8.0 Conclusion and Future studies
The cannabinoid system has been shown in several preclinical and clinical studies to be involved in the regulation of inflammatory and immunomodulatory responses. Even though the exact role of the endocannabinoid system in inflammation is not fully elucidated, a pool of evidence points to the potential pharmacological modulation of this system in the treatment or management of several inflammatory disease conditions, including both central and peripheral inflammatory disorders. Although individual variations in patient response to cannabinoid-inclusive therapy have been reported, findings from these studies have largely pointed to the potential successful translation of pre-clinical research to the clinic. Additional well-controlled randomized trials are however required to comprehensively evaluate the true clinical efficacy and long-term risks associated with cannabinoid therapy in inflammatory disorders.
CB2 receptors are primarily expressed on immune cells, and pharmacological targeting of these receptors have been shown to produce selective immunomodulation without profound immunosuppression. Interestingly, CB2 receptor activation is without psychotropic side effects, thus making it a suitable target for pharmacotherapy. Since the psychotropic effects of cannabinoids pose legal, social and therapeutic challenges, future studies may therefore focus on the synthesis or identification of novel molecules with increased affinities for the CB2 receptor for use in inflammatory and autoimmune diseases. In addition, more studies are required to investigate the exact biological effects of the “not-so-popular” endocannabinoids virodhamine, 2-AG ether and N-arachidonoyl dopamine and their possible effects on co-stimulatory molecules, adhesion molecules, chemokines and cytokines, to ascertain their roles in the inflammatory and immunomodulatory process.
Owing to the complexity of the pathophysiology of inflammatory disorders, multi-target drug development and pharmacotherapy strategies may be advantageous compared to single-target therapy as partly evidenced by the effectiveness of OMDM198 over single-target small molecules such as the FAAH inhibitor URB597 and the TRPV1 receptor antagonist SB366791 in the management of osteoarthritis (Mlost et al., 2018).
It has been demonstrated that gut inflammation alters the expression of metabolizing enzymes of the endocannabinoid system, resulting in marked changes in the levels of these enzymes in the local environment (Sharkey and Wiley, 2016). Further studies aimed toward identifying genetic and/or epigenetic alterations that affect functioning of the endocannabinoid system, including the effect of glucocorticoid receptors on the regulation of the expression of cannabinoid receptors andvice versa , are needed to shed more light on the relation between inflammation and cannabinoid signaling. Notwithstanding, pharmacological targeting of the cannabinoid system demonstrates potential for safe and effective use in the treatment of inflammatory diseases.
REFERENCES
Acharya, N., Penukonda, S., et al. (2017). Endocannabinoid system acts as a regulator of immune homeostasis in the gut: Proceedings of the National Academy of Sciences, 114(19), 5005-5010.
Ahluwalia, J., Urban, L., et al. (2003). Anandamide regulates neuropeptide release from capsaicin‐sensitive primary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro: European Journal of Neuroscience, 17(12), 2611-2618.
Alger, B. E., Kim, J. (2011). Supply and demand for endocannabinoids: Trends in neurosciences, 34(6), 304-315.
Alhouayek, M., Muccioli, G. G. (2014). COX-2-derived endocannabinoid metabolites as novel inflammatory mediators: Trends in pharmacological sciences, 35(6), 284-292.
Ali, A., Akhtar, N. (2015). The safety and efficacy of 3% Cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content: Pakistan journal of pharmaceutical sciences, 28(4).
Arango Duque, G., Descoteaux, A. (2014). Macrophage cytokines: involvement in immunity and infectious diseases. Frontiers in immunology, 5, 491.
Argenziano, M., Tortora, C., et al. (2019). The endocannabinoid system in pediatric inflammatory and immune diseases: International journal of molecular sciences, 20(23), 5875.
Ashton, J. C., Glass, M. (2007). The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration: Current neuropharmacology, 5(2), 73-80.
Bánvölgyi, A., Pozsgai, G., et al. (2004). Mustard oil induces a transient receptor potential vanilloid 1 receptor-independent neurogenic inflammation and a non-neurogenic cellular inflammatory component in mice: Neuroscience, 125(2), 449-459.
