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Cabranes, A. et al. Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis. Neurobiol. Dis. 20, 207–217 (2005).
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Maresz, K. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nature Med. 13, 492–497 (2007).
The first study that really clarifies the distinct beneficial roles of the two cannabinoid receptor types in autoimmune neuroinflammation.
Croxford, J. L. et al. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J. Neuroimmunol. 193, 120–129 (2007).
Bilsland, L. G. et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J. 20, 1003–1005 (2006).
Kim, K., Moore, D. H., Makriyannis, A. & Abood, M. E. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur. J. Pharmacol. 542, 100–105 (2006).
Shoemaker, J. L., Seely, K. A., Reed, R. L., Crow, J. P. & Prather, P. L. The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J. Neurochem. 101, 87–98 (2007).
Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).
Perhaps the first example of the site- and time-specific activation of the endocannabinoid system following a stressor and with a protective function in the adaptation to new environmental conditions.
Kamprath, K. et al. Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J. Neurosci. 26, 6677–6686 (2006).
Patel, S., Roelke, C. T., Rademacher, D.J., Cullinan, W. E. & Hillard, C. J. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic–pituitary–adrenal axis. Endocrinology 145, 5431–5438 (2004).
An important study showing how the endocannabinoids and CB1 receptors can be involved in the control of stress.
Hohmann, A. G. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005).
Another elegant example of the site- and time-specific activation of the endocannabinoid system following a stressor, and of the therapeutic exploitation of specific inhibitors of endocannabinoid degradation.
Hill, M. N. et al. Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology 31, 2591–2599 (2006).
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The first study that suggests that inhibition of endocannabinoid degradation can be used against allergic contact dermatitis.
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Costa, B. et al. Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve. Pain 116, 52–61 (2005).
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Croci, T. & Zarini, E. Effect of the cannabinoid CB1 receptor antagonist rimonabant on nociceptive responses and adjuvant-induced arthritis in obese and lean rats. Br. J. Pharmacol. 150, 559–566 (2007).
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Teixeira-Clerc, F. et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nature Med. 12, 671–676 (2006).
An important study showing how CB1 and CB2 receptors play opposing roles in liver fibrosis, and how CB1 antagonists might be used to treat this disorder.
Batkai, S. et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 21, 1788–1800 (2007).
Ofek, O. et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc. Natl Acad. Sci. USA 103, 696–701 (2006).
Idris, A. I. et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nature Med. 11, 774–779 (2005).
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Sarnataro, D. et al. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol. Pharmacol. 70, 1298–1306 (2006).
Massa, F. et al. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113, 1202–1209 (2004).
D'Argenio, G. et al. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J. 20, 568–570 (2006).
The first study showing that endocannabinoid enhancers can be as effective as well-established drugs against experimental colitis.
Croci, T., Landi, M., Galzin, A. M. & Marini, P. Role of cannabinoid CB1 receptors and tumor necrosis factor-α in the gut and systemic anti-inflammatory activity of SR 141716 (rimonabant) in rodents. Br. J. Pharmacol. 140, 115–122 (2003).
Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006).
An elegant study showing how the endocannabinoids and CB1 receptors work in a neuron-type-specific way to dampen excitotoxicity.
Maione, S. et al. Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J. Pharmacol. Exp. Ther. 316, 969–982 (2006).
Lunn, C. A. et al. Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. Br. J. Pharmacol. 153, 226–239 (2007).
Miller, A. M. & Stella, N. CB2 receptor-mediated migration of immune cells: it can go either way. Br. J. Pharmacol. 153, 299–308 (2007).
Marsch, R. et al. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J. Neurosci. 27, 832–839 (2007).
Dinis, P. et al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J. Neurosci. 24, 11253–11263 (2004).
Singh Tahim, A., Santha, P. & Nagy, I. Inflammatory mediators convert anandamide into a potent activator of the vanilloid type 1 transient receptor potential receptor in nociceptive primary sensory neurons. Neuroscience 136, 539–548 (2005).
Orliac, M. L., Peroni, R., Celuch, S. M. & Adler-Graschinsky, E. Potentiation of anandamide effects in mesenteric beds isolated from endotoxemic rats. J. Pharmacol. Exp. Ther. 304, 179–184 (2003).
Domenicali, M. et al. Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors. Gut 54, 522–527 (2005).
