Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia
Abstract
Although the N-arachidonoyl ethanolamine (anandamide) binds to cannabinoid receptors and has been implicated in the suppression of pain, its rapid catabolism in vivo by fatty acid amide hydrolase (FAAH) has presented a challenge in investigating the physiological functions of this endogenous cannabinoid. In order to test whether anandamide and other non-cannabinoid fatty amides modulate nociception, we compared FAAH (+/+) and (-/-) mice in the tail immersion, hot plate, and formalin tests, as well as for thermal hyperalgesia in the carrageenan and the chronic constriction injury (CCI) models. FAAH (-/-) mice exhibited a CB1 receptor-mediated phenotypic hypoalgesia in thermal nociceptive tests. These mice also exhibited CB1 receptor-mediated hypoalgesia in both phases of the formalin test accompanied with a phenotypic anti-edema effect, which was not blocked by either CB1 or CB2 antagonists. Additionally, FAAH (-/-) mice displayed thermal anti-hyperalgesic and anti-inflammatory effects in the carrageenan model that were mediated, in part, by CB2, but not CB1 receptors. In contrast, no genotype differences in pain behavior were evident following CCI, which was instead found to obliterate the phenotypic hypoalgesia displayed by FAAH (-/-) mice in the tail immersion and hot plate tests, suggesting that nerve injury may promote adaptive changes in these animals. Collectively, these findings demonstrate a cannabinoid receptor-mediated analgesic phenotype in FAAH (-/-) mice. In more general terms, these findings suggest that selective inhibitors of FAAH might represent a viable pharmacological approach for the clinical treatment of pain disorders.
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FAAH inhibitors attenuate carrageenan-induced edema, an effect that is mediated through the CB2 receptor.
“FAAH inhibitors also attenuate carrageenaninduced edema, an effect that is mediated through the CB 2 receptor (Holt et al, 2005;Lichtman et al, 2004).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lichtman et al, 2004
Pharmacological inhibition or genetic deletion of FAAH attenuates carrageenan-induced inflammation as well as mechanical allodynia and thermal hyperalgesia.
“For example, pharmacological inhibition or genetic deletion of FAAH attenuates carrageenan-induced inflammation as well as mechanical allodynia and thermal hyperalgesia (increased sensitivity to a noxious heat stimuli) (Ghosh et al, 2013;Karbarz et al, 2009;Lichtman et al, 2004).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Lichtman et al, 2004
FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain, and these effects are blocked by a CB1 antagonist.
“FAAH-/- mice are hypoalgesic in models of acute and inflammatory pain; these effects are blocked by a CB1 antagonist.29, 30”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [30]
Basal hypoalgesia is absent in FAAH-/- mice subjected to nerve injury, where genotype differences in evoked neuropathic pain behaviors are not apparent.
“This basal hypoalgesia is absent in FAAH-/- mice subjected to nerve injury, where genotype differences in evoked neuropathic pain behaviors are not apparent.30”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [30]
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Self-citation
- Authors
- Lichtman, A. H., Shelton, C. C., Advani, T., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Lichtman, Aron H
- Venue
- Pain
- Published
- 2004-06
- Volume
- 109
- Issue
- 3
- Pages
- 319-327
- ISSN
- 0304-3959 (ISSN-L)
- OpenAlex
- W2094469214
- Cited by
- 301
- References
- 53
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 8 · 2019: 5 · 2018: 10 · 2017: 8 · 2016: 7 · 2015: 14 · 2014: 21 · 2013: 14 · 2012: 23
- FWCI
- 17.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pain (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (DA015197, P01DA009789, R01DA015197, DA‐03672, DA 09789)
- 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, anandamide, endocannabinoid system, CB1 receptor, CB2 receptor, thermal hyperalgesia, formalin test, chronic constriction injury, nerve injury, analgesic effect, FAAH inhibitors
- MeSH terms
- Fatty Acid Amide Hydrolases, Adaptation, Physiological, Amidohydrolases, Animals, Arachidonic Acids, Disease Models, Animal, Enzyme Inhibitors, Female, Genotype, Inflammation, Male, Pain, Pain Measurement, Peripheral Nerves, Phenotype, Pain Threshold, Mice, Knockout, Somatosensory Disorders, Receptors, Cannabinoid, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Mice, Polyunsaturated Alkamides, Peripheral Nerve Injuries, Cannabinoid Receptor Antagonists, Endocannabinoids
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