Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models
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Unlabelled Common pharmacological treatments of neuropathic and chronic inflammatory pain conditions generally lack efficacy and/or are associated with significant untoward side effects. However, recent preclinical data indicate that combined inhibition of cyclooxygenase (COX) and fatty acid amide hydrolase (FAAH), the primary catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA), produces enhanced antinociceptive effects in a variety of murine models of pain. Accordingly, the primary objective of the present study was to investigate the consequences of co-administration of the COX inhibitor diclofenac and the highly selective FAAH inhibitor PF-3845 in models of neuropathic pain (i.e., chronic constrictive injury of the sciatic nerve (CCI)) and inflammatory pain induced by an intraplantar injection of carrageenan. Here, we report that combined administration of subthreshold doses of these drugs produced enhanced antinociceptive effects in CCI and carrageenan pain models, the latter of which was demonstrated to require both CB1 and CB2 receptors. The combined administration of subthreshold doses of these drugs also increased AEA levels and decreased prostaglandin levels in whole brain. Together, these data add to the growing research that dual blockade of FAAH and COX represents a potential therapeutic strategy for the treatment of neuropathic and inflammatory pain states.Perspective Tandem inhibition of FAAH and COX attenuates inflammatory and neuropathic pain states, which may avoid potentially harmful side effects of other therapeutic options, such as NSAIDs or opioids.
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Mechanical allodynia induced by carrageenan injection is reduced by coadministration of the FAAH inhibitor PF-3845 and the NSAID diclofenac.
“Mechanical allodynia induced by carrageenan injection is also reduced by coadministration of the FAAH inhibitor PF-3845 and the NSAID diclofenac (Grim et al, 2014).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Grim et al, 2014
The anti-allodynic effect of PF-3845 and diclofenac is blocked by SR144528 or rimonabant, indicating that both cannabinoid receptors mediate this antinociceptive effect.
“The anti-allodynic effect is blocked by SR144528 or rimonabant, indicating that both cannabinoid receptors mediate this antinociceptive effect (Grim et al, 2014).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Grim et al, 2014
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- Authors
- Grim, T. W., Ghosh, S., Hsu, K.-L., Cravatt, B. F., Kinsey, S. G., & Lichtman, A. H.
- Affiliations
- Virginia Commonwealth University (US)
- Scripps Research Institute (US)
- West Virginia University (US)
- Corresponding author
- Grim, Travis W.
- Venue
- Pharmacology Biochemistry and Behavior
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 124
- Pages
- 405-411
- ISSN
- 0091-3057 (ISSN-L)
- PMC
- PMC4206939
- OpenAlex
- W1979046480
- Cited by
- 50
- References
- 58
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 2
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology Biochemistry and Behavior (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute for Drug Abuse (P01-DA009789, P01-DA017259, T32-DA007027, K99 DA035864)
- Tony Rosenburg Fellowship
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- fatty acid amide hydrolase inhibition, cyclooxygenase inhibition, anandamide, endocannabinoid system, neuropathic pain, inflammatory pain, diclofenac, chronic constriction injury, carrageenan-induced inflammation, CB1 receptor, CB2 receptor, antinociception, prostaglandins, combination therapy
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Disease Models, Animal, Enzyme Inhibitors, Hyperalgesia, Inflammation, Male, Mice, Inbred C57BL, Neuralgia, Prostaglandin-Endoperoxide Synthases, Mice
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