Emerging role of the cannabinoid receptor CB 2 in immune regulation: therapeutic prospects for neuroinflammation
Open accessAbstract
There is now a large body of data indicating that the cannabinoid receptor type 2 (CB 2 ) is linked to a variety of immune events. This functional relevance appears to be most salient in the course of inflammation, a process during which there is an increased number of receptors that are available for activation. Studies aimed at elucidating signal transduction events resulting from CB 2 interaction with its native ligands, and of the role of exogenous cannabinoids in modulating this process, are providing novel insights into the role of CB 2 in maintaining a homeostatic immune balance within the host. Furthermore, these studies suggest that the CB 2 may serve as a selective molecular target for therapeutic manipulation of untoward immune responses, including those associated with a variety of neuropathies that exhibit a hyperinflammatory component.
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Endocannabinoids mediate inflammation by regulating cytokines at different steps throughout the inflammatory response.
“Endocannabinoids mediate inflammation by regulating cytokines at different steps throughout the inflammatory response (Cabral and Griffin-Thomas, 2009).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Cabral and Griffin-Thomas, 2009
THC and AEA suppress proinflammatory cytokines and enhance anti-inflammatory cytokines in both innate and adaptive immune responses.
“For example, THC and AEA suppress proinflammatory cytokines and enhance anti-inflammatory cytokines in both innate and adaptive immune responses (Cabral and Griffin-Thomas, 2009).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Cabral and Griffin-Thomas, 2009
Cannabinoids inhibit the cell-specific proliferation of B and T cells.
“Cannabinoids also inhibit the cell-specific proliferation of B and T cells (Cabral and Griffin-Thomas, 2009;Klein and Cabral, 2006).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Cabral and Griffin-Thomas, 2009
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Amide Bond Bioisosteres: Strategies, Synthesis, and Successes
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“Indeed, CB2 activation affects a myriad of immune responses from inflammation to neuroprotection (Cabral and Griffin-Thomas, 2009).”
BackgroundThe serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors
Marrs, W., Blankman, J. L., Horne, E. A., Thomazeau, A., Lin, Y. H., Coy, J. W., Bodor, Á. L., Muccioli, G. G., Hu, S. S., Woodruff, G., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2601 · Cited by 442 · see citing works
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“…cerebromicrovascular endothelial cells (Golech et al., 2004; Nunez et al., 2004; Rivers & Ashton, 2010) and such expression could play a role in pathogenesis and treatment of conditions involving neuroinflammation and neurodegeneration (Arevalo-Martin et al., 2008; Cabral & Griffin-Thomas, 2009).”
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Kim, T., Song, B., Cho, K. S., & Lee, I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062187 · Cited by 282 · see citing works
Louvet, A., Teixeira-Clerc, F., Chobert, M.-N., Deveaux, V., Pavoine, C., Zimmer, A., Pecker, F., Mallat, A., & Lotersztajn, S. (2011) · Hepatology · doi:10.1002/hep.24524 · Cited by 260 · see citing works
“In addition, in vitro studies have shown that CB2-receptor activation impairs several macrophage functions, such as oxidized low-density lipoprotein (oxLDL)-induced inflammatory response, oxidative stress, migration, and antigen processing.(22) In the liver, recent data indicate that CB2 receptors are induced after ac…”
BackgroundO’Sullivan, S. E., & Kendall, D. A. (2009) · Immunobiology · doi:10.1016/j.imbio.2009.09.007 · Cited by 247 · see citing works
“It is widely assumed that the majority of such effects are mediated by the CB2 receptor, which is expressed by a wide range of immune cells (Cabral and Griffin-Thomas 2009).”
BackgroundCannabinoids for treatment of Alzheimer’s disease: moving toward the clinic
Aso, E., & Ferrer, I. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00037 · Cited by 239 · see citing works
“…increased the viability of neurons after exposure to different toxic Aβ species (Milton, 2002; Chen et al., 2011; Harvey et al., www.frontiersin.org March 2014 | Volume 5 | Article 37 | 3 2012; Janefjord et al., 2013), and reduced Aβ-induced memory impairment in rats (van der Stelt et al., 2006).”
