Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]
Open accessAbstract
The endocannabinoid system may serve important functions in the central and peripheral regulation of pain. In the present study, we investigated the effects of the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide] on rodent models of acute and persistent nociception (intraplantar formalin injection in the mouse), neuropathic pain (sciatic nerve ligation in the rat), and inflammatory pain (complete Freund's adjuvant injection in the rat). In the formalin model, administration of AM404 (1-10 mg/kg i.p.) elicited dose-dependent antinociceptive effects, which were prevented by the CB(1) cannabinoid receptor antagonist rimonabant (SR141716A; 1 mg/kg i.p.) but not by the CB2 antagonist SR144528 (1 mg/kg i.p.) or the vanilloid antagonist capsazepine (30 mg/kg i.p.). Comparable effects were observed with UCM707 [N-(3-furylmethyl)-eicosa-5,8,11,14-tetraenamide], another anandamide transport inhibitor. In both the chronic constriction injury and complete Freund's adjuvant model, daily treatment with AM404 (1-10 mg/kg s.c.) for 14 days produced a dose-dependent reduction in nocifensive responses to thermal and mechanical stimuli, which was prevented by a single administration of rimonabant (1 mg/kg i.p.) and was accompanied by decreased expression of cyclooxygenase-2 and inducible nitric-oxide synthase in the sciatic nerve. The results provide new evidence for a role of the endocannabinoid system in pain modulation and point to anandamide transport as a potential target for analgesic drug development.
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AM404 normalizes CCI-induced changes in nitric oxide activity, COX-2, cytokine levels, and NF-κB levels.
“AM404 also normalizes CCI-induced changes in NO activity,52, 53 COX-253 activity, cytokine levels (e.g. TNF-α and IL10),52 and NF-κB52 levels.”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [53]
AM404, administered chronically or acutely, does not affect locomotor behavior.
“AM404, administered chronically or acutely, does not affect locomotor behavior, indicating a low propensity of this agent to produce unwanted motor side-effects associated with direct activation of CB1 receptors.52, 53”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [53]
Cites
A 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 · cited 4× · see citing works
“The sciatic nerve of Wistar rats was surgically ligated as described previously (Bennett and Xie, 1988).”
BackgroundMethodInfluentialA 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 · cited 2× · see citing works
“We measured thermal hyperalgesia us-ing a Hargreaves apparatus (Hargreaves et al., 1988) (Ugo Basile).”
Dubuisson, D., & Dennis, S. G. (1977) · Pain · doi:10.1016/0304-3959(77)90130-0 · Cited by 2,534 · cited 3× · see citing works
“tically distinct rodent models of pain: the formalin model of acute and persistent nociception (Dubuisson and Dennis, 1977), the CCI model of neuropathic pain (Bennett and Xie, 1988), and the CFA model of arthritis-induced pain (Billingham, 1990).”
BackgroundMolecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Cravatt, B. F., Giang, D. K., Mayfield, S. P., Boger, D. L., Lerner, R. A., & Gilula, N. B. (1996) · Nature · doi:10.1038/384083a0 · Cited by 2,125 · see citing works
A second endogenous cannabinoid that modulates long-term potentiation
Stella, N., Schweitzer, P., & Piomelli, D. (1997) · Nature · doi:10.1038/42015 · Cited by 1,496 · cited 2× · see citing works
“Intracellular 2-AG is hydrolyzed by monoacylglycerol lipase (Stella et al., 1997; Dinh et al., 2002), which is inhibited by the compound URB602 (Hohmann et al.”
BackgroundBrain monoglyceride lipase participating in endocannabinoid inactivation
Dinh, T. P., Carpenter, D., Leslie, F. M., Freund, T. F., Katona, I., Sensi, S. L., Kathuria, S., & Piomelli, D. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.152334899 · Cited by 1,373 · cited 2× · see citing works
“Intracellular 2-AG is hydrolyzed by monoacylglycerol lipase (Stella et al., 1997; Dinh et al., 2002), which is inhibited by the compound URB602 (Hohmann et al.”
BackgroundCravatt, 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 · cited 4× · see citing works
“Third, genetic deletion or pharmacological inhibition of FAAH ele-vates brain anandamide levels and reduces nocifensive behaviors in mice and rats (Cravatt et al., 2001; Kathuria et al., 2003; Lichtman et al., 2004).”
BackgroundInfluentialModulation 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 · cited 10× · see citing works
“, 1996), an intracellular membrane-bound serine hydrolase whose activity is selectively inhibited by the compounds URB597 and OL135 (Kathuria et al., 2003; Lichtman et al., 2004) as well as by a variety of nonselective agents (for review, see Piomelli, 2005).”
BackgroundInfluentialControl of pain initiation by endogenous cannabinoids
Calignano, A., Rana, G. L., Giuffrida, A., & Piomelli, D. (1998) · Nature · doi:10.1038/28393 · Cited by 1,055 · cited 4× · see citing works
“In addition to these central effects, cannabinoid agonists may also prevent formalin-evoked pain responses in mice (Calignano et al., 1998) and capsaicin-evoked pain in monkeys and human volunteers (Ko and Woods, 1999; Rukwied et al.”
BackgroundInfluentialFunctional Role of High-Affinity Anandamide Transport, as Revealed by Selective Inhibition
Beltramo, M., Stella, N., Calignano, A., Lin, S. Y., Makriyannis, A., & Piomelli, D. (1997) · Science · doi:10.1126/science.277.5329.1094 · Cited by 813 · cited 9× · see citing works
“The endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), are removed from the extracellular space by a high-affinity transport system present both in neural and non-neural cells (Beltramo et al., 1997; Hillard et al., 1997).”
