Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 310 (5746): 329-332

Copyright © 2005 by the American Association for the Advancement of Science

Identification and Functional Characterization of Brainstem Cannabinoid CB2 Receptors

Marja D. Van Sickle,1* Marnie Duncan,1* Philip J. Kingsley,2 Abdeslam Mouihate,1 Paolo Urbani,3 Ken Mackie,4 Nephi Stella,5 Alexandros Makriyannis,6 Daniele Piomelli,7 Joseph S. Davison,1 Lawrence J. Marnett,2 Vincenzo Di Marzo,3 Quentin J. Pittman,1 Kamala D. Patel,1 Keith A. Sharkey1{dagger}

Abstract: The presence and function of CB2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB2 receptor messenger RNA and protein localization on brainstem neurons. These functional CB2 receptors in the brainstem were activated by a CB2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB1 receptors. CB2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.

1 Institute of Infection, Immunity, and Inflammation and Hotchkiss Brain Institute, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada T2N 4N1.
2 Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232–0146, USA.
3 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
4 Department of Anesthesiology and Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195–6540, USA.
5 Department of Pharmacology, Psychiatry, and Behavioral Sciences, University of Washington, Seattle, WA 98195–7280, USA.
6 Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA.
7 Department of Pharmacology, Gillespie Neuroscience Facility, University of California, Irvine, CA 92697–6180, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: ksharkey{at}

Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation.
M. Duncan, M. A. Galic, A. Wang, A. P. Chambers, D.-M. McCafferty, D. M. McKay, K. A. Sharkey, and Q. J. Pittman (2013)
Am J Physiol Regulatory Integrative Comp Physiol 305, R224-R231
   Abstract »    Full Text »    PDF »
Synaptic Targets of {Delta}9-Tetrahydrocannabinol in the Central Nervous System.
A. F. Hoffman and C. R. Lupica (2013)
Cold Spring Harb Perspect Med 3, a012237
   Abstract »    Full Text »    PDF »
Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease.
J. Bouchard, J. Truong, K. Bouchard, D. Dunkelberger, S. Desrayaud, S. Moussaoui, S. J. Tabrizi, N. Stella, and P. J. Muchowski (2012)
J. Neurosci. 32, 18259-18268
   Abstract »    Full Text »    PDF »
Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain.
L. Callen, E. Moreno, P. Barroso-Chinea, D. Moreno-Delgado, A. Cortes, J. Mallol, V. Casado, J. L. Lanciego, R. Franco, C. Lluis, et al. (2012)
J. Biol. Chem. 287, 20851-20865
   Abstract »    Full Text »    PDF »
Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors.
F. S. den Boon, P. Chameau, Q. Schaafsma-Zhao, W. van Aken, M. Bari, S. Oddi, C. G. Kruse, M. Maccarrone, W. J. Wadman, and T. R. Werkman (2012)
PNAS 109, 3534-3539
   Abstract »    Full Text »    PDF »
3-Substituted Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Receptor Antagonist Rimonabant: Cannabinoid Agonist-Like Effects in Mice via Non-CB1, Non-CB2 Mechanism.
J. L. Wiley, D. E. Selley, P. Wang, R. Kottani, S. Gadthula, and A. Mahadeven (2012)
J. Pharmacol. Exp. Ther. 340, 433-444
   Abstract »    Full Text »    PDF »
CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling.
J. Palazuelos, Z. Ortega, J. Diaz-Alonso, M. Guzman, and I. Galve-Roperh (2012)
J. Biol. Chem. 287, 1198-1209
   Abstract »    Full Text »    PDF »
The endocannabinoid system and emotional processing: pathophysiology and therapeutic potential.
D. P. Finn, M.-P. Viveros, and E. M. Marco (2012)
J Psychopharmacol 26, 3-6
   Full Text »    PDF »
Psychopharmacology of the endocannabinoids: far beyond anandamide.
F. Pamplona and R. Takahashi (2012)
J Psychopharmacol 26, 7-22
   Abstract »    Full Text »    PDF »
CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity.