BackgroundRamirez, S. H., Haskó, J., Skuba, A., Fan, S., Dykstra, H., McCormick, R. C., Reichenbach, N. L., Krizbai, I. A., Mahadevan, A., Zhang, M., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.4628-11.2012 · Cited by 238 · see citing works
“Previous studies indicated that CB2R expression was restricted to peripheral tissues, particularly in immune cells (Cabral and Griffin-Thomas, 2009).”
BackgroundBioactive lipid mediators in skin inflammation and immunity
Kendall, A. C., & Nicolaou, A. (2013) · Progress in Lipid Research · doi:10.1016/j.plipres.2012.10.003 · Cited by 229 · see citing works
Endocannabinoids drive the acquisition of an alternative phenotype in microglia
Mecha, M., Feliú, A., Carrillo-Salinas, F. J., Rueda-Zubiaurre, A., Ortega-Gutiérrez, S., de Sola, R. G., & Guaza, C. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.06.002 · Cited by 234 · see citing works
Vallée, A., Lecarpentier, Y., Guillevin, R., & Vallée, J.-N. (2017) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmx073 · Cited by 226 · see citing works
“Interactions of CBD with Wnt/β-catenin pathway and PPARγ in AD CBD effects in AD References CBD attenuates Aβ-induced neurotoxicity [24,203] CBD reduces Aβ formation and production [27,198] CBD attenuates tau protein-induced phosphorylation [23,203] CBD induces ubiquitination of APP protein [27,201] CBD attenuates neu…”
Background2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain
Baggelaar, M. P., Maccarrone, M., & van der Stelt, M. (2018) · Progress in Lipid Research · doi:10.1016/j.plipres.2018.05.002 · Cited by 224 · see citing works
The Role of the Endocannabinoid System in Pain
Woodhams, S. G., Sagar, D. R., Burston, J. J., & Chapman, V. (2015) · Handbook of experimental pharmacology · doi:10.1007/978-3-662-46450-2_7 · Cited by 205 · see citing works
Cassano, T., Calcagnini, S., Pace, L., Marco, F. D., Romano, A., & Gaetani, S. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00030 · Cited by 193 · see citing works
“In particular, CB2 receptor expression is found in neurons within the brainstem, microglia and astrocytes only after specific insults (e.g., neuroinflammation), whereas it cannot be detected in resting microglia (Van Sickle et al., 2005; Núñez et al., 2008; Cabral and Griffin-Thomas, 2009).”
Brain Cannabinoid CB2 Receptor in Schizophrenia
Ishiguro, H., Horiuchi, Y., Ishikawa, M., Koga, M., Imai, K., Suzuki, Y., Morikawa, M., Inada, T., Watanabe, Y., Takahashi, M., et al. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.09.024 · Cited by 184 · see citing works
CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity
Onaivi, E. S., Ishiguro, H., Gu, S., & Liu, Q. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881111400652 · Cited by 184 · see citing works
Miller, L. K., & Devi, L. A. (2011) · Pharmacological Reviews · doi:10.1124/pr.110.003491 · Cited by 178 · see citing works
“Cannabinoid receptor signaling is discussed in detail in several recent reviews (Cabral and Griffin-Thomas, 2009; Turu and Hunyady, 2010).”
BackgroundActivation of Cannabinoid CB2 Receptor–Mediated AMPK/CREB Pathway Reduces Cerebral Ischemic Injury
Choi, I.-Y., Ju, C., Jalin, A. M. A. A., Lee, D. I., Prather, P. L., & Kim, W.-K. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.11.024 · Cited by 157 · see citing works
Atwood, B. K., Wager‐Miller, J., Haskins, C. P., Straiker, A. J., & Mackie, K. (2011) · Molecular Pharmacology · doi:10.1124/mol.111.074013 · Cited by 152 · see citing works
“CB2 activation is immunomodulatory and neuroprotective (Berdyshev, 2000; Howlett et al., 2002; Cabral and Griffin-Thomas, 2009).”