Barrie, N., Manolios, N. (2017). The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease: European Journal of Rheumatology, 4(3), 210.
Benito, C., Kim, W. K., et al. (2005). A glial endogenous cannabinoid system is upregulated in the brains of macaques with simian immunodeficiency virus-induced encephalitis: Journal of Neuroscience, 25(10), 2530-2536.
Berdyshev, E. V., Boichot, E., et al. (1997). Influence of fatty acid ethanolamides and Δ9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells: European journal of pharmacology, 330(2-3), 231-240.
Bie, B., Wu, J., et al. (2018). An overview of the cannabinoid type 2 (CB2) receptor system and its therapeutic potential: Current opinion in anaesthesiology, 31(4), 407.
Blankman, J. L., Cravatt, B. F. (2013). Chemical probes of endocannabinoid metabolism: Pharmacological reviews, 65(2), 849-871.
Blankman, J. L., Simon, G. M., et al. (2007). A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol: Chemistry & biology, 14(12), 1347-1356.
Borrelli, F., Aviello, G., et al. (2009). Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis: Journal of molecular medicine, 87(11), 1111.
Borrelli, F., Fasolino, I., et al. (2013). Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease: Biochemical pharmacology, 85(9), 1306-1316.
Borrelli, F., Romano, B., et al. (2015). Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti‐inflammatory agent: British journal of pharmacology, 172(1), 142-158.
Brancato, S. K., Albina, J. E. (2011). Wound macrophages as key regulators of repair: origin, phenotype, and function: The American journal of pathology, 178(1), 19-25.
Braun, M., Khan, Z. T., et al. (2018). Selective activation of cannabinoid receptor-2 reduces neuroinflammation after traumatic brain injury via alternative macrophage polarization: Brain, behavior, and immunity, 68, 224-237.
Burstein, S. H. (2018). Ajulemic acid: potential treatment for chronic inflammation: Pharmacology research & perspectives, 6(2), e00394.
Burstein, S. H., Zurier, R. B. (2009). Cannabinoids, endocannabinoids, and related analogs in inflammation: The AAPS journal, 11(1), 109.
Cabral, G. A., Griffin-Thomas, L. (2009). Emerging role of the cannabinoid receptor CB 2 in immune regulation: therapeutic prospects for neuroinflammation: Expert reviews in molecular medicine, 11.
Cabral, G. A., Marciano‐Cabral, F. (2005). Cannabinoid receptors in microglia of the central nervous system: immune functional relevance: Journal of leukocyte biology, 78(6), 1192-1197.
Candido, J., Hagemann, T. (2013). Cancer-related inflammation: Journal of clinical immunology, 33(1), 79-84.
Cani, P. D., Plovier, H., et al. (2016). Endocannabinoids—at the crossroads between the gut microbiota and host metabolism: Nature Reviews Endocrinology, 12(3), 133.
Chang, Y. H., Lee, S. T., et al. (2001). Effects of cannabinoids on LPS‐stimulated inflammatory mediator release from macrophages: involvement of eicosanoids: Journal of cellular biochemistry, 81(4), 715-723.
Changoer, L., Anastassov, G. (2019). Method to treat psoriasis: U.S. Patent Application No. 16/106,420.
Chen, K., Zeidi, M., et al. (2019). FRI0307 LENABASUM, A cannabinoid type 2 receptor agonist, reduces CD4 cell populations and downregulates type 1 and 2 interferon activities in lesional dermatomyositis skin: Annals of the rheumatic disease 78, 835.
Chen, L., Chen, H., et al. (2015). Endocannabinoid and ceramide levels are altered in patients with colorectal cancer: Oncology reports, 34(1), 447-454.
Chovatiya, R., Silverberg, J. I. (2019). Pathophysiology of Atopic Dermatitis and Psoriasis: Implications for Management in Children. Children, 6(10), 108.