E. S. Onaivi, H. Ishiguro, S. Gu, and Q.-R. Liu (2012)
J Psychopharmacol 26, 92-103
   Abstract »    Full Text »    PDF »
Adolescent exposure to cannabis as a risk factor for psychiatric disorders.
T. Rubino, E. Zamberletti, and D. Parolaro (2012)
J Psychopharmacol 26, 177-188
   Abstract »    Full Text »    PDF »
The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives.
E. M. Marco and G. Laviola (2012)
J Psychopharmacol 26, 150-163
   Abstract »    Full Text »    PDF »
Cannabinoid Receptor 2 Is Critical for the Homing and Retention of Marginal Zone B Lineage Cells and for Efficient T-Independent Immune Responses.
S. Basu, A. Ray, and B. N. Dittel (2011)
J. Immunol. 187, 5720-5732
   Abstract »    Full Text »    PDF »
Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice.
S. G. Kinsey, D. K. Nomura, S. T. O'Neal, J. Z. Long, A. Mahadevan, B. F. Cravatt, J. R. Grider, and A. H. Lichtman (2011)
J. Pharmacol. Exp. Ther. 338, 795-802
   Abstract »    Full Text »    PDF »
Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis.
J. L. Lanciego, P. Barroso-Chinea, A. J. Rico, L. Conte-Perales, L. Callen, E. Roda, V. Gomez-Bautista, I. P. Lopez, C. Lluis, J. L. Labandeira-Garcia, et al. (2011)
J Psychopharmacol 25, 97-104
   Abstract »    PDF »
International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2.
R. G. Pertwee, A. C. Howlett, M. E. Abood, S. P. H. Alexander, V. Di Marzo, M. R. Elphick, P. J. Greasley, H. S. Hansen, G. Kunos, K. Mackie, et al. (2010)
Pharmacol. Rev. 62, 588-631
   Abstract »    Full Text »    PDF »
Nabilone produces marked impairments to cognitive function and changes in subjective state in healthy volunteers.
K. Wesnes, P. Annas, C. Edgar, C. Deeprose, R. Karlsten, A. Philipp, J. Kalliomaki, and M. Segerdahl (2010)
J Psychopharmacol 24, 1659-1669
   Abstract »    PDF »
Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a Peripherally Restricted Cannabinoid CB1/CB2 Receptor Agonist, Inhibits Gastrointestinal Motility but Has No Effect on Experimental Colitis in Mice.
N. L. Cluny, C. M. Keenan, M. Duncan, A. Fox, B. Lutz, and K. A. Sharkey (2010)
J. Pharmacol. Exp. Ther. 334, 973-980
   Abstract »    Full Text »    PDF »
The Role of Endocannabinoid Signaling in Motor Control.
A. El Manira and A. Kyriakatos (2010)
Physiology 25, 230-238
   Abstract »    Full Text »    PDF »
A Lipid Pathway for Ligand Binding Is Necessary for a Cannabinoid G Protein-coupled Receptor.
D. P. Hurst, A. Grossfield, D. L. Lynch, S. Feller, T. D. Romo, K. Gawrisch, M. C. Pitman, and P. H. Reggio (2010)
J. Biol. Chem. 285, 17954-17964
   Abstract »    Full Text »    PDF »
Activation of cannabinoid 2 receptors protects against cerebral ischemia by inhibiting neutrophil recruitment.
S. Murikinati, E. Juttler, T. Keinert, D. A. Ridder, S. Muhammad, Z. Waibler, C. Ledent, A. Zimmer, U. Kalinke, and M. Schwaninger (2010)
FASEB J 24, 788-798
   Abstract »    Full Text »    PDF »
Signaling Pathways from Cannabinoid Receptor-1 Activation to Inhibition of N-Methyl-D-Aspartic Acid Mediated Calcium Influx and Neurotoxicity in Dorsal Root Ganglion Neurons.