BackgroundA systematic review on the neuroprotective perspectives of beta‐caryophyllene
Machado, K. D. C., Islam, M. T., Ali, E. S., Rouf, R., Uddin, S. J., Dev, S., Shilpi, J. A., Shill, M. C., Reza, H. M., Das, A. K., et al. (2018) · Phytotherapy Research · doi:10.1002/ptr.6199 · Cited by 152 · see citing works
Haspula, D., & Clark, M. A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207693 · Cited by 137 · see citing works
“For a comprehensive overview on the mechanisms of CB2R-mediated regulation of peripheral and central inflammatory states, please refer to the review by Cabral and Griffin-Thomas [334].”
MethodEndocannabinoid System Components as Potential Biomarkers in Psychiatry
Navarrete, F., García‐Gutiérrez, M. S., Barba, R. J., Rubio, G., Gasparyan, A., Austrich-Olivares, A., & Manzanares, J. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.00315 · Cited by 134 · see citing works
CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease
Aso, E., & Ferrer, I. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00243 · Cited by 131 · see citing works
“CB2 receptors, mainly expressed in microglia, inhibit microglia-mediated neurotoxicity by reducing the production of pro-inflammatory molecules and by modulating macrophage migration in several pathological conditions (Cabral and Griffin-Thomas, 2009).”
BackgroundDifferential changes in GPR55 during microglial cell activation
Pietr, M., Kozela, E., Levy, R., Rimmerman, N., Lin, Y. H., Stella, N., Vogel, Z., & Juknat, A. (2009) · FEBS Letters · doi:10.1016/j.febslet.2009.05.028 · Cited by 130 · see citing works
“These effects are mostly due to cannabinoid binding to the CB2-R, which is abundantly expressed by macrophages, dendritic cells and B cells [15].”
BackgroundShadfar, S., Hwang, C. J., Lim, M., Choi, D., & Hong, J. T. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0648-x · Cited by 128 · see citing works
Navarro, G., Borroto‐Escuela, D. O., Angelats, E., Etayo, I., Reyes‐Resina, I., Pulido-Salgado, M., Rodriguez-Perez, A. I., Canela, E. I., Saura, J., Lanciego, J. L., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.08.015 · Cited by 127 · see citing works
Luchicchi, A., & Pistis, M. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8299-0 · Cited by 126 · see citing works
Juknat, A., Pietr, M., Kozela, E., Rimmerman, N., Levy, R., Gao, F., Coppola, G., Geschwind, D. H., & Vogel, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061462 · Cited by 117 · see citing works
“been reported to have effects on both the nervous and the immune systems [7,11,18,22].”
BackgroundRegulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation
Zoppi, S., Perez‐Nievas, B. G., Madrigal, J. L. M., Manzanares, J., Leza, J. C., & García‐Bueno, B. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.214 · Cited by 116 · see citing works
“Currently, the endocannabinoid system (ECS) is considered as an endogenous homeostatic system activated by different immune challenges, restoring brain balance at different levels (Mechoulam and Shohami, 2007) in different experimental settings (Galve-Roperh et al, 2008; Wolf et al, 2008; Bambico et al, 2009; Cabral a…”
BackgroundInfluentialWhat we know and do not know about the cannabinoid receptor 2 (CB2)
Malfitano, A. M., Basu, S., Maresz, K., Bifulco, M., & Dittel, B. N. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.04.002 · Cited by 112 · see citing works
Huestis, M. A., Mazzoni, I. E., & Rabin, O. (2011) · Sports Medicine · doi:10.2165/11591430-000000000-00000 · Cited by 110 · see citing works
Panlilio, L. V., Justinová, Z., & Goldberg, S. R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.003 · Cited by 106 · see citing works
Persidsky, Y., Ho, W., Ramirez, S. H., Potula, R., Abood, M. E., Unterwald, E. M., & Tuma, R. F. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.03.001 · Cited by 106 · see citing works
“These data indicate that during inflammation more molecular targets are present that may dampen exaggerated immune responses (Cabral and Griffin-Thomas, 2009).”
Amenta, P. S., Jallo, J., Tuma, R. F., & Elliott, M. B. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23114 · Cited by 106 · see citing works
“preservation, all of which have been reviewed (Cabral and Griffin-Thomas, 2009; Palazuelos et al., 2009).”
