The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice
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Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of bioactive fatty acid ethanolamides, such as the endogenous cannabinoid agonist anandamide. Genetic deletion of the faah gene in mice elevates brain anandamide levels and amplifies the antinociceptive effects of this compound. Likewise, pharmacological blockade of FAAH activity reduces nocifensive behavior in animal models of acute and inflammatory pain. In the present study, we investigated the effects of the selective FAAH inhibitor URB597 (KDS-4103, cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester) in the mouse chronic constriction injury (CCI) model of neuropathic pain. Oral administration of URB597 (1-50 mg/kg, once daily) for 4 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single i.p. administration of the cannabinoid CB(1) receptor antagonist rimonabant (1 mg/kg). The antihyperalgesic effects of URB597 were accompanied by a reduction in plasma extravasation induced by CCI, which was prevented by rimonabant (1 mg/kg i.p.) and attenuated by the CB(2) antagonist SR144528 (1 mg/kg i.p.). Oral dosing with URB597 achieved significant, albeit transient, drug levels in plasma, inhibited brain FAAH activity, and elevated spinal cord anandamide content. The results provide new evidence for a role of the endocannabinoid system in pain modulation and reinforce the proposed role of FAAH as a target for analgesic drug development.
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In CCI rats, chronic administration of either AM404 or URB597 suppresses plasma extravasation, a condition associated with neuropeptide release at peripheral levels.
“In CCI rats, chronic administration of either AM404 or URB597 suppresses plasma extravasation, a condition associated with neuropeptide release at peripheral levels.54, 55”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [55]
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- Authors
- Russo, R., LoVerme, J., La Rana, G., Compton, T. R., Parrott, J., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Calignano, A., & Piomelli, D.
- Affiliations
- University of Naples Federico II (IT)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 322
- Issue
- 1
- Pages
- 236-242
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2105546002
- Cited by
- 182
- References
- 40
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 4 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 5 · 2015: 12 · 2014: 14 · 2013: 13 · 2012: 21
- FWCI
- 12.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.escholarship.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Funders
- National Institute on Drug Abuse (DA-3412, R01DA012447, DA12447)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
- Keywords
- URB597, fatty acid amide hydrolase inhibitors, neuropathic pain, chronic constriction injury, endocannabinoid system, anandamide, CB1 receptor, CB2 receptor, rimonabant, SR144528, antihyperalgesia, oral administration, plasma drug concentration, analgesic drug development
- MeSH terms
- Fatty Acid Amide Hydrolases, Administration, Oral, Amidohydrolases, Analgesics, Animals, Benzamides, Capillary Permeability, Carbamates, Enzyme Inhibitors, Hyperalgesia, Male, Spinal Cord, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Mice
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