BackgroundInfluentialAn endocannabinoid mechanism for stress-induced analgesia
Hohmann, A. G., Suplita, R. L., Bolton, N. M., Neely, M. H., Fegley, D., Mangieri, R., Krey, J. F., Michael Walker, J., Holmes, P. V., Crystal, J. D., et al. (2005) · Nature · doi:10.1038/nature03658 · Cited by 778 · cited 4× · see citing works
“…blockade enhances pain behaviors in several pain models (Calig-nano et al., 1998; Strangman et al., 1998; for contrasting results, see Beaulieu et al., 2000) and abrogates nonopioid stress-induced analgesia (Hohmann et al., 2005), suggesting the existence of an analgesic endocannabinoid tone.”
BackgroundInfluentialSelf-citationIbrahim, M. M., Porreca, F., Lai, J., Albrecht, P. J., Rice, F. L., Khodorova, A., Davar, G., Makriyannis, A., Vanderah, T. W., Mata, H. P., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409888102 · Cited by 521 · cited 2× · see citing works
“, 2003) presumably by interacting with CB1 or CB2 receptors localized on sensory neuron terminals or resident non-neural cells (Hohmann and Herkenham, 1999; Nackley et al., 2004; Ibrahim et al., 2005).”
BackgroundPain modulation by release of the endogenous cannabinoid anandamide
Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K., & Sañudo-Peña, M. C. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.21.12198 · Cited by 486 · cited 1× · see citing works
“First, intraplantar formalin injection and electric foot shock administration stimulate the release of anandamide and 2-AG in the rat periaqueductal gray, a key pain-processing structure of the midbrain (Walker et al., 1999; Hohmann et al., 2005).”
BackgroundAn analgesia circuit activated by cannabinoids
Meng, I. D., Manning, B. H., Martin, W. J., & Fields, H. L. (1998) · Nature · doi:10.1038/26481 · Cited by 411 · cited 2× · see citing works
“In animals, systemic or intracerebral administration of cannabinoid agonists produces profound antinociceptive effects and suppresses activity in CB1-expressing nociceptive neurons of the thalamus, midbrain, and brainstem (Hohmann et al., 1995, 1999, 2005; Meng et al., 1998).”
BackgroundDe Petrocellis, L., Bisogno, T., Davis, J. B., Pertwee, R. G., & Di Marzo, V. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)02082-2 · Cited by 347 · see citing works
Karst, M., Salim, K., Burstein, S., Conrad, I., Hoy, L., & Schneider, U. (2003) · JAMA · doi:10.1001/jama.290.13.1757 · Cited by 340 · cited 1× · see citing works
“Likewise, neuropathic pain patients orally treated with the synthetic cannabinoid agonist CT-3 reported significantly less pain than did placebo-treated patients (Karst et al., 2003).”
BackgroundHillard, C. J., Edgemond, W. S., Jarrahian, A., & Campbell, W. B. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69020631.x · Cited by 337 · cited 2× · see citing works
“The endocannabinoids, anandamide and 2-arachidonoyl-glycerol (2-AG), are removed from the extracellular space by a high-affinity transport system present both in neural and non-neural cells (Beltramo et al., 1997; Hillard et al., 1997).”
BackgroundLichtman, A. H., Leung, D., Shelton, C. C., Saghatelian, A., Hardouin, C., Boger, D. L., & Cravatt, B. F. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.069401 · Cited by 329 · cited 6× · see citing works
“, 1996), an intracellular membrane-bound serine hydrolase whose activity is selectively inhibited by the compounds URB597 and OL135 (Kathuria et al., 2003; Lichtman et al., 2004) as well as by a variety of nonselective agents (for review, see Piomelli, 2005).”
BackgroundInfluentialHohmann, A. G., & Herkenham, M. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00524-7 · Cited by 301 · cited 2× · see citing works
“, 2003) presumably by interacting with CB1 or CB2 receptors localized on sensory neuron terminals or resident non-neural cells (Hohmann and Herkenham, 1999; Nackley et al., 2004; Ibrahim et al., 2005).”
BackgroundEvidence against the presence of an anandamide transporter
Glaser, S. T., Abumrad, N. A., Fatade, F., Kaczocha, M., Studholme, K. M., & Deutsch, D. G. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0730816100 · Cited by 280 · see citing works
Structural determinants for recognition and translocation by the anandamide transporter
Piomelli, D., Beltramo, M., Glasnapp, S., Lin, S., Goutopoulos, A., Xie, X., & Makriyannis, A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.10.5802 · Cited by 268 · cited 4× · see citing works
“However, it is worth noting that although LY2183240 and UCM707 inhibit both first and second phase of formalin nociception, AM404 only inhibits the former.”
BackgroundInfluentialReversal of Dopamine D2Receptor Responses by an Anandamide Transport Inhibitor
Beltramo, M., de Fonseca, F. R., Navarro, M. A., Calignano, A., Gorriti, M. Á., Grammatikopoulos, G., Sadile, A. G., Giuffrida, A., & Piomelli, D. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-09-03401.2000 · Cited by 232 · cited 2× · see citing works
“Previous studies have shown that AM404 does not closely reproduce the pharmacological profile of direct-acting cannabinoid agonists (Beltramo et al., 2000; Fegley et al., 2004).”
BackgroundSelective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus
Makara, J. K., Mor, M., Fegley, D., Szabó, S. I., Kathuria, S., Astarita, G., Duranti, A., Tontini, A., Tarzia, G., Rivara, S., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1521 · Cited by 231 · cited 2× · see citing works
“, 2002), which is inhibited by the compound URB602 (Hohmann et al., 2005; Makara et al., 2005).”
BackgroundFegley, D., Kathuria, S., Mercier, R., Li, C., Goutopoulos, A., Makriyannis, A., & Piomelli, D. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400997101 · Cited by 230 · cited 9× · see citing works
“This lack of effect might be accounted for by enzymatic degradation (Fegley et al., 2004).”
