title: Montelukast attenuates neuropathic pain through inhibiting p38 mitogen-activated protein kinase and nuclear factor-kappa B in a rat model of chronic constriction injury.
abstract: BACKGROUND
  Cysteinyl leukotrienes and their receptors have been shown to be involved in the generation of neuropathic pain. We performed this study to determine the antagonistic effect of montelukast, a cysteinyl leukotrienes receptor antagonist, on neuropathic pain and its underlying mechanism.
  
  
  METHODS
  Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. After CCI, rats were repeatedly administered montelukast (0.5, 1.0, and 2.0 mg/kg intraperitoneal, once daily) for a period of 14 days. Mechanical withdrawal threshold and thermal withdrawal latency were assessed before surgery and on days 1, 3, 5, 7, and 14 after CCI. The levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the spinal cord were determined by enzyme-linked immunosorbent assay. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activation of nuclear factor-kappaB (NF-κB) were assessed by Western blot. The expression of astrocyte marker glial fibrillary acidic protein and microglia marker Iba-1 and the coexpression of p-p38MAPK and Iba-1 or NF-κB and Iba-1 were observed by immunofluorescent staining.
  
  
  RESULTS
  The CCI group displayed significantly decreased mechanical withdrawal threshold and thermal withdrawal latency on days 1, 3, 5, 7 and 14 compared with sham groups (P <0.05, P < 0.0001), which were markedly increased by montelukast (P < 0.05, P < 0.01, P <0.0001). After administration with montelukast for 14 days, as biological markers of inflammation, the levels of IL-1β (P < 0.0001), IL-6 (P = 0.001 for low dosage, P < 0.0001 for middle and high dosages), and TNF-α (P =0.002, 0.001, < 0.0001 for low, middle, and high dosage, respectively) in the spinal cord were lower than those in the CCI group. Western blot analysis demonstrated that montelukast reduced the elevated expression of p-p38 MAPK (P =0.006, 0.015, < 0.0001 for low, middle, and high dosage, respectively) and NF-κB (P < 0.0001) in the spinal cord induced by CCI. Immunofluorescent staining showed that montelukast could inhibit CCI-induced activation of microglia but not astrocytes in the spinal cord. In addition, montelukast (2.0 mg/kg) significantly decreased the number of p38MAPK and Iba-1 or NF-κBp65 and Iba-1 double-positive cells.
  
  
  CONCLUSIONS
  These results suggest that montelukast could effectively attenuate neuropathic pain in CCI rats by inhibiting the activation of p38MAPK and NF-κB signaling pathways in spinal microglia.
authors.affiliation: From the *Department of Pharmacology, School of Pharmacy, Xuzhou Medical College, Xuzhou, P R. China; †Department of Clinical Pharmacy, The Sixth People's Hospital of Xuzhou city, Xuzhou, P R. China; and ‡Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, P R. China.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Zhou
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Shi
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Yangzi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002908:Chronic Disease; D003251:Constriction, Pathologic; D003521:Cyclopropanes; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006358:Hot Temperature; D007378:Interleukins / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D010766:Phosphorylation; D010812:Physical Stimulation; D047428:Protein Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D007378:Interleukins; D020024:Leukotriene Antagonists; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C093875:montelukast