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Cannabinoid Type 2 Receptor System Modulates Paclitaxel-Induced Microglial Dysregulation and Central Sensitization in Rats

  • Jiang Wu
    Affiliations
    Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
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  • Mark Hocevar
    Affiliations
    Brown University, Providence, Rhode Island
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  • Bihua Bie
    Affiliations
    Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
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  • Joseph F. Foss
    Affiliations
    Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
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  • Mohamed Naguib
    Correspondence
    Address reprint requests to Mohamed Naguib, MB, BCh, MSc, FCARCSI, MD, Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code NB3-78, Cleveland, OH 44195.
    Affiliations
    Anesthesiology Institute, Cleveland Clinic, and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
    Search for articles by this author
Published:November 08, 2018DOI:https://doi.org/10.1016/j.jpain.2018.10.007

      Highlights

      • MDA7 (1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl] carbonyl) piperidine) modulated microglial expression of cytokines induced by paclitaxel.
      • MDA7 modulated epigenetic upregulation of microglial brain-derived neurotrophic factor (BDNF) induced by paclitaxel.
      • BDNF regulated glutamatergic and GABAergic transmission in dorsal horn.
      • MDA7 (cannabinoid type 2 [CB2] agonist) attenuated paclitaxel-induced molecular and behavioral changes.

      Abstract

      Paclitaxel induces microglial activation and production of proinflammatory mediators in the dorsal horn, which contribute to the development and maintenance of central sensitization and pain behavior. MDA7, 1-([3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl]carbonyl) piperidine, is a novel highly selective cannabinoid type 2 (CB2) agonist. We tested the hypothesis that activation of CB2 receptor by MDA7 modulates microglial dysregulation, suppresses the overexpression of brain-derived neurotrophic factor (BDNF) in microglia in the dorsal horn, and attenuates the central sensitization and pain behavior induced by paclitaxel. For 4 consecutice days, groups of rats randomly received saline or 1.0 mg/kg of paclitaxel daily intraperitoneally for a total cumulative dose of 4 mg/kg. MDA7 15 mg/kg intraperitoneally or vehicle were administered 15 min before administering paclitaxel for 4 days and then continued for another 10 days. Behavioral and molecular studies were performed. Paclitaxel induced the expression of CB2 receptors and production of interleukin (IL)-6 in microglia in the dorsal horn. MDA7 attenuated the expression of IL-6 and promoted the expression of IL-10. Paclitaxel induced epigenetic upregulation of IRF8 and P2X purinoceptor 4 (P2X4) in microglia and subsequently increased the expression of alpha isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIα), transcriptional factors p-CREB and ΔFosB, leading to the overproduction of BDNF in microglia. Paclitaxel also upregulated the expression of glutamate receptor subunits GluR1 and NR2B, decreased the expression of K+-Cl cotransporter, and induced mechanical allodynia in rats. All of the aforementioned molecular changes were attenuated by MDA7. Our data show that MDA7 attenuated paclitaxel-induced molecular and behavioral changes in rats.
      Perspective: This study provides evidence that paclitaxel induced microglia dysregulation and epigenetically upregulated the microglial expression of BDNF, which led to sensitization of dorsal horn neurons and mechanical allodynia in rats. The CB2 agonist MDA7 alleviated these pathological processes. MDA7 represents an innovative therapeutic approach for treatment of chemotherapy-induced neuropathy.

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