BackgroundInfluentialCellular accumulation of anandamide: consensus and controversy
Hillard, C. J., & Jarrahian, A. (2003) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0705468 · Cited by 199 · cited 1× · see citing works
“The molecular identity of this putative transporter is still unknown, but some of its biochemical and pharmacological properties have been characterized (for review, see Hillard and Jarrahian, 2003).”
BackgroundModels of arthritis and the search for anti-arthritic drugs
Billingham, M. E. J. (1983) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(83)90062-1 · Cited by 190 · cited 3× · see citing works
“tically distinct rodent models of pain: the formalin model of acute and persistent nociception (Dubuisson and Dennis, 1977), the CCI model of neuropathic pain (Bennett and Xie, 1988), and the CFA model of arthritis-induced pain (Billingham, 1990).”
BackgroundMethodInfluentialIdentification of a high-affinity binding site involved in the transport of endocannabinoids
Moore, S. A., Nomikos, G. G., Chesterfield, A. K., Schober, D. A., Schaus, J. M., Ying, B.-P., Xu, Y., Phebus, L. A., Simmons, R. M. A., Li, D., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507470102 · Cited by 164 · cited 6× · see citing works
“Finally, the nonaliphatic anandamide transport inhibitor LY2183240, although structurally unrelated to AM404 and UCM707, exerts significant antinociceptive effects in the formalin model (Moore et al., 2005).”
InfluentialThe endocannabinoid system: a drug discovery perspective.
Piomelli, D. (2005) · PubMed · Cited by 152 · see citing works
Local expression of inducible nitric oxide synthase in an animal model of neuropathic pain
Levy, D., Höke, A., & Zochodne, D. W. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00982-3 · Cited by 134 · cited 3× · see citing works
“Notably, the analgesic actions of AM404 cannot be attributed to sedation since they are accompanied by an improvement rather than an impairment of motor activity in the Rotorod test and are associated with a marked reduction in the expression of Cox-2 and iNOS, two proteins that are involved in the pathogenesis of neu…”
BackgroundAlba, J. D., Clayton, N. M., Collins, S. D., Colthup, P. V., Chessell, I. P., & Knowles, R. G. (2005) · Pain · doi:10.1016/j.pain.2005.10.028 · Cited by 131 · see citing works
Hohmann, A. G., Tsou, K., & Walker, J. M. (1999) · Journal of Neurophysiology · doi:10.1152/jn.1999.81.2.575 · Cited by 126 · see citing works
Hohmann, A. G., Martin, W. J., Tsou, K., & Walker, J. M. (1995) · Life Sciences · doi:10.1016/0024-3205(95)00196-d · Cited by 121 · see citing works
Nackley, A. G., Zvonok, A. M., Makriyannis, A., & Hohmann, A. G. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00886.2003 · Cited by 111 · cited 2× · see citing works
“, 2003) presumably by interacting with CB1 or CB2 receptors localized on sensory neuron terminals or resident non-neural cells (Hohmann and Herkenham, 1999; Nackley et al., 2004; Ibrahim et al., 2005).”
BackgroundEvidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity
Strangman, N. M., Patrick, S. L., Hohmann, A. G., Tsou, K., & Walker, J. M. (1998) · Brain Research · doi:10.1016/s0006-8993(98)01031-2 · Cited by 109 · cited 4× · see citing works
“First, CB1 receptor blockade enhances pain behaviors in several pain models (Calignano et al., 1998; Strangman et al., 1998; for contrasting results, see Beaulieu et al., 2000) and abrogates nonopioid stress-induced analgesia (Hohmann et al.”
BackgroundInfluentialCannabinoid agonists attenuate capsaicin-induced responses in human skin
Rukwied, R., Watkinson, A., McGlone, F. P., & Dvorak, M. M. (2003) · Pain · doi:10.1016/s0304-3959(02)00401-3 · Cited by 108 · cited 2× · see citing works
“, 1998) and capsaicin-evoked pain in monkeys and human volunteers (Ko and Woods, 1999; Rukwied et al., 2003) presumably by interacting with CB1 or CB2 receptors localized on sensory neuron terminals or resident non-neural cells (Hohmann and Herkenham, 1999; Nackley et al.”
BackgroundRole of the endogenous cannabinoid system in the formalin test of persistent pain in the rat
Beaulieu, P., Bisogno, T., Punwar, S., Farquhar-Smith, W. P., Ambrosino, G., Marzo, V. D., & Rice, A. S. C. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00226-0 · Cited by 101 · cited 3× · see citing works
“…CB 1 receptor blockade enhances pain behaviors in several pain models (Calig-nano et al., 1998; Strangman et al., 1998; for contrasting results, see Beaulieu et al., 2000) and abrogates nonopioid stress-induced analgesia (Hohmann et al., 2005), suggesting the existence of an analgesic…”
BackgroundOrtega‐Gutiérrez, S., Hawkins, E. G., Viso, A., López-Rodríguez, M. L., & Cravatt, B. F. (2004) · Biochemistry · doi:10.1021/bi049395f · Cited by 91 · cited 1× · see citing works
“However, the discovery that pharmacological or genetic inactivation of FAAH does not affect anandamide internalization in neurons strongly argues against this possibility and in favor of the transporter hypothesis (Kathuria et al., 2003; Fegley et al., 2004; Ortega-Gutierrez et al., 2004).”
BackgroundLópez-Rodríguez, M. L., Viso, A., Ortega‐Gutiérrez, S., Lastres‐Becker, I., González, S. R., Fernández‐Ruíz, J., & Ramos, J. A. (2001) · Journal of Medicinal Chemistry · doi:10.1021/jm015545y · Cited by 70 · cited 6× · see citing works
“This discrepancy might be accounted for by the known sensitivity of AM404 to enzymatic degradation (Fegley et al., 2004), but current information on the pharmacological properties of UCM707 and LY2183240 is too limited to allow us to exclude the possibility that these compounds may act through alternative noncannabino…”
BackgroundInfluentialBingham, S., Beswick, P., Bountra, C., Brown, T., Campbell, I. B., Chessell, I. P., Clayton, N. M., Collins, S. D., Davey, P. T., Goodland, H., et al. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.075267 · Cited by 63 · cited 1× · see citing works
“To further investigate the antihyperalgesic properties of AM404, we asked whether this endocannabinoid transport inhibitor alters the expression of Cox-2 and iNOS, two enzymes that have been implicated in the pathogenesis of neuropathic pain (Bingham et al., 2005; De Alba et al., 2005).”
