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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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].”
BackgroundCannabinoids and Pain: New Insights From Old Molecules
Vučković, S., Srebro, D., Vujović, K. S., Vučetić, Č., & Prostran, M. S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01259 · Cited by 440
Chemical Probes of Endocannabinoid Metabolism
Blankman, J. L., & Cravatt, B. F. (2013) · Pharmacological Reviews · doi:10.1124/pr.112.006387 · Cited by 327
“…in ABHD12 cause the human neurodegenerative disease PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract) (Fiskerstrand et al., 2010), although whether ABHD12-disruption leads to neuronal death by dysregulation of 2-AG or an alternate mechanism remains to be determined.”
BackgroundInfluentialDonvito, G., Nass, S. R., Wilkerson, J. L., Curry, Z. A., Schurman, L. D., Kinsey, S. G., & Lichtman, A. H. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.204 · Cited by 301
The cannabinoid system and pain
Woodhams, S. G., Chapman, V., Finn, D. P., Hohmann, A. G., & Neugebauer, V. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.06.015 · Cited by 285
“Both brain impermeant (Clapper et al., 2010) and brain permeant inhibitors of FAAH have been shown to suppress inflammatory pain induced by formalin, carrageenan, and Complete Freund's Adjuvant (CFA) (for review, see Guindon and Hohmann, 2009).”
InfluentialSelf-citationFraguas‐Sánchez, A. I., & Torres‐Suárez, A. I. (2018) · Drugs · doi:10.1007/s40265-018-0996-1 · Cited by 287
Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease
García‐Osta, A., Cuadrado‐Tejedor, M., García, C., Oyarzábal, J., & Franco, R. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn3000907 · Cited by 264
Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies
Finn, D. P., Haroutounian, S., Hohmann, A. G., Krane, E. J., Soliman, N., & Rice, A. S. C. (2021) · Pain · doi:10.1097/j.pain.0000000000002268 · Cited by 280
Self-citationTurcotte, C., Chouinard, F., Lefebvre, J. S., & Flamand, N. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.3ru0115-021r · Cited by 258
“hydrolysis of exogenously added AEA [44, 63–65], emphasizing”
BackgroundPeripheral gating of pain signals by endogenous lipid mediators
Piomelli, D., & Sasso, O. (2014) · Nature Neuroscience · doi:10.1038/nn.3612 · Cited by 240
Self-citationBaron, E. P. (2015) · Headache The Journal of Head and Face Pain · doi:10.1111/head.12570 · Cited by 219
The Role of the Endocannabinoid System in Pain
Woodhams, S. G., Sagar, D. R., Burston, J. J., & Chapman, V. (2015) · Handbook of experimental pharmacology · doi:10.1007/978-3-662-46450-2_7 · Cited by 216
Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain
Roques, B. P., Fournié‐Zaluski, M., & Wurm, M. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3673 · Cited by 198
Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years
Maccarrone, M., Di Marzo, V., Gertsch, J., Grether, U., Howlett, A. C., Hua, T., Makriyannis, A., Piomelli, D., Ueda, N., & van der Stelt, M. (2023) · Pharmacological Reviews · doi:10.1124/pharmrev.122.000600 · Cited by 183
Self-citationModulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy
Stein, C., & Machelska, H. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.003145 · Cited by 185
“In view of peripheral antinociceptive actions of endocannabinoids (Guindon and Beaulieu, 2009; Guindon and Hohmann, 2009; Clapper et al., 2010), it would be interesting to identify their cellular source(s) in peripheral tissues.”
BackgroundKinsey, S. G., Wise, L. E., Ramesh, D., Abdullah, R., Selley, D. E., Cravatt, B. F., & Lichtman, A. H. (2013) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.201426 · Cited by 169
“For example, FAAH inhibition attenuates neuropathic pain (Jhaveri et al., 2006; Russo et al., 2007; Kinsey et al., 2009; Clapper et al., 2010), inflammatory pain (Booker et al., 2011), collagen-induced arthritis (Kinsey et al., 2011a), and gastric ulceration (Naidu et al., 2009; Sasso et al.,…”
Guindon, J., Lai, Y., Takacs, S. M., Bradshaw, H. B., & Hohmann, A. G. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2012.10.013 · Cited by 160
“) was previously shown to elevate AEA (and other fatty-acid amides) outside the CNS in rats without altering endocannabinoid levels in the brain [48].”
