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Montelukast attenuates neuropathic pain through inhibiting p38 mitogen-activated protein kinase and nuclear factor-kappa B in a rat model of chronic constriction injury.
Anesth Analg. 2014 May; 118(5):1090-6.A&A

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+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24686047

Citation

Zhou, Chenghua, et al. "Montelukast Attenuates Neuropathic Pain Through Inhibiting P38 Mitogen-activated Protein Kinase and Nuclear Factor-kappa B in a Rat Model of Chronic Constriction Injury." Anesthesia and Analgesia, vol. 118, no. 5, 2014, pp. 1090-6.
Zhou C, Shi X, Huang H, et al. Montelukast attenuates neuropathic pain through inhibiting p38 mitogen-activated protein kinase and nuclear factor-kappa B in a rat model of chronic constriction injury. Anesth Analg. 2014;118(5):1090-6.
Zhou, C., Shi, X., Huang, H., Zhu, Y., & Wu, Y. (2014). Montelukast attenuates neuropathic pain through inhibiting p38 mitogen-activated protein kinase and nuclear factor-kappa B in a rat model of chronic constriction injury. Anesthesia and Analgesia, 118(5), 1090-6. https://doi.org/10.1213/ANE.0000000000000174
Zhou C, et al. Montelukast Attenuates Neuropathic Pain Through Inhibiting P38 Mitogen-activated Protein Kinase and Nuclear Factor-kappa B in a Rat Model of Chronic Constriction Injury. Anesth Analg. 2014;118(5):1090-6. PubMed PMID: 24686047.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Montelukast attenuates neuropathic pain through inhibiting p38 mitogen-activated protein kinase and nuclear factor-kappa B in a rat model of chronic constriction injury. AU - Zhou,Chenghua, AU - Shi,Xiaotian, AU - Huang,He, AU - Zhu,Yangzi, AU - Wu,Yuqing, PY - 2014/4/2/entrez PY - 2014/4/2/pubmed PY - 2014/6/13/medline SP - 1090 EP - 6 JF - Anesthesia and analgesia JO - Anesth Analg VL - 118 IS - 5 N2 - 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. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/24686047/Montelukast_attenuates_neuropathic_pain_through_inhibiting_p38_mitogen_activated_protein_kinase_and_nuclear_factor_kappa_B_in_a_rat_model_of_chronic_constriction_injury_ L2 - https://doi.org/10.1213/ANE.0000000000000174 DB - PRIME DP - Unbound Medicine ER -