The DOI matches its Crossref record; 51 of the 52 references it cites were found in a registry or an index.
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Open accessAbstract
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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“Similarly, the peripherally restricted FAAH inhibitor URB937 attenuates carrageenaninduced allodynia and hyperalgesia through a CB 1 mechanism of action.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Clapper et al, 2010
In the citing paper
“However, unlike brain-permeating FAAH inhibitors, the anti-edematous effects of URB937 are mediated by both CB 1 and CB 2 receptors (Clapper et al, 2010).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Clapper et al, 2010
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Cites
1 retracted
Ahluwalia, J., Yaqoob, M., Urbán, L., Bevan, S., & Nagy, I. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01550.x · Cited by 82
RetractedA peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man
Bennett, G. J., & Xie, Y.-K. (1988) · Pain · doi:10.1016/0304-3959(88)90209-6 · Cited by 5,376
A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
Hargreaves, K., Dubner, R. A., Brown, F. J., Flores, C., & Joris, J. L. (1988) · Pain · doi:10.1016/0304-3959(88)90026-7 · Cited by 5,155
The formalin test: an evaluation of the method
Tjølsen, A., Berge, O., Hunskaar, S., Rosland, J. H., & Hole, K. (1992) · Pain · doi:10.1016/0304-3959(92)90003-t · Cited by 2,434
SYNTHETIC ANALGESICS. II. DITHIENYLBUTENYL- AND DITHIENYLBUTYLAMINES
Eddy, N. B., & Leimbach, D. G. (1953) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)05180-8 · Cited by 1,765
Cravatt, B. F., Demarest, K., Patricelli, M. P., Bracey, M. H., Giang, D. K., Martin, B. R., & Lichtman, A. H. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.161191698 · Cited by 1,310
Modulation of anxiety through blockade of anandamide hydrolysis
Kathuria, S., Gaetani, S., Fegley, D., Valiño, F., Duranti, A., Tontini, A., Mor, M., Tarzia, G., Rana, G. L., Calignano, A., et al. (2003) · Nature Medicine · doi:10.1038/nm803 · Cited by 1,293
Self-citationControl of pain initiation by endogenous cannabinoids
Calignano, A., Rana, G. L., Giuffrida, A., & Piomelli, D. (1998) · Nature · doi:10.1038/28393 · Cited by 1,069
Self-citationBlood-brain barrier active efflux transporters: ATP-binding cassette gene family
Löscher, W., & Potschka, H. (2004) · NeuroRx · doi:10.1602/neurorx.2.1.86 · Cited by 873
Attacking pain at its source: new perspectives on opioids
Stein, C., Schäfer, M., & Machelska, H. (2003) · Nature Medicine · doi:10.1038/nm908 · Cited by 603
Cited by
Sorted by citations
Zou, S., & Kumar, U. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030833 · Cited by 1,448
“The CB1R is also abundantly expressed in the peripheral nervous system (PNS) as well as in the peripheral tissues in a region-specific manner [59,63,64,65] (Figure 2).”
BackgroundMultiple Functions of Endocannabinoid Signaling in the Brain
Katona, I., & Freund, T. F. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062111-150420 · Cited by 630
“It is clear however that anandamide also acts through CB1 receptors in several neurobiological paradigms (Kinsey et al., 2009; Clapper et al., 2010; Straiker et al., 2011), where it may function as a retrograde synaptic messenger and mediate certain forms of synaptic homeostasis and plasticity in…”
BackgroundMcPartland, J. M., Duncan, M., Marzo, V. D., & Pertwee, R. G. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12944 · Cited by 552
“CBD inhibition of FAAH and consequential increase in AEA may synergize with THC CB1 receptor agonism in peripheral injury: AEA suppresses pain through a peripheral mechanism (Clapper et al., 2010), whereas THC works through central CB1 receptor-mediated mechanisms.”
BackgroundLigresti, A., PETROCELLIS, L. D., & Marzo, V. D. (2016) · Physiological Reviews · doi:10.1152/physrev.00002.2016 · Cited by 505
“The antinociceptive effects of systemic FAAH inhibitors were suggested to be mediated only by peripheral CB1 (813), and, indeed, a peripherally restricted FAAH inhibitor produced antinociception in models of nerve injury and inflammation (149).”
BackgroundModulating the endocannabinoid system in human health and disease – successes and failures
Pacher, P., & Kunos, G. (2013) · FEBS Journal · doi:10.1111/febs.12260 · Cited by 418
“Recent studies with a peripherally restricted FAAH inhibitor, URB937, showed efficacy in neuropathic and inflammatory pain[165], confirming that the analgesic effects of AEA are initiated at the peripheral sites[107].”
Background
Metadata
- 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
- Venue
- Nature Neuroscience
- Published
- 2010-09-19
- Volume
- 13
- Issue
- 10
- Pages
- 1265-1270
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- 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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