BackgroundSelf-citationAnandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities
Mock, E. D., Gagestein, B., & van der Stelt, M. (2022) · Progress in Lipid Research · doi:10.1016/j.plipres.2022.101194 · Cited by 164
Inhibition of Fatty Acid Binding Proteins Elevates Brain Anandamide Levels and Produces Analgesia
Kaczocha, M., Rebecchi, M. J., Ralph, B. P., Teng, Y.-H. G., Berger, W. T., Galbavy, W., Elmes, M. W., Glaser, S. T., Wang, L., Rizzo, R. C., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0094200 · Cited by 142
“Therefore, it is possible that the PPARa-mediated antinociceptive effects may stem from elevated PEA levels in peripheral nerves [29] or possibly in subsets of brain regions that regulate nociception, such that local changes in PEA levels may have eluded our analysis.”
BackgroundMore surprises lying ahead. The endocannabinoids keep us guessing
Piomelli, D. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.07.026 · Cited by 128
“…turn, to unmask important functions served by anandamide in the control of stress-coping responses (Bortolato et al., 2007; Dlugos et al., 2012; Gobbi et al., 2005; Gunduz-Cinar et al., 2012; Hill et al., 2010; Khaturia et al., 2003) and pain initiation (Clapper et al., 2010; Hohmann et al., 2005).”
Self-citationIgnatowska‐Jankowska, B. M., Ghosh, S., Crowe, M. S., Kinsey, S. G., Niphakis, M. J., Abdullah, R. A., Tao, Q., O' Neal, S. T., Walentiny, D. M., Wiley, J. L., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12298 · Cited by 128
“, 2009; 2010; Starowicz and Przewlocka, 2012), inflammatory ( Jayamanne et al., 2006; Ahn et al., 2009a,b; 2011; Clapper et al., 2010; Naidu et al., 2010; Booker et al., 2012), and acute thermal nociception (Kathuria et al.”
BackgroundGhosh, S., Wise, L. E., Chen, Y., Gujjar, R., Mahadevan, A., Cravatt, B. F., & Lichtman, A. H. (2013) · Life Sciences · doi:10.1016/j.lfs.2012.06.020 · Cited by 127
“[PubMed: 18096503] Booker L, Kinsey SG, Abdullah RA, Blankman JL, Long JZ, Ezzili C, et al. The FAAH inhibitor PF-3845 acts in the nervous system to reverse lipopolysaccharide-induced tactile allodynia in mice.”
BackgroundInfluentialThe carbon footprint of indoor Cannabis production
Mills, E. (2012) · Energy Policy · doi:10.1016/j.enpol.2012.03.023 · Cited by 123
Habib, A. M., Okorokov, A. L., Hill, M. N., Brás, J., Lee, M.-C., Li, S., Gossage, S. J., van Drimmelen, M., Morena, M., Houlden, H., et al. (2019) · British Journal of Anaesthesia · doi:10.1016/j.bja.2019.02.019 · Cited by 129
Harnessing the anti-inflammatory potential of palmitoylethanolamide
Alhouayek, M., & Muccioli, G. G. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.06.007 · Cited by 123
Pálóczi, J., Varga, Z. V., Hasko, G., & Pacher, P. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7144 · Cited by 129
“JWH-015 Agonists with higher selectivity for CB2 (253, 268, 270) JWH-133 (253, 268, 270) HU-910 (137) HU-308 (253, 268, 270) AM1241 (253, 270) O-1966 (253, 345) O-3853 (362) LEI-101 (225) SR141716A (Rimonabant) CB1 inverse agonist/antagonist (253, 270) AM251 (268, 270) Taranabant (90, 270) SR144528 CB2 inverse agonist…”
Guindon, J., Guijarro, A. I., Piomelli, D., & Hohmann, A. G. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01192.x · Cited by 120
“…inhibitors of FAAH, including URB937, URB597, PF-3845, N-arachidonoyl 5-HT (AA-5-HT) and ibuprofen (see Guindon and Hohmann, 2009), in models of inflammatory pain are well characterized (Maione et al., 2007; Jhaveri et al., 2008; Ahn et al., 2009; Clapper et al., 2010; Costa et al., 2010).”