BackgroundKo, M., & Woods, J. H. (1999) · Psychopharmacology · doi:10.1007/s002130050955 · Cited by 58 · cited 2× · see citing works
“…by an improvement rather than an impairment of motor activity in the Rotorod test and are associated with a marked reduction in the expression of Cox-2 and iNOS, two proteins that are involved in the pathogenesis of neuropathic pain and inflammation (Levy et al., 1999; De Alba et al., 2005).”
BackgroundA role for the endogenous cannabinoid system in the peripheal control of pain initiation
Calignano, A., Rana, G. L., Loubet‐Lescoulié, P., & Piomelli, D. (2000) · Progress in brain research · doi:10.1016/s0079-6123(00)29034-1 · Cited by 34 · see citing works
Rodella, L. F., Borsani, E., Rezzani, R., Ricci, F., Buffoli, B., & Bianchi, R. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2004.12.031 · Cited by 32 · cited 2× · see citing works
“Second, administration of AM404 increases endogenous anandamide levels in the mouse brain (Fegley et al., 2004) and decreases cFOS immunoreactivity in the dorsal superficial laminae of the spinal cord in CCI rats (Rodella et al., 2005).”
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The Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pacher, P., Bátkai, S., & Kunos, G. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.2 · Cited by 2,077 · see citing works
“…transport inhibitors unmasked cannabinoid-like tonic effects on pain sensitivity, anxiety-like behaviors, locomotor activity, and muscle spasticity, which is an indication of the potential therapeutic usefulness of such compounds (Moore et al., 2005; Bortolato et al., 2006; La Rana et al., 2006).”
BackgroundTargeting the endocannabinoid system: to enhance or reduce?
Marzo, V. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2553 · Cited by 798 · see citing works
The Endocannabinoid System and Pain
Guindon, J., & Hohmann, A. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709789824660 · Cited by 476 · see citing works
“In the formalin test, endocannabinoid uptake inhibitors (AM404, UCM707, LY2318912, LY2183240, OMDM132) produce antinociception [93,214,215] (see Table 3).”
BackgroundInfluentialCannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside
Rahn, E. J., & Hohmann, A. G. (2009) · Neurotherapeutics · doi:10.1016/j.nurt.2009.08.002 · Cited by 305 · see citing works
“127 Cold and mechanical allodynia, but not thermal hyperalgesia, have been reported in a model of autoimmune encephalomyelitis in which mice were immunized with myelin oligodendrocyte glycoprotein (MOG(35-55))128; autoimmune encephalomyelitis has been postulated to underlie the development of neuropathic pain in MS.”
BackgroundPotential Analgesic Mechanisms of Acetaminophen
Smith, H. S. (2009) · Pain Physician · doi:10.36076/ppj.2009/12/269 · Cited by 248 · see citing works
Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia
Mallet, C., Daulhac, L., Bonnefont, J., Ledent, C., Etienne, M., Chapuy, E., Libert, F., & Eschalier, A. (2008) · Pain · doi:10.1016/j.pain.2008.03.030 · Cited by 223 · see citing works
Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats
Petrosino, S., Palazzo, E., de Novellis, V., Bisogno, T., Rossi, F., Maione, S., & Di Marzo, V. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.08.011 · Cited by 227 · see citing works
Paracetamol – An old drug with new mechanisms of action
Przybyła, G. W., Szychowski, K. A., & Gmiński, J. (2021) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13392 · Cited by 190 · see citing works
Kaczocha, M., Vivieca, S., Sun, J. Y., Glaser, S. T., & Deutsch, D. G. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.304907 · Cited by 188 · see citing works
A catalytically silent FAAH-1 variant drives anandamide transport in neurons
Fu, J., Bottegoni, G., Sasso, O., Bertorelli, R., Rocchia, W., Masetti, M., Guijarro, A., Lodola, A., Armirotti, A., Garau, G., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.2986 · Cited by 175 · see citing works
TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception
Mallet, C., Barrière, D. A., Ermund, A., Jönsson, B. A. G., Eschalier, A., Zygmunt, P. M., & Högestätt, E. D. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012748 · Cited by 165 · see citing works
Transport of endocannabinoids across the plasma membrane and within the cell
Fowler, C. J. (2013) · FEBS Journal · doi:10.1111/febs.12212 · Cited by 168 · see citing works
Targeting Fatty Acid Amide Hydrolase (FAAH) to Treat Pain and Inflammation
Schlosburg, J. E., Kinsey, S. G., & Lichtman, A. H. (2009) · The AAPS Journal · doi:10.1208/s12248-008-9075-y · Cited by 165 · see citing works
Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain
Jhaveri, M. D., Richardson, D. S., & Chapman, V. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707433 · Cited by 145 · see citing works
“…2000) and an inhibitor of the putative AEA transport process, attenuates thermal and mechanical hyperalgesia in models of acute, inflammatory and neuropathic pain (Costa et al., 2006; La Rana et al., 2006) and spinal expression of Fos- immunoreactivity in neuropathic rats (Rodella et al., 2005).”
