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JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy.
Pharmacol Res. 2014 Dec; 90:67-75.PR

Abstract

Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [(3)H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [(3)H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model.

Authors+Show Affiliations

Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.College of Biological Sciences, University of Minnesota, USA.Pharmacology Graduate Program, University of Minnesota, USA.Department of Neuroscience, Medical School, University of Minnesota, USA.Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, USA.Department of Neuroscience, Medical School, University of Minnesota, USA. Electronic address: vseybold@umn.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25304184

Citation

Khasabova, Iryna A., et al. "JZL184 Is Anti-hyperalgesic in a Murine Model of Cisplatin-induced Peripheral Neuropathy." Pharmacological Research, vol. 90, 2014, pp. 67-75.
Khasabova IA, Yao X, Paz J, et al. JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. Pharmacol Res. 2014;90:67-75.
Khasabova, I. A., Yao, X., Paz, J., Lewandowski, C. T., Lindberg, A. E., Coicou, L., Burlakova, N., Simone, D. A., & Seybold, V. S. (2014). JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. Pharmacological Research, 90, 67-75. https://doi.org/10.1016/j.phrs.2014.09.008
Khasabova IA, et al. JZL184 Is Anti-hyperalgesic in a Murine Model of Cisplatin-induced Peripheral Neuropathy. Pharmacol Res. 2014;90:67-75. PubMed PMID: 25304184.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy. AU - Khasabova,Iryna A, AU - Yao,Xu, AU - Paz,Justin, AU - Lewandowski,Cutler T, AU - Lindberg,Amy E, AU - Coicou,Lia, AU - Burlakova,Natasha, AU - Simone,Don A, AU - Seybold,Virginia S, Y1 - 2014/10/07/ PY - 2014/08/15/received PY - 2014/09/29/revised PY - 2014/09/30/accepted PY - 2014/10/12/entrez PY - 2014/10/12/pubmed PY - 2015/8/14/medline KW - 2-Arachidonoyl-glycerol KW - Anandamide KW - Cannabinoid receptor KW - Cisplatin KW - Dorsal root ganglion KW - Hyperlagesia KW - JZL184 KW - Spinal cord SP - 67 EP - 75 JF - Pharmacological research JO - Pharmacol Res VL - 90 N2 - Cisplatin has been used effectively to treat a variety of cancers but its use is limited by the development of painful peripheral neuropathy. Because the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG) is anti-hyperalgesic in several preclinical models of chronic pain, the anti-hyperalgesic effect of JZL184, an inhibitor of 2-AG hydrolysis, was tested in a murine model of cisplatin-induced hyperalgesia. Systemic injection of cisplatin (1mg/kg) produced mechanical hyperalgesia when administered daily for 7 days. Daily peripheral administration of a low dose of JZL184 in conjunction with cisplatin blocked the expression of mechanical hyperalgesia. Acute injection of a cannabinoid (CB)-1 but not a CB2 receptor antagonist reversed the anti-hyperalgesic effect of JZL184 indicating that downstream activation of CB1 receptors suppressed the expression of mechanical hyperalgesia. Components of endocannabinoid signaling in plantar hind paw skin and lumbar dorsal root ganglia (DRGs) were altered by treatments with cisplatin and JZL184. Treatment with cisplatin alone reduced levels of 2-AG and AEA in skin and DRGs as well as CB2 receptor protein in skin. Combining treatment of JZL184 with cisplatin increased 2-AG in DRGs compared to cisplatin alone but had no effect on the amount of 2-AG in skin. Evidence that JZL184 decreased the uptake of [(3)H]AEA into primary cultures of DRGs at a concentration that also inhibited the enzyme fatty acid amide hydrolase, in conjunction with data that 2-AG mimicked the effect of JZL184 on [(3)H]AEA uptake support the conclusion that AEA most likely mediates the anti-hyperalgesic effect of JZL184 in this model. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/25304184/JZL184_is_anti_hyperalgesic_in_a_murine_model_of_cisplatin_induced_peripheral_neuropathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(14)00161-3 DB - PRIME DP - Unbound Medicine ER -