BackgroundSelf-citationLötsch, J., Weyer-Menkhoff, I., & Tegeder, I. (2017) · European Journal of Pain · doi:10.1002/ejp.1148 · Cited by 123
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. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01445.x · Cited by 116
“In the light of the recent report by Clapper et al. (2010) showing that a peripherally restricted FAAH inhibitor reduces pain responses, we next evaluated whether i.pl. administration of PF-3845 reverses LPS-induced allodynia.”
BackgroundInfluentialTuo, W., Leleu‐Chavain, N., Spencer, J., Sansook, S., Millet, R., & Chavatte, P. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00538 · Cited by 116
Medical Marijuana and Chronic Pain: a Review of Basic Science and Clinical Evidence
Jensen, B., Chen, J. L., Furnish, T. J., & Wallace, M. S. (2015) · Current Pain and Headache Reports · doi:10.1007/s11916-015-0524-x · Cited by 118
Targeted treatment of pruritus: a look into the future
Tey, H. L., & Yosipovitch, G. (2011) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2011.10217.x · Cited by 108
Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain
Zambelli, V. O., Gross, E. R., Chen, C., Gutierrez, V. P., Cury, Y., & Mochly‐Rosen, D. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009539 · Cited by 106
Sasso, O., Moreno‐Sanz, G., Martucci, C., Realini, N., Dionisi, M., Mengatto, L., Duranti, A., Tarozzo, G., Tarzia, G., Mor, M., et al. (2012) · Pain · doi:10.1016/j.pain.2012.10.018 · Cited by 106
“Many of these effects are reversed by antagonizing CB1- or CB2-type cannabinoid receptors, which is consistent with the key role played by FAAH in the intracellular degradation of the endocannabinoid anandamide [7,24].”
BackgroundSelf-citationAn, K., Hao, H., Zheng, X., Liang, Y. L., Xie, Y., Xie, T., Dai, C., Zhao, Q., Wu, X., Xie, L. Y., et al. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-100 · Cited by 106
“More recently, a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase has been found to be capable of attenuating behavior responses in various rodent models of pain and, meanwhile, avoiding unwanted side effects from activation of brain cannabinoid receptors [62].”
BackgroundEnhanced endocannabinoid tone as a potential target of pharmacotherapy
Toczek, M., & Malinowska, B. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.04.054 · Cited by 108
Cannabinoid signaling in health and disease
Lu, Y., & Anderson, H. D. (2017) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2016-0346 · Cited by 105
Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications
Pertwee, R. G. (2013) · Proceedings of The Nutrition Society · doi:10.1017/s0029665113003649 · Cited by 100
Insights into drug discovery from natural medicines using reverse pharmacokinetics
Hao, H., Zheng, X., & Wang, G. (2014) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2014.02.001 · Cited by 99
Sasso, O., Bertorelli, R., Bandiera, T., Scarpelli, R., Colombano, G., Armirotti, A., Moreno-Sanz, G., Reggiani, A., & Piomelli, D. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.02.012 · Cited by 96
“This effect is likely mediated by activation of CB1 receptors because it is blocked by the CB1 antagonist AM251, but not by the CB2 antagonist AM630 [15].”
BackgroundMethodInfluentialSelf-citationAlba, R. G., Barragán‐Iglesias, P., González‐Hernández, A., Valdez-Moráles, E. E., Granados‐Soto, V., Condés‐Lara, M., Rodríguez, M. G., & Marichal‐Cancino, B. A. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01496 · Cited by 95
“, 2007), the synthesis of CB1 receptor agonists with limited CNS penetration is under development (Clapper et al., 2010; Yu et al., 2010).”
BackgroundA perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents
Tripathi, R. K. P. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111953 · Cited by 95
New directions of activity-based sensing for in vivo NIR imaging
East, A. K., Lucero, M. Y., & Chan, J. (2020) · Chemical Science · doi:10.1039/d0sc03096a · Cited by 94
Chiurchiù, V., Cencioni, M. T., Bisicchia, E., Bardi, M. D., Gasperini, C., Borsellino, G., Centonze, D., Battistini, L., & Maccarrone, M. (2013) · Annals of Neurology · doi:10.1002/ana.23875 · Cited by 90
Medical Cannabis for Neuropathic Pain
Lee, G., Grovey, B., Furnish, T. J., & Wallace, M. S. (2018) · Current Pain and Headache Reports · doi:10.1007/s11916-018-0658-8 · Cited by 87
Mofford, D. M., Adams, S. T., Reddy, G. S., Reddy, G. R., & Miller, S. C. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b04357 · Cited by 85
Kinsey, S. G., Naidu, P. S., Cravatt, B. F., Dudley, D. T., & Lichtman, A. H. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.06.022 · Cited by 87
“These findings are consistent with a recent report showing that the peripheral FAAH inhibitor URB937 possesses anti-hyperalgesic, anti-allodynic, and anti-inflammatory properties (Clapper et al., 2010).”
