Cited by 361Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsIon Channels and Receptors

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Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism

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Clapper, Jason R, Moreno-Sanz, Guillermo, Russo, Roberto, Guijarro, Ana, Vacondio, Federica, Duranti, Andrea, Tontini, Andrea, Sanchini, Silvano, Sciolino, Natale R, Spradley, Jessica M, Hohmann, Andrea G, Calignano, Antonio, Mor, Marco, Tarzia, Giorgio, Piomelli, Daniele·2010·Nature Neuroscience

DOI 10.1038/nn.2632PMC PMC3260554

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Abstract

Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB₁ cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB₁ receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.

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1 retracted

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“Unlike URB597, its derivative URB937 is actively extruded from the central nervous system, and therefore increases anandamide levels solely in peripheral tissues (Clapper et al., 2010).”
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Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats
Kwilasz, A. J., Abdullah, R. A., Poklis, J. L., Lichtman, A. H., & Negus, S. S. (2014) · Behavioural Pharmacology · doi:10.1097/fbp.0000000000000023 · Cited by 45
“(Naidu et al., 2009; Clapper et al., 2010; Miller et al., 2012), first and second phases of nociceptive behavior elicited by intraplantar formalin injection (Hasanein et al., 2009), tail-flick responses elicited by noxious heat (Hasanein et al., 2009), and hypersensitive withdrawal responses…”
Background
Brain-Permeant and -Impermeant Inhibitors of Fatty Acid Amide Hydrolase Synergize with the Opioid Analgesic Morphine to Suppress Chemotherapy-Induced Neuropathic Nociception Without Enhancing Effects of Morphine on Gastrointestinal Transit
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“[51] This scaffold merges key pharmacophores of two known classes of FAAH and COX inhibitors – O-aryl carbamates [52-58] such as [3-(3-carbamoylphe nyl)phenyl] Ncyclohexylcarbamate (URB597, 2) [54, 57], and 2-aryl propionic acids [6] such as flurbiprofen, 3a [59-61] – which share a biphenyl core as a common structural…”
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Background
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Aizawa, N., Hedlund, P., Füllhase, C., Ito, H., Homma, Y., & Igawa, Y. (2014) · The Journal of Urology · doi:10.1016/j.juro.2014.04.008 · Cited by 43
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“We further showed that the anti-hyperalgesic effects of URB937 are CB1 mediated, thus confirming the role of the peripheral CB1 receptor in the anti-hyperlgesic effect [6,39].”
BackgroundMethod
Computational insights into function and inhibition of fatty acid amide hydrolase
Palermo, G., Röthlisberger, U., Cavalli, A., & Vivo, M. D. (2014) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2014.09.037 · Cited by 41
“carbamate-based compounds URB597 (6) [37] and URB937 (7) [38], the urea-based compounds PF-750 (8) [42], PF-622 (9) [42], JNJ1661010 (10) [41] and LY2183240 (11) [33].”
Background
Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy
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Background
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“01–1 mg/kg a peripherally restricted FAAH inhibitor) (Clapper et al., 2010).”
BackgroundInfluential
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Background
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“The dose of URB937 was chosen on the basis of previous published work demonstrating that at this dose, URB937 inhibits FAAH activity and increases AEA levels peripherally, but not in the rodent brain (Clapper et al, 2010).”
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BackgroundInfluential
Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide
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“It has been shown that the activation of CB1 receptors by subcutaneous administration of URB937, a peripherally restricted inhibitor of fatty acid amide hydrolase, reduces visceral pain in the acetic acid model [40].”
BackgroundInfluential
Quantum Mechanics/Molecular Mechanics Modeling of Fatty Acid Amide Hydrolase Reactivation Distinguishes Substrate from Irreversible Covalent Inhibitors
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“5 clearly shows that the n-FABS method was able to detect the strong inhibition of FAAH activity in cells by molecule 1 and molecule 2, two known potent FAAH inhibitors [43].”
MethodSelf-citation
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Background
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Method
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“This is not necessarily a disadvantage since selective inhibition of peripheral FAAH produces antinociceptive responses (Clapper et al., 2010; Sasso et al., 2012; see also Thors et al., 2010) and reduces NSAID-induced gastrointestinal damage (Sasso et al., 2012), but would not be expected to be…”
Background
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Background
Brain permeant and impermeant inhibitors of fatty-acid amide hydrolase suppress the development and maintenance of paclitaxel-induced neuropathic pain without producing tolerance or physical dependence in vivo and synergize with paclitaxel to reduce tumor cell line viability in vitro
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Background
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Self-citation
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Background
Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?
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“When URB937 is given systemically (intraperitoneal) it results in an increase in the bioavailability of anandamide in the periphery,(4) and a reduction in pain-related behavior in murine models of visceral pain, neuropathic pain, and inflammatory pain.(47) Interestingly, URB937 has also displayed a reduction of Fos ex…”
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Cannabinoid functions in the amygdala contribute to conditioned fear memory in streptozotocin-induced diabetic mice: Interaction with glutamatergic functions
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Authors: Clapper, J. R., Moreno-Sanz, G., Russo, R., Guijarro, A., Vacondio, F., Duranti, A., Tontini, A., Sanchini, S., Sciolino, N. R., Spradley, J. M., Hohmann, A. G., Calignano, A., Mor, M., Tarzia, G., & Piomelli, D.
Affiliations: University of California, Irvine (US)
University of Naples Federico II (IT)
University of Parma (IT)
University of Urbino (IT)
University of Georgia (US)
Corresponding author: Piomelli, Daniele
ORCID: Clapper, Jason R
Russo, Roberto
Guijarro, Ana
Vacondio, Federica
Duranti, Andrea
Tontini, Andrea
Sciolino, Natale R
Hohmann, Andrea G
Calignano, Antonio
Mor, Marco
Piomelli, Daniele
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2010-09-19
Volume: 13
Issue: 10
Pages: 1265-1270
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.2632
PMC: PMC3260554
OpenAlex: W2143684129
Cited by: 346
References: 52
Citations by year: 2026: 9 · 2025: 13 · 2024: 13 · 2023: 21 · 2022: 23 · 2021: 17 · 2020: 21 · 2019: 18 · 2018: 14 · 2017: 23 · 2016: 24 · 2015: 27 · 2014: 32 · 2013: 31 · 2012: 34
FWCI: 22.06
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
Funders: National Institute on Drug Abuse (R01DA012413)
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: anandamide, CB1 receptor, fatty acid amide hydrolase, FAAH inhibitors, chronic pain, peripheral nerve injury, inflammation, spinal cord nociception, analgesia, blood-brain barrier
MeSH terms: Rimonabant, Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Cannabinoids, Carrageenan, Chlorobenzenes, Chromatography, Liquid, Disease Models, Animal, Drug Administration Routes, Drug Administration Schedule, Enzyme Inhibitors, Escape Reaction, Ethylene Glycols, Feeding Behavior, Formaldehyde, Gene Expression Regulation, Hyperalgesia, Indoles, Male, Mice, Inbred C57BL, Monoacylglycerol Lipases, Motor Activity, Pain, Pain Measurement, Peripheral Nervous System Diseases, Piperidines, Pyrazoles, Sciatica, Mass Spectrometry, Spinal Cord, Time Factors, Tissue Distribution, Tritium, Oncogene Proteins v-fos, Rats, Sprague-Dawley, Pain Threshold, Mice, Knockout, Statistics, Nonparametric, PPAR alpha, Mice, Rats, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids

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Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism

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