Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive
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We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators--fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively--which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.
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Combined administration of the peripherally-restricted FAAH inhibitor URB937 and the epoxide hydrolase inhibitor TPPU attenuates carrageenan-induced mechanical and thermal hyperalgesia, as well as paw edema, in a synergistic manner.
“Combined administration of the peripherally-restricted FAAH inhibitor, URB937, and the epoxide hydrolase inhibitor, TPPU, attenuates carrageenaninduced mechanical and thermal hyperalgesia, as well as, paw edema, in a synergistic manner (Sasso et al, 2015).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Sasso et al, 2015
FAAH and MAGL inhibitors reduce nociceptive behavior in STZ-injected rats.
“In addition, FAAH (Hasanein et al, 2009;Sasso et al, 2015) and MAGL (Niphakis et al, 2013) inhibitors reduce nociceptive behavior in STZ-injected rats.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Sasso et al, 2015
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“We used the peripherally restricted FAAH inhibitor URB937, which has no access to the brain and spinal cord yet causes pronounced antihyperalgesic effects that are due to its ability to elevate anandamide levels outside the brain and spinal cord [28].”
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- Authors
- Sasso, O., Wagner, K., Morisseau, C., Inceoglu, B., Hammock, B. D., & Piomelli, D.
- Affiliations
- Italian Institute of Technology (IT)
- UC Davis Comprehensive Cancer Center (US)
- University of California, Irvine (US)
- Corresponding author
- Wagner, Karen
- Venue
- Pharmacological Research
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 97
- Pages
- 7-15
- ISSN
- 1043-6618 (ISSN-L)
- PMC
- PMC4464910
- OpenAlex
- W1973847365
- Cited by
- 68
- References
- 58
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 8 · 2017: 3 · 2016: 2 · 2015: 2
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- American Asthma Foundation (R01 ES002710)
- National Institutes of Health (5t32dc008072-05, NS079202, ES002710)
- National Institute on Drug Abuse (R01DA012413, DP1DA031387)
- National Institute on Deafness and Other Communication Disorders (T32 DC-008072, NIH 5T32DC008072-05)
- National Institute of Neurological Disorders and Stroke (U54NS079202, NS079202)
- National Institute of Environmental Health Sciences (NIH 5T32DC008072-05, NIEHS T32ES007059, P42ES004699, ES002710, ES004699, R01ES002710, T32ES007059)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR062866)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- fatty acid amide hydrolase, soluble epoxide hydrolase, FAAH inhibitors, sEH inhibitors, fatty acid ethanolamides, antinociception, hyperalgesia, allodynia, synergistic drug combination, TPPU, isobolographic analysis, peripheral pain, endocannabinoid system
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Analgesics, Animals, Cannabinoids, Carrageenan, Diabetic Neuropathies, Drug Synergism, Enzyme Inhibitors, Epoxide Hydrolases, Hyperalgesia, Male, Pain Measurement, Phenylurea Compounds, Piperidines, Streptozocin, Rats, Sprague-Dawley, Mice, Rats, Small Molecule Libraries
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