Cioni, C., Tassi, M., et al. (2019). A Novel Highly Selective Cannabinoid CB2 Agonist Reduces in vitro Growth and TGF-beta Release of Human Glial Cell Tumors: Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents), 19(3), 206-214.
D’argenio, G., Valenti, M., et al. (2006). Up‐regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation: The FASEB journal, 20(3), 568-570.
De Filippis, D., Esposito, G., et al. (2011). Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis: PLoS One, 6(12), e28159.
De Petrocellis, L., Ligresti, A., et al. (2011). Effects of cannabinoids and cannabinoid‐enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes: British journal of pharmacology, 163(7), 1479-1494.
De Petrocellis, L., Orlando, P., et al. (2012). Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation: Acta physiologica, 204(2), 255-266.
Del Río, C., Navarrete, C., et al. (2016). The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways: Scientific reports, 6, 21703.
Devane, W. A., Hanus, L., et al. (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor: Science, 258(5090), 1946-1949.
Di Marzo, V., Fontana, A., et al. (1994). Formation and inactivation of endogenous cannabinoid anandamide in central neurons: Nature, 372(6507), 686-691.
Di Sabatino, A., Battista, N., et al. (2011). The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease: Mucosal immunology, 4(5), 574-583.
Dobrosi, N., Tóth, B. I., et al. (2008). Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor‐2‐mediated signaling: The FASEB Journal, 22(10), 3685-3695.
Donvito, G., Nass, S. R., et al. (2018). The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain: Neuropsychopharmacology, 43(1), 52-79.
Du, A. X., Osman, M., et al. (2020). Use of extracorporeal photopheresis in scleroderma: a review: Dermatology, 236(2), 105-110.
Duru, N., Wolfson, B., et al. (2016). Mechanisms of the alternative activation of macrophages and non-coding RNAs in the development of radiation-induced lung fibrosis: World journal of biological chemistry, 7(4), 231.
Ehrhart, J., Obregon, D., et al. (2005). Stimulation of cannabinoid receptor 2 (CB 2) suppresses microglial activation: Journal of neuroinflammation, 2(1), 1-13.
Eljaschewitsch, E., Witting, A., et al. (2006). The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells: Neuron, 49(1), 67-79.
Feng, Y. J., Li, Y. Y., et al. (2016). Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK: World journal of gastroenterology, 22(43), 9515.
Gaffal, E., Cron, M., et al. (2013). Anti‐inflammatory activity of topical THC in DNFB‐mediated mouse allergic contact dermatitis independent of CB 1 and CB 2 receptors: Allergy, 68(8), 994-1000.
Galiègue, S., Mary, S., et al. (1995). Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations: European journal of biochemistry, 232(1), 54-61.
Grill, M., Hasenoehrl, C., et al. (2018). Medical Cannabis and Cannabinoids: An Option for the Treatment of Inflammatory Bowel Disease and Cancer of the Colon?: Medical Cannabis and Cannabinoids, 1(1), 28-35.
Hanuš, L., Breuer, A., et al. (1999). HU-308: a specific agonist for CB2, a peripheral cannabinoid receptor: Proceedings of the National Academy of Sciences, 96(25), 14228-14233.
Harvey, B. S., Sia, T. C., et al. (2014). Interleukin 17A evoked mucosal damage is attenuated by cannabidiol and anandamide in a human colonic explant model: Cytokine, 65(2), 236-244.
He, C., Ryan, A. J., et al. (2013). Accelerated development of pulmonary fibrosis via Cu, Zn-superoxide dismutase-induced alternative activation of macrophages: Journal of Biological Chemistry, 288(28), 20745-20757.
Heppelmann, B., Pawlak, M. (1997). Sensitisation of articular afferents in normal and inflamed knee joints by substance P in the rat: Neuroscience letters, 223(2), 97-100.
Hermann, H., De Petrocellis, L., et al. (2003). Dual effect of cannabinoid CB 1 receptor stimulation on a vanilloid VR1 receptor-mediated response: Cellular and Molecular Life Sciences CMLS, 60(3), 607-616.