BackgroundEvidence for Bidirectional Endocannabinoid Transport across Cell Membranes
Chicca, A., Marazzi, J., Nicolussi, S., & Gertsch, J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.373241 · Cited by 138 · see citing works
Ignatowska‐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 · see citing works
“…receptor mechanism of action, the CB1 receptor antagonist rimonabant (1 mg·kg−1) or the CB2 receptor antagonist SR144528 (3 mg·kg−1) was administered 30 min prior to KML29 or vehicle (Lichtman et al., 2004a; La Rana et al., 2006; Russo et al., 2007; Kinsey et al., 2009; 2011; Ghosh et al., 2013).”
MethodBiology and therapeutic potential of cannabinoid CB2receptor inverse agonists
Lunn, C. A., Reich, E., Fine, J. S., Lavey, B. J., Kozlowski, J. A., Hipkin, R. W., Lundell, D. J., & Bober, L. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707480 · Cited by 119 · see citing works
“…alone failed to induce significant pain hypersensitivity in model systems where cannabinoid CB2 receptor agonists clearly demonstrate decreased pain sensitivity (see Nackley et al., 2003; Elmes et al., 2004; Hohmann et al., 2004; Beltramo et al., 2006; La Rana et al., 2006; Gutierrez et al., 2007).”
BackgroundLuongo, L., Palazzo, E., Tambaro, S., Giordano, C. S. D. S., Gatta, L., Scafuro, M. A., Rossi, F., Lazzari, P., Pani, L., de Novellis, V., et al. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.09.021 · Cited by 113 · see citing works
Cannabinoids and Multiple Sclerosis
Pertwee, R. G. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-0005-2 · Cited by 110 · see citing works
Cannabichromene is a cannabinoid CB 2 receptor agonist
Udoh, M., Santiago, M., Devenish, S. O., McGregor, I. S., & Connor, M. A. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14815 · Cited by 109 · see citing works
“Stimulation of both CB1 and CB2 receptors have been implicated in antinociception (Bisogno et al., 2009; Guindon, Desroches, & Beaulieu, 2007; Kinsey et al., 2010; La Rana et al., 2006; Lichtman et al., 2004).”
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
The endocannabinoid system and migraine
Greco, R., Gasperi, V., Maccarrone, M., & Tassorelli, C. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.03.029 · Cited by 100 · see citing works
“…to characterize the antinociceptive effects of (endo)cannabinoids showed that activation of the CB1R by synthetic agonists, and/or pharmacological elevation of ECs levels via inhibition of FAAH activity, reduces hyperalgesia and allodynia in animal models of neuropathic pain (La Rana et al., 2006).”
Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice
Umathe, S. N., Manna, S. S. S., & Jain, N. S. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.031 · Cited by 96 · see citing works
Role of Cannabinoids in the Treatment of Pain and (Painful) Spasticity
Karst, M., Wippermann, S., & Ahrens, J. (2010) · Drugs · doi:10.2165/11585260-000000000-00000 · Cited by 91 · see citing works
Trezza, V., & Vanderschuren, L. J. M. J. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.141069 · Cited by 91 · see citing works
“…levels without the well known effects of CB1 cannabinoid receptor agonists (Beltramo et al., 1997), and it has potentially beneficial properties for the treatment of pain, motor impairments, and anxiety disorders (Fernandez-Espejo et al., 2004; Bortolato et al., 2006; La Rana et al., 2006).”
BackgroundPalazzo, E., De Novellis, V., Petrosino, S., Marabese, I., Vita, D., Giordano, C., Di Marzo, V., Mangoni, G. S., Rossi, F., & Maione, S. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05086.x · Cited by 86 · see citing works
“…DR neurones, 5-HT release and 5-HT receptor expression in the DR. Doses of cannabinoids used in the study were chosen according to previous studies in which repeated treatments with cannabinoids were carried out in neuropathic rats (Costa et al., 2004; Rodella et al., 2005; La Rana et al., 2006).”
BackgroundMethodResultInfluentialFowler, C. J. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.01.001 · Cited by 85 · 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
Russo, R., D’Agostino, G., Mattace Raso, G., Avagliano, C., Cristiano, C., Meli, R., & Calignano, A. (2012) · Peptides · doi:10.1016/j.peptides.2012.08.005 · Cited by 66 · see citing works
Klinger-Gratz, P. P., Ralvenius, W. T., Neumann, E., Kato, A., Nyilas, R., Lele, Z., Katona, I., & Zeilhofer, H. U. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1945-17.2017 · Cited by 74 · see citing works
“After spinal or systemic application, AM 404 exerts analgesic activity against acute pain, evoked by noxious chemical stimuli, as well as against inflammatory and neuropathic pain (Gühring et al., 2002; La Rana et al., 2006).”
BackgroundVera, G., Chiarlone, A., Cabezos, P. A., Pascual, D., Martín, M. I., & Abalo, R. (2007) · Life Sciences · doi:10.1016/j.lfs.2007.06.012 · Cited by 73 · see citing works
Drew, G. M., Mitchell, V. A., & Vaughan, C. W. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4876-07.2008 · Cited by 76 · see citing works
“Modulation of the endocannabinoid system represents a promising new target for anxiety and chronic pain states (Kathuria et al., 2003; Costa et al., 2006; Jayamanne et al., 2006; La Rana et al., 2006).”
BackgroundAlkaitis, M. S., Solórzano, C., Landry, R. P., Piomelli, D., DeLeo, J. A., & Romero-Sandoval, E. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010891 · Cited by 72 · see citing works
Enhancement of endocannabinoid signaling and the pharmacotherapy of depression
Mangieri, R. A., & Piomelli, D. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.09.003 · Cited by 71 · see citing works
Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model
Barnes, N. S. A., Mitchell, V. A., Kazantzis, N. P., & Vaughan, C. W. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13337 · Cited by 70 · see citing works
“This lack of tolerance is similar to that previously reported for the anti-allodynic actions of URB597 and the putative anandamide transport blocker AM404 over a similar treatment period to that used in the present study (La Rana et al., 2006; Russo et al., 2007).”