ResultFavia, A. D., Habrant, D., Scarpelli, R., Migliore, M., Albani, C., Bertozzi, S. M., Dionisi, M., Tarozzo, G., Piomelli, D., Cavalli, A., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3011146 · Cited by 82
Self-citationGhafouri, N., Ghafouri, B., Larsson, B. K., Stensson, N., Fowler, C. J., & Gerdle, B. U. C. (2013) · Pain · doi:10.1016/j.pain.2013.05.002 · Cited by 78
IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain
Eijkelkamp, N., Steen-Louws, C., Hartgring, S. A. Y., Willemen, H. L. D. M., Prado, J., Lafeber, F. P. J. G., Heijnen, C. J., Hack, C. E., van Roon, J. A. G., & Kavelaars, A. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.0092-16.2016 · Cited by 79
“IL4-10 fusion protein inhibits persistent inflammatory pain The potential of IL4-10 fusion protein to inhibit persistent hyperalgesia was evaluated in the well-established murine model of carrageenan-induced persistent inflammatory pain (Ren and Dubner, 1999; Clapper et al., 2010; Eijkelkamp et al., 2010; Willemen et…”
Incerta-thalamic Circuit Controls Nocifensive Behavior via Cannabinoid Type 1 Receptors
Wang, H., Dong, P., He, C., Feng, X.-Y., Huang, Y., Yang, W.-W., Gao, H.-J., Shen, X., Lin, S., Cao, S.-X., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.04.027 · Cited by 78
Endocannabinoid-Based Therapies
Piomelli, D., & Tagne, A. M. (2021) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-052220-021800 · Cited by 82
Self-citationPeripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain
Seltzman, H. H., Shiner, C., Hirt, E. E., Gilliam, A. F., Thomas, B. F., Maitra, R., Snyder, R. W., Black, S. R., Patel, P. R., Mulpuri, Y., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00516 · Cited by 75
Khasabova, I. A., Chandiramani, A., Harding-Rose, C., Simone, D. A., & Seybold, V. S. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.03.007 · Cited by 75
“In contrast to AEA, which inhibits nociception through CB1 receptors on DRG neurons [3,33], CB2 receptors occurred in skin but were not associated with somatosensory neurons of tumor-bearing mice.”
BackgroundEndocannabinoid System and Migraine Pain: An Update
Greco, R., Demartini, C., Zanaboni, A. M., Piomelli, D., & Tassorelli, C. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00172 · Cited by 71
“In agreement with these data, URB937 decreases the c-Fos expression induced by plantar formalin injection in spinal cord regions involved in nociceptive processing by the CB1 receptors (Clapper et al., 2010).”
BackgroundResultSelf-citationPeripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive
Sasso, O., Wagner, K., Morisseau, C., Inceoglu, B., Hammock, B. D., & Piomelli, D. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.04.001 · Cited by 68
“We used the peripherally restricted FAAH inhibitor URB937, which has no access to the brain and spinal cord yet causes pronounced antihyperalgesic effects that are due to its ability to elevate anandamide levels outside the brain and spinal cord [28].”
BackgroundMethodSelf-citationCoulon, D., Faure, L., Grison, M., Wattelet‐Boyer, V., & Bessoule, J. (2011) · Biochimie · doi:10.1016/j.biochi.2011.04.023 · Cited by 68
“palmitoylethanolamine are involved in neuroprotection or neurotoxicity [7e9], cell proliferation [10], pain initiation [11,12] inflammation [13,14].”
BackgroundVeress, G., Mészár, Z., Muszil, D., Avelino, A., Matesz, K., Mackie, K., & Nagy, I. (2012) · Brain Structure and Function · doi:10.1007/s00429-012-0425-2 · Cited by 67
“…tissues, increasing anandamide or 2-AG levels by blocking their hydrolysis, respectively, produces analgesic effects, which is mediated, at least partly, by the CB1 receptor at both sites (Suplita et al. 2006; Jhaveri et al. 2006; Guindon et al. 2010; Spradley et al. 2010; Clapper et al. 2010).”