BackgroundInfluentialParedes, J. M. V., González-Castañeda, R. E., Gertsch, J., Chaparro-Huerta, V., López-Roa, R. I., Vázquez-Valls, E., Beas‐Zárate, C., Camins, A., & Flores-Soto, M. E. (2017) · Pharmaceuticals · doi:10.3390/ph10030060 · Cited by 109 · see citing works
“CB2Rs were initially thought to be expressed primarily in activated microglia and peripheral immune cells where they regulate cytokine/chemokine production and cell migration [12].”
Westphal, M. V., Schafroth, M. A., Sarott, R. C., Imhof, M. A., Bold, C. P., Leippe, P., Dhopeshwarkar, A., Grandner, J. M., Katritch, V., Mackie, K., et al. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.7b06456 · Cited by 103 · see citing works
Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice
Verty, A. N. A., Stefanidis, A., McAinch, A. J., Hryciw, D. H., & Oldfield, B. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0140592 · Cited by 103 · see citing works
Bedse, G., Romano, A., Lavecchia, A. M., Cassano, T., & Gaetani, S. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141635 · Cited by 104 · see citing works
“in resting microglia [60].”
Cannabidiol as a potential treatment for psychosis
Schubart, C. D., Sommer, I. E., Fusar‐Poli, P., de Witte, L. D., Kahn, R. S., & Boks, M. P. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.11.002 · Cited by 100 · see citing works
Regulatory role of the cannabinoid CB2receptor in stress‐induced neuroinflammation in mice
Zoppi, S., Madrigal, J. L. M., Caso, J. R., García‐Gutiérrez, M. S., Manzanares, J., Leza, J. C., & García‐Bueno, B. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12607 · Cited by 99 · see citing works
“The ECS is considered to be an endogenous homeostatic system activated by different immune challenges, restoring brain balance in different experimental settings (Mechoulam and Shohami, 2007; Bambico et al., 2009; Cabral and Griffin-Thomas, 2009).”
BackgroundThe cannabinoid system and microglia in health and disease
Duffy, S. S., Hayes, J. P., Fiore, N. T., & Moalem‐Taylor, G. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108555 · Cited by 96 · see citing works
Mending the broken brain: neuroimmune interactions in neurogenesis
Molina‐Holgado, E., & Molina‐Holgado, F. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06849.x · Cited by 96 · see citing works
Kinsey, S. G., Mahadevan, A., Zhao, B., Sun, H., Naidu, P. S., Razdan, R. K., Selley, D. E., Damaj, M. I., & Lichtman, A. H. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.09.004 · Cited by 94 · see citing works
Feng, Z., Alqarni, M. H., Yang, P., Tong, Q., Chowdhury, A., Wang, L., & Xie, X. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci5002718 · Cited by 94 · see citing works
Central and peripheral control of food intake
Abdalla, M. M. I. (2017) · Endocrine Regulations · doi:10.1515/enr-2017-0006 · Cited by 92 · see citing works
Activation of murine microglial N9 cells is attenuated through cannabinoid receptor CB2 signaling
Ma, L., Jia, J., Liu, X., Bai, F., Wang, Q., & Xiong, L. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.073 · Cited by 90 · see citing works
Juknat, A., Pietr, M., Kozela, E., Rimmerman, N., Levy, R., Coppola, G., Geschwind, D. H., & Vogel, Z. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01461.x · Cited by 90 · see citing works
“…component of marijuana, D9-tetrahydrocannabinol (THC) is equally effective at either of these receptors (Rhee et al., 1997) and has effects on both the immune and the nervous systems (Cabral and Staab, 2005; Le Foll and Goldberg, 2005; Cabral and Griffin-Thomas, 2008; 2009; Woelkart et al., 2008).”
BackgroundGómez, O., Arévalo‐Martín, Á., García‐Ovejero, D., Ortega‐Gutiérrez, S., Cisneros, J. A., Almazán, G., Sanchez-Rodriguez, M. A., Molina‐Holgado, F., & Molina‐Holgado, E. (2010) · Glia · doi:10.1002/glia.21061 · Cited by 90 · see citing works
Association of Pertussis Toxin with Severe Pertussis Disease
Scanlon, K. M., Skerry, C. M., & Carbonetti, N. H. (2019) · Toxins · doi:10.3390/toxins11070373 · Cited by 88 · see citing works
“Several PT-sensitive GPCRs have been identified as having immune-resolving capabilities, such as sphingosine-1-phosphate receptor 1 (S1P1) [90], resolvin and lipoxin receptors [91], and cannabinoid receptor 2 [92].”
