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Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy.
Curry, Zachary A; Wilkerson, Jenny L; Bagdas, Deniz; Kyte, S Lauren; Patel, Nipa; Donvito, Giulia; Mustafa, Mohammed A; Poklis, Justin L; Niphakis, Micah J; Hsu, Ku-Lung; Cravatt, Benjamin F; Gewirtz, David A; Damaj, M Imad; Lichtman, Aron H.
Afiliación
  • Curry ZA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Wilkerson JL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Bagdas D; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Kyte SL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Patel N; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Donvito G; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Mustafa MA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Poklis JL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Niphakis MJ; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Hsu KL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Cravatt BF; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Gewirtz DA; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Damaj MI; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
  • Lichtman AH; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (Z.A.C., J.L.W., D.B., S.L.K., N.P., G.D., M.A.M., J.L.P., D.A.G., M.I.D., A.H.L.); The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Joll
J Pharmacol Exp Ther ; 366(1): 169-183, 2018 07.
Article en En | MEDLINE | ID: mdl-29540562
ABSTRACT
Although paclitaxel effectively treats various cancers, its debilitating peripheral neuropathic pain side effects often persist long after treatment has ended. Therefore, a compelling need exists for the identification of novel pharmacologic strategies to mitigate this condition. As inhibitors of monoacylglycerol lipase (MAGL), the primary hydrolytic enzyme of the endogenous cannabinoid, 2-arachidonyolglycerol, produces antinociceptive effects in numerous rodent models of pain, we investigated whether inhibitors of this enzyme (i.e., JZL184 and MJN110) would reverse paclitaxel-induced mechanical allodynia in mice. These drugs dose dependently reversed allodynia with respective ED50 values (95% confidence limit) of 8.4 (5.2-13.6) and 1.8 (1.0-3.3) mg/kg. Complementary genetic and pharmacologic approaches revealed that the antiallodynic effects of each drug require both cannabinoid receptors, CB1 and CB2 MJN110 reduced paclitaxel-mediated increased expression of monocyte chemoattractant protein-1 (MCP-1, CCL2) and phospho-p38 MAPK in dorsal root ganglia as well as MCP-1 in spinal dorsal horn. Whereas the antinociceptive effects of high dose JZL184 (40 mg/kg) underwent tolerance following 6 days of repeated dosing, repeated administration of a threshold dose (i.e., 4 mg/kg) completely reversed paclitaxel-induced allodynia. In addition, we found that the administration of MJN110 to control mice lacked intrinsic rewarding effects in the conditioned place preference (CPP) paradigm. However, it produced a CPP in paclitaxel-treated animals, suggesting a reduced paclitaxel-induced aversive state. Importantly, JZL184 did not alter the antiproliferative and apoptotic effects of paclitaxel in A549 and H460 non-small cell lung cancer cells. Taken together, these data indicate that MAGL inhibitors reverse paclitaxel-induced neuropathic pain without interfering with chemotherapeutic efficacy.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Paclitaxel / Inhibidores Enzimáticos / Nocicepción / Hiperalgesia / Monoacilglicerol Lipasas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2018 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Paclitaxel / Inhibidores Enzimáticos / Nocicepción / Hiperalgesia / Monoacilglicerol Lipasas / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2018 Tipo del documento: Article