BackgroundActions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model
Anderson, W. B., Gould, M. J., Torres, R. D., Mitchell, V. A., & Vaughan, C. W. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.12.018 · Cited by 67
Monoglyceride lipase: Structure and inhibitors
Scalvini, L., Piomelli, D., & Mor, M. (2015) · Chemistry and Physics of Lipids · doi:10.1016/j.chemphyslip.2015.07.011 · Cited by 69
“, 2007) and contributes to the control of nociceptive transmission (Clapper et al., 2007; Clapper et al., 2010).”
BackgroundSelf-citationZheng, X., Liang, Y. L., An, K., Ma, S.-J., Xing, L., Zhou, Y.-Y., Dai, C., Xie, H., Xie, L., Wang, G.-J., et al. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.10.023 · Cited by 66
“In light of these critical issues confronting the conventional brain-centric practices, the emerging evidences that certain agents could produce CNS benefits without directly entering the brain may point to an alternative and intriguing avenue to brain diseases (Campbell et al., 2007; Clapper et al., 2010; Zwilling et…”
BackgroundA Binding Site for Nonsteroidal Anti-inflammatory Drugs in Fatty Acid Amide Hydrolase
Bertolacci, L., Romeo, E., Veronesi, M., Magotti, P., Albani, C., Dionisi, M., Lambruschini, C., Scarpelli, R., Cavalli, A., Vivo, M. D., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja308733u · Cited by 64
Self-citationA Lipid Gate for the Peripheral Control of Pain
Piomelli, D., Hohmann, A. G., Seybold, V. S., & Hammock, B. D. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3475-14.2014 · Cited by 67
“By contrast, in the same model, the antinociceptive effects of FAAH inhibitors are exclusively mediated by CB1, whereas their anti-inflammatory actions require CB2 and PPAR- (presumably via PEA/OEA augmentation, see Endogenous PPAR- agonists) (Guindon and Hohmann, 2009; Clapper et al., 2010).”
BackgroundInfluentialSelf-citationCannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?
Milligan, A. L., Szabo-Pardi, T. A., & Burton, M. D. (2019) · Journal of Dual Diagnosis · doi:10.1080/15504263.2019.1668100 · Cited by 70
“anandamide concentrations and the duration of ligand action (Clapper et al., 2010).”
BackgroundEndocannabinoid system and pain: an introduction
Burston, J. J., & Woodhams, S. G. (2013) · Proceedings of The Nutrition Society · doi:10.1017/s0029665113003650 · Cited by 67
“A peripherally restricted FAAH inhibitor URB937((85)), which cannot cross the blood– brain barrier, blocked the hypersensitivity induced by both inflammation and peripheral nerve injury via a CB1-mediated mechanism, without altering thermal nociceptive thresholds.”
Greco, R., Bandiera, T., Mangione, A., Demartini, C., Siani, F., Nappi, G., Sandrini, G., Guijarro, A., Armirotti, A., Piomelli, D., et al. (2015) · Cephalalgia · doi:10.1177/0333102414566862 · Cited by 63
“URB937 is an inhibitor of the activity of the enzyme fatty acid amide hydrolase (FAAH), which degrades the endocannabinoid anandamide.”