ResultModulation of Fear and Anxiety by the Endogenous Cannabinoid System
Chhatwal, J. P., & Ressler, K. J. (2007) · CNS Spectrums · doi:10.1017/s1092852900020939 · Cited by 70 · see citing works
Pacheco, D. D. F., Klein, A., Perez, A. C., Pacheco, C. M. D. F., Francischi, J. N., Reis, G. M. L., & Duarte, I. D. G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00310.x · Cited by 68 · see citing works
Saliba, S. W., Marcotegui, A. R., Fortwängler, E., Ditrich, J., Perazzo, J. C., Muñoz, E., de Oliveira, A. C. P., & Fiebich, B. L. (2017) · Journal of Neuroinflammation · doi:10.1186/s12974-017-1014-3 · Cited by 62 · see citing works
Hama, A. T., & Sagen, J. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.12.010 · Cited by 61 · see citing works
“Compounds designed to increase endocannabinoids have been found to be efficacious in various rat chronic pain models but the effects of these compounds have yet to be evaluated in an SCI pain model (Jayamanne et al., 2006; La Rana et al., 2006).”
Fowler, C., Naidu, P., Lichtman, A. H., & Onnis, V. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00029.x · Cited by 57 · see citing works
“…that inhibits the cellular accumulation of AEA] could be considered in this respect, because it affects both inflammatory and neuropathic pain (La Rana et al., 2006) and is both an FAAH inhibitor (by acting as a competing substrate) and a COX inhibitor (Lang et al., 1999; Högestätt et al., 2005).”
BackgroundBisogno, T., & Marzo, V. D. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2007.09.002 · Cited by 56 · see citing works
Gamaleddin, I., Guranda, M., Goldberg, S. R., & Foll, B. L. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01440.x · Cited by 53 · see citing works
“The anandamide uptake inhibitors were of potential therapeutic benefit in the treatment of pain, motor impairments and anxiety (Fernandez-Espejo et al., 2004; Bortolato, et al., 2006; La Rana et al., 2006).”
BackgroundFirst evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid
Sharma, C., Long, J. H., Shah, S., Rahman, J., Perrett, D., Ayoub, S., & Mehta, V. (2017) · Journal of Pain Research · doi:10.2147/jpr.s143500 · Cited by 51 · see citing works
“17 In the present study, nanomolar concentrations of AM404 were measured in human CSF samples taken from low level lumbar puncture.”
Cannabinoid receptors and pain
Starowicz, K., Małek, N., & Przewłocka, B. (2013) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.83 · Cited by 50 · see citing works
Mode of action of cannabinoids on nociceptive nerve endings
Kress, M., & Kuner, R. (2009) · Experimental Brain Research · doi:10.1007/s00221-009-1762-0 · Cited by 49 · see citing works
Williams, J., Haller, V. L., Stevens, D. L., & Welch, S. P. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2007.12.035 · Cited by 45 · see citing works
The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review
Fowler, C. J. (2015) · Handbook of experimental pharmacology · doi:10.1007/978-3-319-20825-1_4 · Cited by 45 · see citing works
Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models
Mitchell, V. A., Greenwood, R., Jayamanne, A., & Vaughan, C. W. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04692.x · Cited by 43 · see citing works
“Although the present findings differ to prior studies that have demonstrated that AM404 produces motor effects in unoperated animals,(37) others have reported that AM404 has no effect in sham-operated animals.(23) The difference between unoperated and chronic pain animals may be due to”
BackgroundResultInfluentialLa Rana, G., Russo, R., D'Agostino, G., Sasso, O., Raso, G. M., Iacono, A., Meli, R., Piomelli, D., & Calignano, A. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.10.021 · Cited by 42 · see citing works
“…nerve injury has been associated with local release of several mediators including cytokines, such as tumour necrosis factor-a (Wagner and Myers, 1996) and inflammatory enzymes, such as inducible nitric oxide synthase (iNOS) (Levy et al., 1999) and cyclooxygenase-2 (COX-2) (La Rana et al., 2006).”
BackgroundMethodResultInfluentialAlcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders
Koola, M. M., McMahon, R. P., Wehring, H. J., Liu, F., Mackowick, K. M., Warren, K. R., Feldman, S. M., Shim, J.-C., Love, R. C., & Kelly, D. L. (2012) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2012.04.019 · Cited by 37 · see citing works
Maione, S., Morera, E., Marabese, I., Ligresti, A., Luongo, L., Ortar, G., & Marzo, V. D. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.308 · Cited by 33 · see citing works
Hegyi, Z., Holló, K., Kis, G. N., Mackie, K., & Antal, M. (2012) · Glia · doi:10.1002/glia.22351 · Cited by 33 · see citing works
“…neurons (Di Marzo, 2008; Hohmann et al., 1995, 1998, 1999; Pacher et al., 2006), thus repressing hyperalgesia and allodynia in animal models of chronic pain (Chapman, 1999; Drew et al., 2000; Herzberg et al., 1997; Kelly and Chapman, 2001; La Rana et al., 2006; Morisset and Urban, 2001).”
TRPV1 mediates the anticonvulsant effects of acetaminophen in mice
Suemaru, K., Yoshikawa, M., Aso, H., & Watanabe, M. (2018) · Epilepsy Research · doi:10.1016/j.eplepsyres.2018.06.016 · Cited by 32 · see citing works
Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine
Nagy-Grócz, G., Zádor, F., Dvorácskó, S., Bohár, Z., Benyhe, S., Tömböly, C., Párdutz, Á., & Vécsei, L. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081617 · Cited by 30 · see citing works
“On the other hand, 2-AG created an anti-nociceptive effect in the formalin test [101] and endocannabinoid uptake inhibitors were effective in pain relief in the formalin test [102], which shows that the levels of endocannabinoid are important in the pain inhibition process.”