BackgroundLatest advances in cannabinoid receptor agonists
Thakur, G. A., Tichkule, R. B., Bajaj, S., & Makriyannis, A. (2009) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543770903436505 · Cited by 87 · see citing works
“However, CB2 is upregulated ‘on demand’ during early inflammatory events in both CNS and peripheral tissues [11,13].”
BackgroundFunctional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway
Dhopeshwarkar, A., & Mackie, K. (2016) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.232561 · Cited by 88 · see citing works
“For example, Gai-GTP subunits inhibit adenylyl cyclase, decreasing cAMP production and thus suppressing cAMPdependent protein kinase A activity (Bayewitch et al., 1995; Gonsiorek et al., 2000; Sugiura et al., 2000; Shoemaker et al., 2005; Cabral and Griffin-Thomas, 2009).”
BackgroundGuo, K., Mou, X., Huang, J., Xiong, N., & Li, H. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0243-5 · Cited by 85 · see citing works
“CB2Rs have been reported to be expressed primarily in activated microglia and peripheral immune cells, thereby regulating antigen presentation, cytokine/chemokine production, and cell migration (Cabral and Griffin-Thomas 2009).”
BackgroundAmenta, P. S., Jallo, J., Tuma, R. F., Hooper, D. C., & Elliott, M. B. (2014) · Journal of Neuroinflammation · doi:10.1186/s12974-014-0191-6 · Cited by 82 · see citing works
“Insults to the CNS and pro-inflammatory conditions have been found to result in significant upregulation of CB2R mRNA expression [13].”
BackgroundRizzo, M. D., Crawford, R. B., Henriquez, J. E., Aldhamen, Y. A., Gulick, P. G., Amalfitano, A., & Kaminski, N. E. (2017) · AIDS · doi:10.1097/qad.0000000000001704 · Cited by 82 · see citing works
Gu, Z., Singh, S., Niyogi, R. G., Lamont, G. J., Wang, H., Lamont, R. J., & Scott, D. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02288 · Cited by 81 · see citing works
Soethoudt, M., Stolze, S. C., Westphal, M. V., van Stralen, L., Martella, A., van Rooden, E. J., Guba, W., Varga, Z. V., Deng, H., van Kasteren, S. I., et al. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.7b11281 · Cited by 80 · see citing works
Husni, A. S., McCurdy, C. R., Radwan, M. M., Ahmed, S. A., Slade, D., Ross, S. A., ElSohly, M. A., & Cutler, S. J. (2014) · Medicinal Chemistry Research · doi:10.1007/s00044-014-0972-6 · Cited by 79 · see citing works
“The CB2 receptors play a major role in inflammatory diseases due to their interaction with these receptors in the immune system (Cabral and Griffin-Thomas, 2009).”
Batalla, A., Janssen, H., Gangadin, S. S., & Bossong, M. G. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8071058 · Cited by 77 · see citing works
“, microglia), which suggests their involvement in processes such as cytokine release, immune suppression, and induction of both cell migration and apoptosis [18,19].”
BackgroundCampora, L., Miragliotta, V., Ricci, E., Cristino, L., Marzo, V. D., Albanese, F., della Valle, M. F., & Abramo, F. (2012) · American Journal of Veterinary Research · doi:10.2460/ajvr.73.7.988 · Cited by 81 · see citing works
“Can-nabinoid receptor type 2 is upregulated during early phases of inflammation in cells of CNS and peripheral tissues 14 11,15,16 humans 17,18 has been determined CB1 has been identified only in cells of salivary glands 19 and hair in dogs (via immunohistochemical localization).”
BackgroundElliott, M. B., Tuma, R. F., Amenta, P. S., Barbe, M. F., & Jallo, J. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2010.1672 · Cited by 77 · see citing works
“Growing evidence supports the theory that CB2R agonists modulate microglial activity such as chemotaxis and production of proinflammatory cytokines (Cabral et al., 2008; Cabral and Griffin-Thomas, 2009).”