BackgroundMethodResultInfluentialSelf-citationFichna, J., Sałaga, M., Stuart, J. M., Saur, D., Sobczak, M., Zatorski, H., Timmermans, J., Bradshaw, H. B., Ahn, K., & Storr, M. (2013) · Neurogastroenterology & Motility · doi:10.1111/nmo.12272 · Cited by 64
Subcellular specificity of cannabinoid effects in striatonigral circuits
Gómez, E. S., Zottola, A. C. P., Mariani, Y., Desprez, T., Barresi, M., Río, I. B., Muguruza, C., Bon-Jégo, M. L., Julio‐Kalajzić, F., Flynn, R. E., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.03.007 · Cited by 63
Lischka, A., Laššuthová, P., Çakar, A., Record, C. J., Lent, J. V., Baets, J., Dohrn, M. F., Senderek, J., Lampert, A., Bennett, D., et al. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00365-7 · Cited by 61
Fatty acid amide hydrolase inhibitors: a patent review (2009 – 2014)
Lodola, A., Castelli, R., Mor, M., & Rivara, S. (2015) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2015.1067683 · Cited by 62
“This indicates that a high degree of analgesia can be obtained by heightening the activity of AEA-based signaling involved in the regulation of nociceptive homeostasis outside of the CNS. URB937 was the subject of a patent application claiming its effectiveness in the treatment of pain, inflammation and immunity disor…”
BackgroundInfluentialSelf-citationEffect of endocannabinoid degradation on pain
Cajanus, K., Holmström, E. J., Wessman, M., Anttila, V., Kaunisto, M. A., & Kalso, E. A. (2015) · Pain · doi:10.1097/j.pain.0000000000000398 · Cited by 70
“It plays a role in nociception, inflammatory responses, gastric motility, and many other functions.(7,11,13,23,28,32,34,42,43,46) Inhibition of the enzymatic”
BackgroundCannabinoids Activate Monoaminergic Signaling to Modulate KeyC. elegansBehaviors
Oakes, M., Law, W. J., Clark, T., Bamber, B. A., & Komuniecki, R. W. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3151-16.2017 · Cited by 62
“In mammals, 2-AG and AEA exert antinociceptive action in models of acute inflammatory and neuropathic pain; therefore, we examined their effects on aversive responses to 1-octanol in C. elegans (Iskedjian et al., 2007; Clapper et al., 2010).”
BackgroundRole of Cannabinoids in Pain Management
Russo, E. B., & Hohmann, A. G. (2012) · Springer eBooks · doi:10.1007/978-1-4614-1560-2_18 · Cited by 62
“In preclinical studies, drugs inhibiting endocannabinoid hydrolysis [ 171 , 172 ] and peripherally acting agonists [ 173 ] all show promise for suppressing neuropathic pain.”
BackgroundSelf-citationSasso, O., Migliore, M., Habrant, D., Armirotti, A., Albani, C., Summa, M., Moreno‐Sanz, G., Scarpelli, R., & Piomelli, D. (2015) · The FASEB Journal · doi:10.1096/fj.15-270637 · Cited by 63
“By interrupting the degradation of AEA, these agents heighten its ability to control peripheral nociceptive signals (24, 49) resulting in a superadditive potentiation of NSAID-mediated analgesia.”
BackgroundMethodSelf-citationInvolvement of the endocannabinoid system in osteoarthritis pain
Porta, C. L., Bura, S. A., Negrete, R., & Maldonado, R. J. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12468 · Cited by 61
Cannabinoid Therapeutics in Chronic Neuropathic Pain: From Animal Research to Human Treatment
Campos, R. M. P., Aguiar, A. F. L., Paes-Colli, Y., Trindade, P. M. P., Ferreira, B. K., Reis, R. A. D. M., & Sampaio, L. D. S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.785176 · Cited by 59
Kalliomäki, J., Segerdahl, M., Webster, L. R., Reimfelt, A., Huizar, K., Annas, P., Karlsten, R., & Quiding, H. (2013) · Scandinavian Journal of Pain · doi:10.1016/j.sjpain.2012.08.004 · Cited by 60
Kalliomäki, J., Annas, P., Huizar, K., Clarke, C. P., Zettergren, A., Karlsten, R., & Segerdahl, M. (2013) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12051 · Cited by 60
“Other strategies of exploiting the endogenous cannabinoid systems for analgesia may also be considered; for example, instead of treatment with an exogenous receptor agonist, the levels of endogenous cannabinoids (‘endocannabinoids’) could be elevated through inhibition of a degrading enzyme.(24) Endocannabinoids have…”
BackgroundRahman, S. M. K., Uyama, T., Hussain, Z., & Ueda, N. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-043020-090216 · Cited by 58
Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation
Gyires, K., & Zádori, Z. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160303110150 · Cited by 59
“URB 937, an O-aryl carbamate derivative, is also a potent FAAH inhibitor, but it is extruded from the CNS by membrane transporter ATP-binding cassette, thus it inhibits the inactivation of AEA only in peripheral tissues [39].”
Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction
Wenzel, D., Matthey, M., Bîndilă, L., Lerner, R., Lutz, B., Zimmer, A., & Fleischmann, B. K. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1308130110 · Cited by 54
“This could also provide alternative treatment options for clinically highly relevant pulmonary disorders, in particular, in the light of a recently developed FAAH inhibitor with a pharmacological activity restricted to peripheral organs (31).”