Moezi, L. et al. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB1 and VR1 receptors. Br. J. Pharmacol. 149, 898–908 (2006).
Horvath, G., Kekesi, G., Nagy, E. & Benedek, G. The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Pain 134, 277–284 (2007).
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Evans, R. M., Scott, R. H. & Ross, R. A. Chronic exposure of sensory neurones to increased levels of nerve growth factor modulates CB1/TRPV1 receptor crosstalk. Br. J. Pharmacol. 152, 404–413 (2007).
Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76–81 (2003).
First study demonstrating the potential use of endocannabinoid boosters against anxiety.
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Abouabdellah, A. et al. Derivatives of dioxane-2-alkyl carbamates, preparation thereof and application thereof in therapeutics. Patent US20050182130 A1 (2005).
Zhang, D. et al. Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets. Neuropharmacology 52, 1095–1105 (2007).
Piomelli, D. et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 12, 21–38 (2006).
Russo, R. et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J. Pharmacol. Exp. Ther. 322, 236–242 (2007).
Jayamanne, A. et al. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br. J. Pharmacol. 147, 281–288 (2006).
Holt S., Comelli, F., Costa, B. & Fowler, C. J. Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br. J. Pharmacol. 146, 467–476 (2005).
Batkai, S. et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation. 110, 1996–2002 (2004).
A complete study showing how endocannabinoids and CB1 receptors are produced to play a protective function during certain types of hypertension, and how this might be treated by endocannabinoid boosters.
Nucci, C. et al. Involvement of the endocannabinoid system in retinal damage after high intraocular pressure-induced ischemia in rats. Invest. Ophthalmol. Vis. Sci. 48, 2997–3004 (2007).
First complete study suggesting the potential use of endocannabinoid enhancers against glaucoma.
Sharkey, K. A. et al. Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur. J. Neurosci. 25, 2773–2782 (2007).
Cross-Mellor, S. K., Ossenkopp, K. P., Piomelli, D. & Parker, L. A. Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacology (Berl.) 190, 135–143 (2007).
Patel, S. & Hillard, C. J. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J. Pharmacol. Exp. Ther. 318, 304–311 (2006).
Vlachou, S., Nomikos, G. G. & Panagis, G. Effects of endocannabinoid neurotransmission modulators on brain stimulation reward. Psychopharmacology (Berl.) 188, 293–305 (2006).
Solinas, M., Justinova, Z., Goldberg, S. R. & Tanda, G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J. Neurochem. 98, 408–419 (2006).
Solinas, M. et al. The endogenous cannabinoid anandamide produces Δ-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J. Pharmacol. Exp. Ther. 321, 370–380 (2007).
Hansson, A. C. et al. Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32, 117–126 (2007).
Vinod, K. Y., Sanguino, E., Yalamanchili, R., Manzanares, J. & Hungund, B. L. Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. J. Neurochem. 104, 233–243 (2007).
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Capasso, R. et al. Fatty acid amide hydrolase controls mouse intestinal motility in vivo. Gastroenterology 129, 941–951 (2005).
Bifulco, M. et al. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J. 18, 1606–1608 (2004).
The first study showing that endocannabinoid enhancers can retard cancer growth in vivo.
Suplita, R. L. 2nd, Farthing, J. N., Gutierrez, T. & Hohmann, A. G. Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaqueductal gray and rostral ventromedial medulla. Neuropharmacology 49, 1201–1209 (2005).
Tzavara, E. T. et al. Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol. Psychiatry. 59, 508–515 (2006).
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Costa, B. et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br. J. Pharmacol. 148, 1022–1032 (2006).
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Chhatwal, J. P., Davis, M., Maguschak, K. A. & Ressler, K. J. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30, 516–524 (2005).
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Wettschureck, N. et al. Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Mol. Cell Biol. 26, 5888–5894 (2006).
Fernandez-Espejo, E. et al. Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function. Neuropsychopharmacology 29, 1134–1142 (2004).
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Baker, D. et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15, 300–302 (2001).
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A report on an important clinical trial demonstrating the potential use of rimonabant in obese patients not just as a therapeutic aid to reduce body weight.
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Another important example of a possible role of CB1 receptors in the aetiology of a liver disorder, and of a potential therapeutic use of CB1 antagonists.
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Perhaps the most convincing study of the possible use of CB2 antagonists against inflammation.
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