2) effects of CoPP and tricarbonyldichlororuthenium(II) dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP, and mitogen-activated protein kinases (MAPK) in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activation in all genotypes. Both treatments blocked NOS1 overexpression, and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation and shows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.