Q. Liu, M. Bhat, W. D. Bowen, and J. Cheng (2009)
J. Pharmacol. Exp. Ther. 331, 1062-1070
   Abstract »    Full Text »    PDF »
Cannabinoids for clinicians: the rise and fall of the cannabinoid antagonists.
H. Butler and M. Korbonits (2009)
Eur. J. Endocrinol. 161, 655-662
   Abstract »    Full Text »    PDF »
Endocannabinoids Suppress Excitatory Synaptic Transmission to Dorsal Raphe Serotonin Neurons through the Activation of Presynaptic CB1 Receptors.
S. Haj-Dahmane and R.-Y. Shen (2009)
J. Pharmacol. Exp. Ther. 331, 186-196
   Abstract »    Full Text »    PDF »
Blockade of Endocannabinoid-Degrading Enzymes Attenuates Neuropathic Pain.
S. G. Kinsey, J. Z. Long, S. T. O'Neal, R. A. Abdullah, J. L. Poklis, D. L. Boger, B. F. Cravatt, and A. H. Lichtman (2009)
J. Pharmacol. Exp. Ther. 330, 902-910
   Abstract »    Full Text »    PDF »
Novel endogenous peptide agonists of cannabinoid receptors.
I. Gomes, J. S. Grushko, U. Golebiewska, S. Hoogendoorn, A. Gupta, A. S. Heimann, E. S. Ferro, S. Scarlata, L. D. Fricker, and L. A. Devi (2009)
FASEB J 23, 3020-3029
   Abstract »    Full Text »    PDF »
Selective CB2 Receptor Agonism Protects Central Neurons from Remote Axotomy-Induced Apoptosis through the PI3K/Akt Pathway.
M. T. Viscomi, S. Oddi, L. Latini, N. Pasquariello, F. Florenzano, G. Bernardi, M. Molinari, and M. Maccarrone (2009)
J. Neurosci. 29, 4564-4570
   Abstract »    Full Text »    PDF »
Endocannabinoid-Mediated Control of Synaptic Transmission.
M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, and M. Watanabe (2009)
Physiol Rev 89, 309-380
   Abstract »    Full Text »    PDF »
Divergent Effects of Anandamide Transporter Inhibitors with Different Target Selectivity on Social Play Behavior in Adolescent Rats.
V. Trezza and L. J. M. J. Vanderschuren (2009)
J. Pharmacol. Exp. Ther. 328, 343-350
   Abstract »    Full Text »    PDF »
Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain.
I. Racz, X. Nadal, J. Alferink, J. E. Banos, J. Rehnelt, M. Martin, B. Pintado, A. Gutierrez-Adan, E. Sanguino, J. Manzanares, et al. (2008)
J. Neurosci. 28, 12125-12135
   Abstract »    Full Text »    PDF »
Interferon-{gamma} Is a Critical Modulator of CB2 Cannabinoid Receptor Signaling during Neuropathic Pain.
I. Racz, X. Nadal, J. Alferink, J. E. Banos, J. Rehnelt, M. Martin, B. Pintado, A. Gutierrez-Adan, E. Sanguino, N. Bellora, et al. (2008)
J. Neurosci. 28, 12136-12145
   Abstract »    Full Text »    PDF »
N-Arachidonyl Maleimide Potentiates the Pharmacological and Biochemical Effects of the Endocannabinoid 2-Arachidonylglycerol through Inhibition of Monoacylglycerol Lipase.
J. J. Burston, L. J. Sim-Selley, J. P. Harloe, A. Mahadevan, R. K. Razdan, D. E. Selley, and J. L. Wiley (2008)
J. Pharmacol. Exp. Ther. 327, 546-553
   Abstract »    Full Text »    PDF »
Modulation of the Endocannabinoid System in Cardiovascular Disease: Therapeutic Potential and Limitations.
P. Pacher, P. Mukhopadhyay, R. Mohanraj, G. Godlewski, S. Batkai, and G. Kunos (2008)
Hypertension 52, 601-607
   Full Text »    PDF »
Identification of Novel Endogenous Cytochrome P450 Arachidonate Metabolites with High Affinity for Cannabinoid Receptors.