BackgroundEndocannabinoid regulation of spinal nociceptive processing in a model of neuropathic pain
Sagar, D. R., Jhaveri, M. D., Richardson, D. S., Gray, R., de Lago, E., Fernández‐Ruíz, J., Barrett, D. A., Kendall, D. A., & Chapman, V. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07162.x · Cited by 30 · see citing works
“In vivo, UCM707 inhibits acute and inflammatory pain behaviour (de Lago et al., 2002; La Rana et al., 2006).”
BackgroundIncreased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain
Khasabova, I. A., Holman, M. A., Morse, T., Burlakova, N., Coicou, L. G., Harding-Rose, C., Simone, D. A., & Seybold, V. S. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.04.018 · Cited by 26 · see citing works
Synthesis and Evaluation of Paracetamol Esters As Novel Fatty Acid Amide Hydrolase Inhibitors
Onnis, V., Congiu, C., Björklund, E., Hempel, F., Söderström, E., & Fowler, C. J. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm901891p · Cited by 25 · see citing works
AM404 decreases Fos-immunoreactivity in the spinal cord in a model of inflammatory pain
Borsani, E., Labanca, M., Bianchi, R., & Rodella, L. F. (2007) · Brain Research · doi:10.1016/j.brainres.2007.03.071 · Cited by 25 · see citing works
Caballero, F. J., Soler-Torronteras, R., Lara‐Chica, M., García, V., Fiebich, B. L., Muñóz, E., & Calzado, M. A. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.11.023 · Cited by 24 · see citing works
Olvanil: A non-pungent TRPV1 activator has anti-emetic properties in the ferret
Chu, K.-M., Ngan, M., Wai, M., Yeung, C. K., Andrews, P. L. R., du Sert, N. P., & Rudd, J. A. (2009) · Neuropharmacology · doi:10.1016/j.neuropharm.2009.10.002 · Cited by 23 · see citing works
“The dose of RTX was based on our previous anti-emetic studies in the ferret (Andrews and Bhandari, 1993), and the doses of olvanil and AM404 were extrapolated from investigations showing analagesic activity in rodents (Dray and Dickenson, 1991; La Rana et al., 2006).”
Caballero, F. J., Navarrete, C. M., Hess, S., Fiebich, B. L., Appendino, G., Macho, A., Muñóz, E., & Sancho, R. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.12.001 · Cited by 23 · see citing works
The Pharmacology of the Cannabinoid System—A Question of Efficacy and Selectivity
Fowler, C. J. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-0001-6 · Cited by 23 · see citing works
Ayoub, S. S., Pryce, G., Seed, M. P., Bolton, C., Flower, R. J., & Baker, D. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.111.038638 · Cited by 20 · see citing works
Bosier, B., Doyen, P. J., Brolet, A., Muccioli, G. G., Ahmed, E., Desmet, N., Hermans, E., & Deumens, R. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13324 · Cited by 20 · see citing works
Role of Cannabinoids in the Management of Neuropathic Pain
Fontelles, M. I. M., & Goicoechea, C. (2008) · CNS Drugs · doi:10.2165/00023210-200822080-00003 · Cited by 20 · see citing works
Huang, H.-J., Chen, S.-L., Huang, H., Sun, Y., Lee, G.-C., Lee‐Chen, G., Hsieh‐Li, H. M., & Su, M. (2018) · Psychopharmacology · doi:10.1007/s00213-018-5108-0 · Cited by 18 · see citing works
“In addition to the specific targets CB1 or TRPV1 receptors, the effects of AM404 might be also dependent on nonspecific targets, including antioxidative stress through a receptor-independent mechanism (La Rana et al. 2006; Soliman et al. 2016).”
BackgroundFarghaly, H. S. M., Abdel‐Zaher, A. O., Mostafa, M. G., & Kotb, H. I. (2012) · Nitric Oxide · doi:10.1016/j.niox.2012.05.001 · Cited by 16 · see citing works
Cifani, C., Avagliano, C., Bonaventura, E. M. D., Giusepponi, M. E., Caro, C. D., Cristiano, C., Rana, G. L., Botticelli, L., Romano, A., Calignano, A., et al. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00266 · Cited by 15 · see citing works
“SR1 was administered intraperitoneally (IP) at the dose of 1 mg/kg (La Rana et al., 2006); Nal was administered IP at the dose 1 mg/kg (Wager-Srdar et al., 1987).”
MethodThe analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels
Maatuf, Y., Kushnir, Y., Nemirovski, A., Ghantous, M., Iskimov, A., Binshtok, A. M., & Priel, A. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2413811122 · Cited by 15 · see citing works
Dönertaş, B., Ünel, Ç. Ç., & Erol, K. (2018) · Journal of Experimental Pharmacology · doi:10.2147/jep.s162059 · Cited by 14 · see citing works
Metabotropic Glutamate and Cannabinoid Receptor Crosstalk in Periaqueductal Grey Pain Processing
Palazzo, E., de Novellis, V., Marabese, I., Rossi, F., & Maione, S. (2006) · Current Neuropharmacology · doi:10.2174/157015906778019545 · Cited by 12 · see citing works
PETROCELLIS, L. D., Deva, R., Mainieri, F., Schaefer, M., Bisogno, T., Ciccoli, R., Ligresti, A., Hill, K., Nigam, S., Appendino, G., et al. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800337-jlr200 · Cited by 12 · see citing works
Effects of the endocannabinoid transport inhibitors AM404 and UCM707 on diabetic neuropathy in rats
Hasanein, P., & Soltani, N. (2009) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2009.05197.x · Cited by 11 · see citing works
“The drug doses used in the present study were selected on the basis of results from preliminary experiments and from published data.(11,14,15) Rats were handled in accordance with the criteria outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health (NIH) publication 86–23; revis…”
BackgroundMethodResultInfluentialPET Imaging of Endocannabinoid System
Horti, A. G., Raymont, V., & Terry, G. E. (2014) · Springer eBooks · doi:10.1007/978-3-642-42014-6_11 · Cited by 11 · see citing works
Role of Endocannabinoids in Neuron-Glial Crosstalk
Luongo, L., Palazzo, E., de Novellis, V., & Maione, S. (2010) · The Open Pain Journal · doi:10.2174/1876386301003010029 · Cited by 11 · see citing works
“it animal models of neuropathic pain [3, 6-10].”