Hermanson, D. J., Gamble-George, J. C., et al. (2014). Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation: Trends in pharmacological sciences, 35(7), 358-367.
Huestis, M. A. (2007). Human cannabinoid pharmacokinetics: Chemistry & biodiversity, 4(8), 1770.
Ibrahim, M. M., Deng, H., et al. (2003). Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS: Proceedings of the National Academy of Sciences, 100(18), 10529-10533.
Jamontt, J. M., Molleman, A., et al. (2010). The effects of Δ9‐tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis: British journal of pharmacology, 160(3), 712-723.
Jin, K., Xie, L., et al. (2004). Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice: Molecular Pharmacology, 66(2), 204-208.
Kaplan, D. H., Igyártó, B. Z., et al. (2012). Early immune events in the induction of allergic contact dermatitis: Nature Reviews Immunology, 12(2), 114-124.
Karwad, M. A., Couch, D. G., et al. (2017). The role of CB1 in intestinal permeability and inflammation: The FASEB Journal, 31(8), 3267-3277.
Katona, I., Freund, T. F. (2012). Multiple functions of endocannabinoid signaling in the brain: Annual review of neuroscience, 35, 529-558.
Kettenmann, H., Kirchhoff, F., et al. (2013). Microglia: new roles for the synaptic stripper: Neuron, 77(1), 10-18.
Kim, H. J., Kim, B., et al. (2015). Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone‐induced atopic dermatitis model: International journal of dermatology, 54(10), e401-e408.
Kimball, E. S., Schneider, C. R., et al. (2006). Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium: American Journal of Physiology-Gastrointestinal and Liver Physiology, 291(2), G364-G371.
Klein, T. W. (2005). Cannabinoid-based drugs as anti-inflammatory therapeutics: Nature Reviews Immunology, 5(5), 400-411.
Klein, T. W., Cabral, G. A. (2006). Cannabinoid-induced immune suppression and modulation of antigen-presenting cells: Journal of Neuroimmune Pharmacology, 1(1), 50.
Klein, T. W., Newton, C. A., et al. (1985). The effect of delta-9-tetrahydrocannabinol and 11-hydroxy-delta-9-tetrahydrocannabinol on T-lymphocyte and B-lymphocyte mitogen responses: Journal of immunopharmacology, 7(4), 451-466.
Kozela, E., Juknat, A., et al. (2015). Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells: Journal of neuroinflammation, 12(1), 52.
Lan, X., Han, X., et al. (2017). Modulators of microglial activation and polarization after intracerebral haemorrhage: Nature Reviews Neurology, 13(7), 420.
Lauckner, J. E., Jensen, J. B., et al. (2008). GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current: Proceedings of the National Academy of Sciences, 105(7), 2699-2704.
Ledent, C., Valverde, O., et al. (1999). Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice: Science, 283(5400), 401-404.
Leinwand, K. L., Jones, A. A., et al. (2017). Cannabinoid receptor-2 ameliorates inflammation in murine model of Crohn’s disease: Journal of Crohn’s and Colitis, 11(11), 1369-1380.
Li, S. S., Wang, L. L., et al. (2016). Cannabinoid CB2 receptors are involved in the regulation of fibrogenesis during skin wound repair in mice:  Molecular medicine reports, 13(4), 3441-3450.
Ligresti, A., Petrosino, S., et al. (2009). From endocannabinoid profiling to ‘endocannabinoid therapeutics’: Current opinion in chemical biology, 13(3), 321-331.
Lin, S., Li, Y., et al. (2017). The anti-inflammatory effect and intestinal barrier protection of HU210 differentially depend on TLR4 signaling in dextran sulfate sodium-induced murine colitis: Digestive diseases and sciences, 62(2), 372-386.
Luo, X. Q., Li, A., et al. (2018). Paeoniflorin exerts neuroprotective effects by modulating the M1/M2 subset polarization of microglia/macrophages in the hippocampal CA1 region of vascular dementia rats via cannabinoid receptor 2: Chinese medicine, 13(1), 1-17.
Maione, S., Bisogno, T., et al. (2006). 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: Journal of Pharmacology and Experimental Therapeutics, 316(3), 969-982.
