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The fatty acid amide hydrolase (FAAH) inhibitor PF‐3845 acts in the nervous system to reverse LPS‐induced tactile allodynia in mice
Open accessAbstract
BACKGROUND AND PURPOSE Inflammatory pain presents a problem of clinical relevance and often elicits allodynia, a condition in which non‐noxious stimuli are perceived as painful. One potential target to treat inflammatory pain is the endogenous cannabinoid (endocannabinoid) system, which is comprised of CB 1 and CB 2 cannabinoid receptors and several endogenous ligands, including anandamide (AEA). Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without the psychomimetic side effects associated with Δ 9‐tetrahydrocannabinol (THC). EXPERIMENTAL APPROACH Allodynia was induced by intraplantar injection of LPS. Complementary genetic and pharmacological approaches were used to determine the strategy of blocking FAAH to reverse LPS‐induced allodynia. Endocannabinoid levels were quantified using mass spectroscopy analyses. KEY RESULTS FAAH (−/−) mice or wild‐type mice treated with FAAH inhibitors (URB597, OL‐135 and PF‐3845) displayed an anti‐allodynic phenotype. Furthermore, i.p. PF‐3845 increased AEA levels in the brain and spinal cord. Additionally, intraplantar PF‐3845 produced a partial reduction in allodynia. However, the anti‐allodynic phenotype was absent in mice expressing FAAH exclusively in the nervous system under a neural specific enolase promoter, implicating the involvement of neuronal fatty acid amides (FAAs). The anti‐allodynic effects of FAAH‐compromised mice required activation of both CB 1 and CB 2 receptors, but other potential targets of FAA substrates (i.e. µ‐opioid, TRPV1 and PPARα receptors) had no apparent role. CONCLUSIONS AND IMPLICATIONS AEA is the primary FAAH substrate reducing LPS‐induced tactile allodynia. Blockade of neuronal FAAH reverses allodynia through the activation of both cannabinoid receptors and represents a promising target to treat inflammatory pain. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
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“Genetic deletion of FAAH also reduces mechanical allodynia induced by low-dose LPS, but this anti-allodynia is absent in mice expressing FAAH only in nervous tissue (Booker et al, 2012) and is mediated by both CB 1 and CB 2 receptors.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Booker et al, 2012
In the citing paper
“Intraplantar administration of PF-3845 also attenuates LPS-induced allodynia (Booker et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Booker et al, 2012
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“Localized administration of low dose (ie, 2.5 μg) LPS evokes tactile allodynia that is attenuated by FAAH inhibition without inducing paw edema (Booker et al, 2012).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Booker et al, 2012
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Cannabinoids and Pain: New Insights From Old Molecules
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“Indeed, several distinct classes of FAAH inhibitors reduce nociceptive behaviour following hindpaw administration of LPS, and a detailed investigation of the mechanism implicates both CB1 and CB2, but not TRPV1, PPARa, or m-opioid receptors (Booker et al., 2012).”
Turcotte, C., Chouinard, F., Lefebvre, J. S., & Flamand, N. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ru0115-021r · Cited by 258
Metadata
- Authors
- Booker, L., Kinsey, S. G., Abdullah, R. A., Blankman, J. L., Long, J. Z., Ezzili, C., Boger, D. L., Cravatt, B. F., & Lichtman, A. H.
- Affiliations
- Virginia Commonwealth University (US)
- Scripps Research Institute (US)
- Corresponding author
- Lichtman, Aron H
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2012-03-23
- Volume
- 165
- Issue
- 8
- Pages
- 2485-2496
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC3423256
- OpenAlex
- W1500005891
- Cited by
- 116
- References
- 49
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 17 · 2020: 4 · 2019: 10 · 2018: 7 · 2017: 13 · 2016: 8 · 2015: 9 · 2014: 11 · 2013: 11 · 2012: 3
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA015648, P01DA009789, R01DA015683, F31DA028333, P01DA017259, R01DA003672, R01-DA-03672, P50DA005274, T32DA007027)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- fatty acid amide hydrolase, FAAH inhibitors, anandamide, endocannabinoid system, mechanical allodynia, inflammatory pain, lipopolysaccharide, CB1 receptor, CB2 receptor, antinociception, spinal cord, brain, URB597
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Brain, Enzyme Inhibitors, Female, Glycerides, Hyperalgesia, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Piperidines, Pyridines, Spinal Cord, Peripheral Nervous System, Mice, Knockout, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Mice, Polyunsaturated Alkamides, Endocannabinoids
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