BackgroundHasanein, P., & Javanmardi, K. (2008) · Fundamental and Clinical Pharmacology · doi:10.1111/j.1472-8206.2008.00626.x · Cited by 10 · see citing works
Neurochemical effects of the endocannabinoid uptake inhibitor UCM707 in various rat brain regions
de Lago, E., Ortega‐Gutiérrez, S., Ramos, J. A., López-Rodríguez, M. L., & Fernández‐Ruíz, J. (2006) · Life Sciences · doi:10.1016/j.lfs.2006.11.029 · Cited by 10 · see citing works
Haranishi, Y., Hara, K., & Terada, T. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00250-2 · Cited by 9 · see citing works
The endocannabinoid transport inhibitor AM404 modulates nociception in cholestasis
Hasanein, P. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.07.026 · Cited by 8 · see citing works
Mechanisms of AM404-induced [Ca2+]i rise and death in human osteosarcoma cells
Chang, H., Huang, C.-C., Cheng, H., Wang, J., Lin, K., Hsu, P., Tsai, J., Liao, W., Lu, Y., Huang, J., et al. (2008) · Toxicology Letters · doi:10.1016/j.toxlet.2008.04.002 · Cited by 7 · see citing works
Wang, T. (2015) · The Chinese Journal of Physiology · doi:10.4077/cjp.2015.bad307 · Cited by 6 · see citing works
“Importantly, in the present study, the CB1 and CB2 antagonists were concomitantly administrated, whereas in the above-mentioned studies, CB1 and CB2 antagonists were individually administrated (5, 6, 19).”
BackgroundInfluentialEndocannabinoids and Their Synthetic Analogs
Vemuri, K. V., & Makriyannis, A. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-503-9_2 · Cited by 6 · see citing works
Pharmacological and toxicological effects of paracetamol: current knowledge and a review
Athbhaiya, G., Tiwari, A., Choudhary, R., & Samal, P. K. (2026) · Drug and Chemical Toxicology · doi:10.1080/01480545.2025.2604674 · Cited by 6 · see citing works
“Research conducted by yu et al. and Kozak et al. has revealed that the inhibition of cOx-2 induced by paracetamol leads to a reduction in the degradation of endocannabinoids (la Rana et al., 2006).”
PET Imaging of the Endocannabinoid System
Terry, G. E., Raymont, V., & Horti, A. G. (2020) · Springer eBooks · doi:10.1007/978-3-030-53176-8_12 · Cited by 5 · see citing works
In vivo imaging of the cannabinoid CB1 receptor using positron emission tomography
Terry, G. E. (2009) · Figshare · Cited by 3 · see citing works
The Management of Neuropathic Pain
Toth, C., & Moulin, D. E. (2013) · Cambridge University Press eBooks · doi:10.1017/cbo9781139152211.019 · Cited by 1 · see citing works
Olango, W. M. (2012) · Arrow@dit (Dublin Institute of Technology) · doi:10.13025/17506 · Cited by 1 · see citing works
Control of analgesic and anti-inflammatory pathways by fatty acid amide hydrolase
Long, J. H. (2012) · Cited by 1 · see citing works
Bioactive Lipids in Nociception
Ermund, A. (2008) · Lund University Publications (Lund University)
Reda, H. M., Zaitone, S. A., & Moustafa, Y. M. (2014) · Journal of Physiology and Pharmacology Advances · doi:10.5455/jppa.20141116104755
Removal of Endocannabinoids by the Body: Mechanisms and Therapeutic Possibilities
Fowler, C. J., & Thors, L. (2007) · Springer eBooks · doi:10.1007/978-0-387-74349-3_3
Ware, M. A. (2013) · Cambridge University Press eBooks · doi:10.1017/cbo9781139152211.022
The cannabinoid system and its role in nociception
Beltramo, M. (2016) · Wiley eBooks · doi:10.1002/9781118455968.ch6
Gamaleddin, I. (2013) · TSpace (University of Toronto)
Tsuchiya, H., Takai, Y., & Mizogami, M. (2026) · Medical Principles and Practice · doi:10.1159/mpp/adpag006
“In rodent pain models [54, 55], AM404 (1–10 mg/kg, i.p.) dose-dependently relieved acute and persistent nociception of mice, and inflammatory and neuropathic pain of rats.”
- Authors
- La Rana, G., Russo, R., Campolongo, P., Bortolato, M., Mangieri, R. A., Cuomo, V., Iacono, A., Raso, G. M., Meli, R., Piomelli, D., & Calignano, A.
- ORCID
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 317
- Issue
- 3
- Pages
- 1365-1371
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2160725099
- Cited by
- 97
- References
- 44
- Citations by year
- 2026: 2 · 2025: 1 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 1 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 8
- FWCI
- 9.20
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Institute on Drug Abuse (DA-3412, R01DA012447, DA12447)
- 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
- AM404, endocannabinoid system, neuropathic pain, inflammatory pain, antinociception, CB1 receptor, rimonabant, sciatic nerve ligation, complete Freund's adjuvant, formalin test, cyclooxygenase-2, inducible nitric oxide synthase, analgesic drug development
- MeSH terms
- Animals, Arachidonic Acids, Biological Transport, Disease Models, Animal, Dose-Response Relationship, Drug, Freund's Adjuvant, Furans, Hyperalgesia, Inflammation, Male, Pain, Pain Measurement, Rats, Wistar, Sciatic Neuropathy, 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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