Mechanism implicated in the anti-allodynic and anti-hyperalgesic effects induced by the activation of heme oxygenase 1/carbon monoxide signaling pathway in the central nervous system of mice with neuropathic pain

Biochem Pharmacol. 2018 Feb:148:52-63. doi: 10.1016/j.bcp.2017.12.007. Epub 2017 Dec 13.

Abstract

The administration of a carbon monoxide-releasing compound (tricarbonyldichlororuthenium(II)dimer, CORM-2) or an heme oxygenase 1 (HO-1) inductor (cobalt protoporphyrin IX, CoPP) exerts potent antinociceptive effects during chronic pain, but their actions in the central nervous system of animals with neuropathic pain have not been evaluated. Our objective is to investigate the effects of these treatments on the oxidative, inflammatory and molecular changes induced by sciatic nerve injury in several brain areas. In male C57BL6 mice with neuropathic pain induced by the chronic constriction of sciatic nerve (CCI), we evaluated the effects of CORM-2 and CoPP on the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1 and NAD(P)H:quinone oxidoreductase-1 (NQO1), the microglial marker (CD11b/c), and the mitogen-activated protein kinases (MAPK) (JNK, ERK½ and P38) in the amygdala, prefrontal cortex, hippocampus, hypothalamus and spinal cord, by using western blot assay. Our results showed that, although CORM-2 and CoPP did not alter the protein levels of Nrf2 and NQO1in none of the areas evaluated, both treatments increased the HO-1 expression and inhibited the overexpression of CD11b/c and/or MAPK phosphorylation caused by nerve injury in the spinal cord, hippocampus and amygdala and/or prefrontal cortex. This study demonstrates that treatment with CORM-2 and/or CoPP further to exert potent anti-allodynic and anti-hyperalgesic actions also produce anti-oxidative and anti-inflammatory effects and inhibit MAPK activated by sciatic nerve injury in specific brain areas. In conclusion, these data reveal new mechanism of action of CORM-2 and CoPP in the central nervous system of animals with persistent neuropathic pain.

Keywords: Analgesia; Carbon monoxide; Heme oxygenase 1; MAPK; Neuropathic pain; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Monoxide / metabolism*
  • Central Nervous System / physiology*
  • Gene Expression Regulation / drug effects
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Hyperalgesia / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / metabolism*
  • Organometallic Compounds / pharmacology
  • Pyrazines / pharmacology
  • Pyrroles / pharmacology
  • Sciatic Nerve / injuries
  • Signal Transduction

Substances

  • Organometallic Compounds
  • Pyrazines
  • Pyrroles
  • cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine
  • tricarbonyldichlororuthenium (II) dimer
  • Carbon Monoxide
  • Heme Oxygenase-1