BackgroundRole of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications
Nagappan, A., Shin, J., & Jung, M. H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092109 · Cited by 56
Abdallah, F. W., Hussain, N., Weaver, T. E., & Brull, R. (2020) · Regional Anesthesia & Pain Medicine · doi:10.1136/rapm-2020-101340 · Cited by 57
O’Sullivan, S. E., Yates, A. S., & Porter, R. K. (2021) · Molecules · doi:10.3390/molecules26206178 · Cited by 54
Desroches, J., Charron, S., Bouchard, J., & Beaulieu, P. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.10.006 · Cited by 51
“…spinal cannabinoidergic transmission is well established (for a review see (Walker and Huang, 2002)), and peripheral cannabinoidergic transmission is crucial in pain control (Agarwal et al., 2007; Clapper et al., 2010; Marrs et al., 2010; Yu et al., 2010), involving different mechanisms of action.”
BackgroundMethodFalchi, F., Bertozzi, S. M., Ottonello, G., Ruda, G. F., Colombano, G., Fiorelli, C., Martucci, C., Bertorelli, R., Scarpelli, R., Cavalli, A., et al. (2016) · Analytical Chemistry · doi:10.1021/acs.analchem.6b02075 · Cited by 51
Hossain, M. Z., Ando, H., Unno, S., & Kitagawa, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041423 · Cited by 54
Grim, T. W., Ghosh, S., Hsu, K.-L., Cravatt, B. F., Kinsey, S. G., & Lichtman, A. H. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.07.008 · Cited by 50
Li, Y., Yang, L., Chen, L., Zhu, C., Huang, R., Zheng, X., Qiu, Y., & Fu, J. X. (2012) · PLoS ONE · doi:10.1371/journal.pone.0043023 · Cited by 50
“FAAH inhibitors have been extensively studied and they have exhibited broad pharmacological properties [10,11,12].”
BackgroundFeledziak, M., Lambert, D. M., Marchand‐Brynaert, J., & Muccioli, G. G. (2011) · Recent Patents on CNS Drug Discovery · doi:10.2174/157488912798842223 · Cited by 50
“8 nM) was disclosed to selectively inhibit FAAH in the periphery [81].”
BackgroundShapiro, H., Singer, P., & Ariel, A. (2016) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2016.03.001 · Cited by 50
“For example, anandamide produced by inflammatory (and other) cells activates Gαi-coupled CB1 on PNs to increase pain thresholds and limit inflammatory hyperalgesia [146].”
BackgroundEndogenous N -acyl taurines regulate skin wound healing
Sasso, O., Pontis, S., Armirotti, A., Cardinali, G., Kovacs, D., Migliore, M., Summa, M., Moreno‐Sanz, G., Picardo, M., & Piomelli, D. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1605578113 · Cited by 50
“Anandamide, OEA, and PEA weremeasured by LC/MS as described (57).”
MethodSelf-citationA cryptic pocket in CB1 drives peripheral and functional selectivity
Rangari, V. A., O’Brien, E. S., Powers, A. S., Slivicki, R. A., Bertels, Z., Appourchaux, K., Aydın, D., Ramos‐Gonzalez, N., Mwirigi, J. M., Lin, L., et al. (2025) · Nature · doi:10.1038/s41586-025-08618-7 · Cited by 48
Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH)
Min, X., Thibault, S. T., Porter, A. C., Gustin, D. J., Carlson, T. J., Xu, H., Lindström, M., Xu, G., Uyeda, C., Ma, Z., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016167108 · Cited by 49
“These recently reported inhibitors are highly potent and selective, with some of them demonstrating in vivo efficacy (26, 35).”
BackgroundChemical dampening of Ly6Chi monocytes in the periphery produces anti-depressant effects in mice
Zheng, X., Ma, S., An, K., Wu, M., Wang, L., Wang, Q., Wang, G., & Hao, H. (2016) · Scientific Reports · doi:10.1038/srep19406 · Cited by 48
“However, the dilemma between insufficient brain penetration 40 and undesirable CNS side effects 41,42 are typical challenges that impede the conventional CNS-biased drug discovery paradigm.”
Brain-derived neurotrophic factor and exercise in fibromyalgia syndrome patients: a mini review
Nugraha, B., Karst, M., Engeli, S., & Gutenbrunner, C. M. (2011) · Rheumatology International · doi:10.1007/s00296-011-2348-2 · Cited by 49
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
