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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The peripherally restricted FAAH inhibitor URB937 attenuates carrageenan-induced allodynia and hyperalgesia through a CB1 mechanism of action.
“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
Unlike brain-permeating FAAH inhibitors, the anti-edematous effects of URB937 are mediated by both CB1 and CB2 receptors.
“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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“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 · see citing works
“…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 118 · see citing works
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 · see citing works
“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 114 · see citing works
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 111 · see citing works
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 · see citing works
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 108 · see citing works
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“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 105 · see citing works
“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 104 · see citing works
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 102 · see citing works
Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications
Pertwee, R. G. (2013) · Proceedings of The Nutrition Society · doi:10.1017/s0029665113003649 · Cited by 98 · see citing works
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 · see citing works
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 · see citing works
“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 94 · see citing works
“, 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 · see citing works
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 91 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 79 · see citing works
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 · see citing works
“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 · see citing works
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 77 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“…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 · see citing works
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 66 · see citing works
“, 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 · see citing works
“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 · see citing works
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 65 · see citing works
“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 68 · see citing works
“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 65 · see citing works
“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 · see citing works
“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 · see citing works
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 64 · see citing works
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 58 · see citing works
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 · see citing works
“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 62 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation
Gyires, K., & Zádori, Z. (2016) · Current Neuropharmacology · doi:10.2174/1570159x14666160303110150 · Cited by 57 · see citing works
“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 · see citing works
“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 · see citing works
Abdallah, F. W., Hussain, N., Weaver, T. E., & Brull, R. (2020) · Regional Anesthesia & Pain Medicine · doi:10.1136/rapm-2020-101340 · Cited by 53 · see citing works
O’Sullivan, S. E., Yates, A. S., & Porter, R. K. (2021) · Molecules · doi:10.3390/molecules26206178 · Cited by 52 · see citing works
Desroches, J., Charron, S., Bouchard, J., & Beaulieu, P. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.10.006 · Cited by 51 · see citing works
“…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 · see citing works
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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 · see citing works
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“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 49 · see citing works
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 · see citing works
“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 · see citing works
“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 48 · see citing works
- 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 › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › 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 ›
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