Man, A., Dgetluck, N., et al. (2017). Prospective Validation of the Systemic Sclerosis Skin Symptoms Patient-Reported Outcome (SSPRO) in a Phase 2 Trial of Anabasum (JBT-101) in Diffuse Cutaneous Systemic Sclerosis (dcSSc): Arthritis & Rheumatology, 69.
Martin, W. J., Patrick, S. L., et al. (1995). An examination of the central sites of action of cannabinoid-induced antinociception in the rat: Life sciences, 56(23-24), 2103-2109.
Martyanov, V., Nesbeth, Y., et al. (2017, October). Effect of Anabasum (JBT-101) on Gene Expression in Skin Biopsies from Subjects with Diffuse Cutaneous Systemic Sclerosis (dcSSc) and the Relationship of Baseline Molecular Subsets to Clinical Benefit in the Phase 2 Trial: Arthritis & Rheumatology, 69.
Massa, F., Marsicano, G., et al. (2004). The endogenous cannabinoid system protects against colonic inflammation: The Journal of clinical investigation, 113(8), 1202-1209.
McCoy, K. L. (2016). Interaction between cannabinoid system and toll-like receptors controls inflammation: Mediators of inflammation, 2016.
McKallip, R. J., Lombard, C., et al. (2002). Δ9-Tetrahydrocannabinol-induced apoptosis in the thymus and spleen as a mechanism of immunosuppression in vitro and in vivo: Journal of Pharmacology and Experimental Therapeutics, 302(2), 451-465.
McPartland, J. M., Guy, G. W., et al. (2014). Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system: PloS one, 9(3), e89566.
Mechoulam, R., Ben-Shabat, S., et al. (1995). Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors: Biochemical pharmacology, 50(1), 83-90.
Min, R., Di Marzo, V., et al. (2010). DAG lipase involvement in depolarization-induced suppression of inhibition: does endocannabinoid biosynthesis always meet the demand?: The Neuroscientist, 16(6), 608-613.
Mlost, J., Kostrzewa, M., et al. (2018). Molecular understanding of the activation of CB1 and blockade of TRPV1 receptors: implications for novel treatment strategies in osteoarthritis: International journal of molecular sciences, 19(2), 342.
Monteleone, A. M., Di Marzo, V., et al. (2015). Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa: The American journal of clinical nutrition, 101(2), 262-269.
Munro, S., Thomas, K. L., et al. (1993). Molecular characterization of a peripheral receptor for cannabinoids: Nature, 365(6441), 61-65.
Nagarkatti, P., Pandey, R., et al. (2009). Cannabinoids as novel anti-inflammatory drugs: Future medicinal chemistry, 1(7), 1333-1349.
Naguib, M., Xu, J. J., et al. (2012). Prevention of paclitaxel-induced neuropathy through activation of the central cannabinoid type 2 receptor system: Anesthesia and analgesia, 114(5), 1104.
Novak-Bilić, G., Vučić, M., et al. (2018). Irritant and allergic contact dermatitis–skin lesion characteristics: Acta Clinica Croatica, 57(4.), 713-719.
Oláh, A., Markovics, A., et al. (2016). Differential effectiveness of selected non‐psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment: Experimental dermatology, 25(9), 701-707.
Oláh, A., Tóth, B. I., et al. (2014). Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes: The Journal of clinical investigation, 124(9), 3713-3724.
Pagano, E., Capasso, R., et al. (2016). An orally active cannabis extract with high content in cannabidiol attenuates chemically-induced intestinal inflammation and hypermotility in the mouse: Frontiers in pharmacology, 7, 341.
Paolicelli, R. C., Bolasco, G., et al. (2011). Synaptic pruning by microglia is necessary for normal brain development: Science, 333(6048), 1456-1458.
Petrosino, S., Verde, R., et al. (2018). Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis: Journal of Pharmacology and Experimental Therapeutics, 365(3), 652-663.
Ramírez, B. G., Blázquez, C., et al. (2005). Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation: Journal of Neuroscience, 25(8), 1904-1913.