Hernangómez, M., Carrillo-Salinas, F. J., Mecha, M., Correa, F., Mestre, L., Loría, F., Feliú, A., Docagne, F., & Guaza, C. (2014) · Current Pharmaceutical Design · doi:10.2174/1381612820666140130202911 · Cited by 77 · see citing works
Endocannabinoids: Effectors of glucocorticoid signaling
Balsevich, G., Petrie, G. N., & Hill, M. N. (2017) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2017.07.005 · Cited by 77 · see citing works
“, 1993) and remains best known for its immunosuppressive function (Cabral and Griffin-Thomas, 2009).”
BackgroundLi, L., Tao, Y., Tang, J., Chen, Q., Yang, Y., Feng, Z., Chen, Y., Yang, L. M., Yang, Y., Zhu, G., et al. (2015) · Translational Stroke Research · doi:10.1007/s12975-015-0425-7 · Cited by 72 · see citing works
A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System
Desai, S., Borg, B. A., Cuttler, C., Crombie, K. M., Rabinak, C. A., Hill, M. N., & Marusak, H. A. (2021) · Cannabis and Cannabinoid Research · doi:10.1089/can.2021.0113 · Cited by 73 · see citing works
The endocannabinoid system modulates stress, emotionality, and inflammation
Crowe, M. S., Nass, S. R., Gabella, K. M., & Kinsey, S. G. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.06.007 · Cited by 72 · see citing works
“…two cloned cannabinoid receptor subtypes, CB1, which is expressed in the brain as well as many peripheral tissues, and CB2, which is expressed predominantly on immune cells and damaged tissues, and also at low levels in the brainstem (Cabral and Griffin-Thomas, 2009; Mechoulam and Parker, 2013).”
BackgroundCorrea, F., Hernangómez, M., Mestre, L., Loría, F., Docagne, F., & Guaza, C. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.01.020 · Cited by 72 · see citing works
Zádor, F., Joca, S. R. L., Nagy-Grócz, G., Dvorácskó, S., Szűcs, E., Tömböly, C., Benyhe, S., & Vécsei, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115903 · Cited by 71 · see citing works
Modulation of the Cannabinoid System: A New Perspective for the Treatment of the Alzheimer’s Disease
Talarico, G., Trebbastoni, A., Bruno, G., & de Lena, C. (2018) · Current Neuropharmacology · doi:10.2174/1570159x16666180702144644 · Cited by 69 · see citing works
Cannabinoids in the Management of Acute Pain: A Systematic Review and Meta-analysis
Gazendam, A., Nucci, N. W., Gouveia, K., Khalik, H. A., Rubinger, L., & Johal, H. S. (2020) · Cannabis and Cannabinoid Research · doi:10.1089/can.2019.0079 · Cited by 68 · see citing works
Chemical and Physical Elicitation for Enhanced Cannabinoid Production in Cannabis
Gorelick, J., & Bernstein, N. (2017) · Springer eBooks · doi:10.1007/978-3-319-54564-6_21 · Cited by 68 · see citing works
Wu, J., Hocevar, M., Foss, J. F., Bie, B., & Naguib, M. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.05.044 · Cited by 67 · see citing works
β-Caryophyllene (BCP) ameliorates MPP+ induced cytotoxicity
Wang, G., Ma, W., & Du, J. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.03.168 · Cited by 66 · see citing works
Preventive Effects of Dairy Products on Dementia and the Underlying Mechanisms
Ano, Y., & Nakayama, H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071927 · Cited by 66 · see citing works
“CB2 is also expressed on microglia and contributes to the inhibition of microglia-mediated neurotoxicity by reducing the production of pro-inflammatory molecules [61].”
BackgroundCalina, D., Buga, A. M., Mitroi, M., Buha, A., Caruntu, C., Scheau, C., Bouyahya, A., El Omari, N., El Menyiy, N., & Docea, A. O. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9082395 · Cited by 65 · see citing works
“Studies showed that compared with CB1R, CB2R is mainly expressed in CNS after a specific insult such as anxiety, addiction and inflammation, while in resting microglia, no CB2R was detected [22].”
BackgroundCannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease
Nascimento, G. C., Ferrari, D. P., Guimarães, F. S., Bel, E. A. D., Bortolanza, M., & Ferreira‐Junior, N. C. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107808 · Cited by 67 · see citing works
Rizzo, M. D., Crawford, R. B., Bach, A. P., Sermet, S., Amalfitano, A., & Kaminski, N. E. (2019) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.119.260661 · Cited by 61 · see citing works
“response to TLR activation, including NFkB and cAMP response element binding protein (Gray et al., 1993; Cogswell et al., 1994; Cabral and Griffin-Thomas, 2009; Bosier et al., 2010; McCoy, 2016).”
BackgroundDifferential Activation of Intracellular versus Plasmalemmal CB2 Cannabinoid Receptors
Brailoiu, G. C., Deliu, E., Marcu, J. P., Hoffman, N. E., Console‐Bram, L., Zhao, P., Madesh, M., Abood, M. E., & Brailoiu, E. (2014) · Biochemistry · doi:10.1021/bi500632a · Cited by 61 · see citing works
Mastinu, A., Premoli, M., Ferrari‐Toninelli, G., Tambaro, S., Maccarinelli, G., Memo, M., & Bonini, S. A. (2018) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2018-0013 · Cited by 60 · see citing works
Rossi, F., Bellini, G., Tolone, C., Luongo, L., Mancusi, S., Papparella, A., Sturgeon, C., Fasano, A., Nobili, B., Perrone, L., et al. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.03.011 · Cited by 60 · see citing works
Cannabinoids, the Heart of the Matter
Alfulaij, N., Meiners, F., Michalek, J., Small-Howard, A. L., Turner, H. C., & Stokes, A. J. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.118.009099 · Cited by 59 · see citing works
“cannabidiol.(84) These compounds, as well as native mixtures from marijuana, are the subject of intense interest due to their therapeutic potential.”
BackgroundEndocannabinoids, exercise, pain, and a path to health with aging
Watkins, B. A. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.10.001 · Cited by 59 · see citing works
Agonist-induced CXCR4 and CB2 Heterodimerization Inhibits Gα13/RhoA-mediated Migration
Scarlett, K. A., White, E. Z., Coke, C. J., Carter, J. R., Bryant, L. K., & Hinton, C. V. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-16-0481 · Cited by 58 · see citing works
“Delta-9-tetrahydrocannabinol (D9-THC), the major psychoactive and immunomodulatory component of marijuana, is the most notable cannabinoid (18, 19), and clinically, is used for its antipalliative effects.”
BackgroundEndocannabinoid signaling in social functioning: an RDoC perspective
Karhson, D. S., Hardan, A. Y., & Parker, K. J. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.169 · Cited by 62 · see citing works
Cannabinoids for the treatment of dementia
Kuharić, D. B., Marković, D., Brković, T., Kegalj, M. J., Rubić, Ž., Vuica, A., Jerončić, A., & Puljak, L. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd012820.pub2 · Cited by 55 · see citing works
Ribeiro, R., Wen, J., Li, S., & Zhang, Y. (2012) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2012.11.003 · Cited by 54 · see citing works
Cannabinoid Receptor 2 Protects against Acute Experimental Sepsis in Mice
Gui, H., Sun, Y., Luo, Z., Su, D., Dai, S., & Liu, X. (2013) · Mediators of Inflammation · doi:10.1155/2013/741303 · Cited by 53 · see citing works
“Reasons for this phenomenon may result from the expression of CB2R in macrophages being more abundant than that in T cells [9, 10], and also provide a clue that the possibility of the existence of other subtype cannabinoid receptors in T cells.”
Hanlon, E. C. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104471 · Cited by 51 · see citing works
“There is also evidence that the eCB system is involved in the inflammatory response; eCBs can alter macrophage migration, and macrophages along with T and B cells have the capacity to release eCBs (Cabral and Griffin-Thomas, 2009; Di Marzo et al., 1999; Sido et al., 2016).”
