Cited by 51Pain Mechanisms and TreatmentsCannabis and Cannabinoid ResearchCancer Treatment and Pharmacology

JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy

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Khasabova, Iryna A., Yao, Xu, Paz, Justin, Lewandowski, Cutler T., Lindberg, Amy E., Coicou, Lia, Burlakova, Natasha, Simone, Don A. +1 more·2014·Pharmacological Research

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.

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Crossref · 10.1016/j.phrs.2014.09.008

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Authors
Khasabova, I. A., Yao, X., Paz, J., Lewandowski, C. T., Lindberg, A. E., Coicou, L., Burlakova, N., Simone, D. A., & Seybold, V. S.
Affiliations
University of Minnesota (US)
Corresponding author
Seybold, Virginia S.
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2014-12
Volume
90
Pages
67-75
ISSN
1043-6618 (ISSN-L)
OpenAlex
W2078282973
Cited by
50
References
46
Citations by year
2026: 2 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 4 · 2020: 10 · 2019: 3 · 2018: 8 · 2017: 1 · 2015: 1
FWCI
0.44
Type
journal article
Language
en
Open access
Locations
  • Pharmacological Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (CA138684, DA11471, DA07234)
Topics
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
Keywords
JZL184, cisplatin-induced peripheral neuropathy, mechanical hyperalgesia, endocannabinoid system, anandamide, fatty acid amide hydrolase, CB1 receptor, CB2 receptor, dorsal root ganglia, antihyperalgesia, chemotherapy-induced pain
MeSH terms
Amides, Analgesics, Animals, Antineoplastic Agents, Arachidonic Acids, Cells, Cultured, Cisplatin, Disease Models, Animal, Ethanolamines, Ganglia, Spinal, Glycerides, Hyperalgesia, Indoles, Male, Mesencephalon, Mice, Inbred C3H, Monoacylglycerol Lipases, Morpholines, Neuralgia, Palmitic Acids, Piperidines, Pyrazoles, Skin, Spinal Cord, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Mice, Benzodioxoles, Polyunsaturated Alkamides, Endocannabinoids

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