Ramírez, B. G., Blázquez, C., et al. (2005). Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation: Journal of Neuroscience, 25(8), 1904-1913.
Ramot, Y., Sugawara, K., et al. (2013). A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ: PeerJ, 1, e40.
Raychaudhuri, S. P., Raychaudhuri, S. K., et al. (2011). Nerve growth factor: a key local regulator in the pathogenesis of inflammatory arthritis: Arthritis & Rheumatism, 63(11), 3243-3252.
Romano, B., Borrelli, F., et al. (2013). The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and ameliorates murine colitis: British journal of pharmacology, 169(1), 213-229.
Romero-Sandoval, E. A., Horvath, R. J., et al. (2008). Neuroimmune interactions and pain: focus on glial-modulating targets: Current opinion in investigational drugs (London, England: 2000), 9(7), 726.
Rosa, A. C., Fantozzi, R. (2013). The role of histamine in neurogenic inflammation: British journal of pharmacology, 170(1), 38-45.
Rossi, S., Bozzali, M., et al. (2013). Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis: PLoS One, 8(12), e82848.
Ryberg, E., Larsson, N., et al. (2007). The orphan receptor GPR55 is a novel cannabinoid receptor: British journal of pharmacology, 152(7), 1092-1101.
Sacerdote, P., Massi, P., et al. (2000). In vivo and in vitro treatment with the synthetic cannabinoid CP55, 940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors: Journal of neuroimmunology, 109(2), 155-163.
Sancho, R., Calzado, M. A., et al. (2003). Anandamide inhibits nuclear factor-κB activation through a cannabinoid receptor-independent pathway: Molecular pharmacology, 63(2), 429-438.
Sanclemente, G., Burgos, C., et al. (2017). The impact of skin diseases on quality of life: A multicenter study: Actas Dermo-Sifiliográficas (English Edition), 108(3), 244-252.
Sarnelli, G., D’Alessandro, A., et al. (2016). Palmitoylethanolamide modulates inflammation-associated vascular endothelial growth factor (VEGF) signaling via the Akt/mTOR pathway in a selective peroxisome proliferator-activated receptor alpha (PPAR-α)-dependent manner: PLoS One, 11(5), e0156198.
Schafer, D. P., Stevens, B. (2013). Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system: Current opinion in neurobiology, 23(6), 1034-1040.
Scheau, C., Badarau, I. A., et al. (2019). The Role of Matrix Metalloproteinases in the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma: Analytical Cellular Pathology, 2019.
Scheau, C., Badarau, I. A., et al. (2020). Cannabinoids in the Pathophysiology of Skin Inflammation: Molecules, 25(3), 652.
Schmöle, A. C., Lundt, R., et al. (2015). Expression analysis of CB2-GFP BAC transgenic mice: PLoS One, 10(9), e0138986.
Schwartz, M., Butovsky, O., et al. (2006). Microglial phenotype: is the commitment reversible?:Trends in neurosciences, 29(2), 68-74.
Schwartz, M., Shaked, I., et al. (2003). Protective autoimmunity against the enemy within: fighting glutamate toxicity: Trends in neurosciences, 26(6), 297-302.
Shamran, H., Singh, N. P., et al. (2017). Fatty acid amide hydrolase (FAAH) blockade ameliorates experimental colitis by altering microRNA expression and suppressing inflammation: Brain, behavior, and immunity, 59, 10-20.
Sharkey, K. A., Wiley, J. W. (2016). The role of the endocannabinoid system in the brain–gut axis: Gastroenterology, 151(2), 252-266.
Sheriff, T., Lin, M. J., et al. (2019). The potential role of cannabinoids in dermatology: Journal of Dermatological Treatment, 1-7.
Sibaev, A., Yüce, B., et al. (2009). Cannabinoid-1 (CB1) receptors regulate colonic propulsion by acting at motor neurons within the ascending motor pathways in mouse colon: American Journal of Physiology-Gastrointestinal and Liver Physiology.
