Nociception in a Progressive Multiple Sclerosis Model in Mice Is Dependent on Spinal TRPA1 Channel Activation

Mol Neurobiol. 2020 May;57(5):2420-2435. doi: 10.1007/s12035-020-01891-9. Epub 2020 Feb 24.

Abstract

Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients' daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20-30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG35-55) antigen and CFA (complete Freund's adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice.

Keywords: 4-HNE; A-967079; Central neuropathic pain; EAE; HC 030031; NADPH oxidase.

MeSH terms

  • Acetanilides / pharmacology
  • Acetanilides / therapeutic use
  • Acetophenones / pharmacology
  • Analgesics / pharmacology
  • Analgesics / therapeutic use
  • Animals
  • Antipyrine / analogs & derivatives
  • Antipyrine / pharmacology
  • Antipyrine / therapeutic use
  • Dipyrone / pharmacology
  • Dipyrone / therapeutic use
  • Encephalomyelitis, Autoimmune, Experimental / complications*
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Female
  • Hyperalgesia / drug therapy
  • Hyperalgesia / etiology
  • Hyperalgesia / physiopathology*
  • Mice
  • Mice, Inbred C57BL
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • NADPH Oxidases / antagonists & inhibitors
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology*
  • Neuralgia / drug therapy
  • Neuralgia / etiology
  • Neuralgia / physiopathology*
  • Nociception / drug effects
  • Nociception / physiology*
  • Oligonucleotides, Antisense / pharmacology
  • Oxidative Stress
  • Oximes / pharmacology
  • Oximes / therapeutic use
  • Peptide Fragments / immunology
  • Peptide Fragments / toxicity
  • Pregabalin / pharmacology
  • Pregabalin / therapeutic use
  • Purines / pharmacology
  • Purines / therapeutic use
  • Spinal Cord / physiopathology*
  • TRPA1 Cation Channel / antagonists & inhibitors
  • TRPA1 Cation Channel / biosynthesis
  • TRPA1 Cation Channel / genetics
  • TRPA1 Cation Channel / physiology*
  • Thioctic Acid / pharmacology
  • Up-Regulation / drug effects

Substances

  • 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide
  • A 967079
  • Acetanilides
  • Acetophenones
  • Analgesics
  • Myelin-Oligodendrocyte Glycoprotein
  • Nerve Tissue Proteins
  • Oligonucleotides, Antisense
  • Oximes
  • Peptide Fragments
  • Purines
  • TRPA1 Cation Channel
  • Trpa1 protein, mouse
  • myelin oligodendrocyte glycoprotein (35-55)
  • Pregabalin
  • Dipyrone
  • Thioctic Acid
  • acetovanillone
  • NADPH Oxidases
  • propyphenazone
  • Antipyrine