BackgroundThe Centenary of Immune Thrombocytopenia – Part 1: Revising Nomenclature and Pathogenesis
Consolini, R., Legitimo, A., & Caparello, M. C. (2016) · Frontiers in Pediatrics · doi:10.3389/fped.2016.00102 · Cited by 50 · see citing works
Wang, L., Liu, B., Cao, Y., Xu, W., Sun, D., Li, M., Shi, F.-X., Li, M., Tian, Q., Wang, J., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0676-2 · Cited by 50 · see citing works
“CB2R is found primarily in the immune system [11, 12]; however, mounting evidence has shown that CB2R is also broadly expressed in glia and neurons in some brain areas, such as cerebral cortex, hippocampus [13, 14],cerebellum [15], ventral tegmental area [16], nucleus accumbens, and dorsal striatum [17].”
BackgroundMangiatordi, G. F., Intranuovo, F., Delre, P., Abatematteo, F. S., Abate, C., Niso, M., Creanza, T. M., Ancona, N., Stefanachi, A., & Contino, M. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01357 · Cited by 50 · see citing works
CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura
Rossi, F., Mancusi, S., Bellini, G., Roberti, D., Punzo, F., Vetrella, S., Matarese, S. M. R., Nobili, B., Maione, S., & Perrotta, S. (2011) · Haematologica · doi:10.3324/haematol.2011.045732 · Cited by 49 · see citing works
Cannabinoids in the descending pain modulatory circuit: Role in inflammation
Bouchet, C. A., & Ingram, S. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107495 · Cited by 51 · see citing works
Coelho, M., Duarte, P., Calado, M. S., Almeida, A. J., Reis, C. P., & Gaspar, M. M. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121838 · Cited by 46 · see citing works
Cannabinoid Receptor-2 Ameliorates Inflammation in Murine Model of Crohn’s Disease
Leinwand, K. L., Jones, A., Huang, R. H., Jedlicka, P., Kao, D. J., de Zoeten, E. F., Ghosh, S., Moaddel, R., Wehkamp, J., Ostaff, M. J., et al. (2017) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjx096 · Cited by 48 · see citing works
Emerging potential of cannabidiol in reversing proteinopathies
Dash, R., Ali, M. C., Jahan, I., Munni, Y. A., Mitra, S., Hannan, M. A., Timalsina, B., Oktaviani, D. F., Choi, H. J., & Moon, I. S. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101209 · Cited by 49 · see citing works
“…that CBD reduced the amount of IL-1β, IFN-β, TNF-α, IFN-γ, IL-6, IL-17, NO, and COX-2 through the activation of PPAR-γ (Al-Ghezi et al., 2019a; Cabral and Griffin-Thomas, 2009; Giacoppo et al., 2015a; O’Sullivan et al., 2009; Peres et al., 2018; Rajan et al., 2016); while increasing the…”
BackgroundCannabis dosing and administration for sleep: a systematic review
Velzeboer, R., Malas, A., Boerkoel, P., Cullen, K., Hawkins, M., Roesler, J., & Lai, W. W.-K. (2022) · SLEEP · doi:10.1093/sleep/zsac218 · Cited by 49 · see citing works
- Authors
- Cabral, G. A., & Griffin-Thomas, L.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Cabral, Guy A.
- Venue
- Expert Reviews in Molecular Medicine
- Publisher
- Cambridge University Press (CUP)
- Published
- 2009-01
- Volume
- 11
- Pages
- e3-e3
- ISSN
- 1462-3994 (ISSN-L)
- PMC
- PMC2768535
- OpenAlex
- W2023366312
- Cited by
- 408
- References
- 190
- Citations by year
- 2026: 25 · 2025: 37 · 2024: 22 · 2023: 24 · 2022: 23 · 2021: 29 · 2020: 34 · 2019: 24 · 2018: 28 · 2017: 37 · 2016: 13 · 2015: 15 · 2014: 22 · 2013: 22 · 2012: 17
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Expert Reviews in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Cambridge
- National Institutes of Health
- National Institute on Drug Abuse (DA005832, R01DA005832, R01DA029532)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- CB2 receptor, immune regulation, neuroinflammation, signal transduction, exogenous cannabinoids, immune homeostasis, neuropathy, hyperinflammation, therapeutic target
- MeSH terms
- Amino Acid Sequence, Animals, Humans, Inflammation, Molecular Sequence Data, Nervous System, Research, Neuroimmunomodulation, Receptor, Cannabinoid, CB2
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