JZL184 is anti-hyperalgesic in a murine model of cisplatin-induced peripheral neuropathy
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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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FAAH and MAGL inhibitors reduced cisplatin-induced mechanical and cold allodynia, which are CB1 and CB2 receptors-mediated.
“Finally, FAAH and MAGL inhibitors reduced cisplatin-induced mechanical and cold allodynia, which are CB 1 and CB 2 receptors-mediated (Guindon et al, 2013;Khasabova et al, 2014).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Khasabova et al, 2014
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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)
- PMC
- PMC4268146
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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