Simon, G. M., Cravatt, B. F. (2006). Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for α/β-hydrolase 4 in this pathway: Journal of Biological Chemistry, 281(36), 26465-26472.
Simon, G. M., Cravatt, B. F. (2008). Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain: Journal of Biological Chemistry, 283(14), 9341-9349.
Soethoudt, M., Grether, U., et al. (2017). Cannabinoid CB 2 receptor ligand profiling reveals biased signalling and off-target activity: Nature communications, 8(1), 1-14.
Spiera, R. F., Hummers, L. K., et al. (2017). A phase 2 study of safety and efficacy of anabasum (JBT-101), a cannabinoid receptor type 2 agonist, in diffuse cutaneous systemic sclerosis: Arthritis & Rheumatology, 69.
Starowicz, K., Makuch, W., et al. (2013). Full inhibition of spinal FAAH leads to TRPV1-mediated analgesic effects in neuropathic rats and possible lipoxygenase-mediated remodeling of anandamide metabolism: PLoS One, 8(4), e60040.
Storr, M. A., Keenan, C. M., et al. (2008). Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB 1 and CB 2 receptors: Journal of molecular medicine, 86(8), 925-936.
Storr, M. A., Keenan, C. M., et al. (2009). Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis: Inflammatory bowel diseases, 15(11), 1678-1685.
Sugiura, T., Kondo, S., et al. (2000). Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells: Journal of Biological Chemistry, 275(1), 605-612.
Tang, M., Cao, X., et al. (2018). Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression: Cell death & disease, 9(6), 1-12.
Trautmann, S. M., Sharkey, K. A. (2015). The endocannabinoid system and its role in regulating the intrinsic neural circuitry of the gastrointestinal tract: International review of neurobiology (Vol. 125, pp. 85-126). Academic Press.
Tremblay, M. È., Majewska, A. K. (2011). A role for microglia in synaptic plasticity?: Communicative & integrative biology, 4(2), 220-222.
Turcotte, C., Blanchet, M. R., et al. (2016). The CB 2 receptor and its role as a regulator of inflammation: Cellular and Molecular Life Sciences, 73(23), 4449-4470.
Villacampa, N., Heneka, M. T. (2018). Microglia: You’ll Never Walk Alone!: Immunity, 48(2), 195-197.
Volc-Platzer, B. (2015). Dermatomyositis–update: Der Hautarzt, 66(8), 604-610.
Wake, H., Moorhouse, A. J., et al. (2013). Microglia: actively surveying and shaping neuronal circuit structure and function: Trends in neurosciences, 36(4), 209-217.
Wang, J., Ueda, N. (2009). Biology of endocannabinoid synthesis system: Prostaglandins & other lipid mediators, 89(3-4), 112-119.
Wang, L. L., Zhao, R., et al. (2016). Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing: European journal of pharmacology, 786, 128-136.
Wen, J., Ribeiro, R., et al. (2015). Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis: Neuropharmacology, 99, 196-209.
Wilkinson, J. D., Williamson, E. M. (2007). Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis: Journal of dermatological science, 45(2), 87-92.
Wright, K. L., Duncan, M., et al. (2008). Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation: British journal of pharmacology, 153(2), 263-270.
Yuan, M., Kiertscher, S. M., et al. (2002). Δ9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells: Journal of neuroimmunology, 133(1-2), 124-131.
Zeng, J., Li, X., et al. (2019). Activation of cannabinoid receptor type 2 reduces lung ischemia reperfusion injury through PI3K/Akt pathway: International Journal of Clinical and Experimental Pathology, 12(11), 4096.
Zhao, X., Liang, P., et al. (2017). Elevation of arachidonoylethanolamide levels by activation of the endocannabinoid system protects against colitis and ameliorates remote organ lesions in mice: Experimental and Therapeutic Medicine, 14(6), 5664-5670.
Zhao, Y., Yuan, Z., et al. (2010). Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules: Journal of cardiovascular pharmacology, 55(3), 292-298.
Zipp, F., Aktas, O. (2006). The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases: Trends in neurosciences, 29(9), 518-527.