J.-K. Chen, J. Chen, J. D. Imig, S. Wei, D. L. Hachey, J. S. Guthi, J. R. Falck, J. H. Capdevila, and R. C. Harris (2008)
J. Biol. Chem. 283, 24514-24524
   Abstract »    Full Text »    PDF »
Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation.
J. Zhang and C. Chen (2008)
J. Biol. Chem. 283, 22601-22611
   Abstract »    Full Text »    PDF »
Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects.
A A Izzo and M Camilleri (2008)
Gut 57, 1140-1155
   Abstract »    Full Text »    PDF »
Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats.
M. Duncan, A. Mouihate, K. Mackie, C. M. Keenan, N. E. Buckley, J. S. Davison, K. D. Patel, Q. J. Pittman, and K. A. Sharkey (2008)
Am J Physiol Gastrointest Liver Physiol 295, G78-G87
   Abstract »    Full Text »    PDF »
Attenuation of Experimental Autoimmune Hepatitis by Exogenous and Endogenous Cannabinoids: Involvement of Regulatory T Cells.
V. L. Hegde, S. Hegde, B. F. Cravatt, L. J. Hofseth, M. Nagarkatti, and P. S. Nagarkatti (2008)
Mol. Pharmacol. 74, 20-33
   Abstract »    Full Text »    PDF »
Characterization of biotin-anandamide, a novel tool for the visualization of anandamide accumulation.
F. Fezza, S. Oddi, M. Di Tommaso, C. De Simone, C. Rapino, N. Pasquariello, E. Dainese, A. Finazzi-Agro, and M. Maccarrone (2008)
J. Lipid Res. 49, 1216-1223
   Abstract »    Full Text »    PDF »
Pleiotropic effects of the CB2 cannabinoid receptor activation on human monocyte migration: implications for atherosclerosis and inflammatory diseases.
P. Pacher and Z. Ungvari (2008)
Am J Physiol Heart Circ Physiol 294, H1133-H1134
   Full Text »    PDF »
Regression of Fibrosis after Chronic Stimulation of Cannabinoid CB2 Receptor in Cirrhotic Rats.
J. Munoz-Luque, J. Ros, G. Fernandez-Varo, S. Tugues, M. Morales-Ruiz, C. E. Alvarez, S. L. Friedman, V. Arroyo, and W. Jimenez (2008)
J. Pharmacol. Exp. Ther. 324, 475-483
   Abstract »    Full Text »    PDF »
Hemopressin is an inverse agonist of CB1 cannabinoid receptors.
A. S. Heimann, I. Gomes, C. S. Dale, R. L. Pagano, A. Gupta, L. L. de Souza, A. D. Luchessi, L. M. Castro, R. Giorgi, V. Rioli, et al. (2007)
PNAS 104, 20588-20593
   Abstract »    Full Text »    PDF »
Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis.
M. Rajesh, H. Pan, P. Mukhopadhyay, S. Batkai, D. Osei-Hyiaman, G. Hasko, L. Liaudet, B. Gao, and P. Pacher (2007)
J. Leukoc. Biol. 82, 1382-1389
   Abstract »    Full Text »    PDF »
A neutral CB1 receptor antagonist reduces weight gain in rat.
A. P. Chambers, V. K. Vemuri, Y. Peng, J. T. Wood, T. Olszewska, Q. J. Pittman, A. Makriyannis, and K. A. Sharkey (2007)
Am J Physiol Regulatory Integrative Comp Physiol 293, R2185-R2193
   Abstract »    Full Text »    PDF »
CB2-receptor stimulation attenuates TNF-{alpha}-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion.
M. Rajesh, P. Mukhopadhyay, S. Batkai, G. Hasko, L. Liaudet, J. W. Huffman, A. Csiszar, Z. Ungvari, K. Mackie, S. Chatterjee, et al. (2007)
Am J Physiol Heart Circ Physiol 293, H2210-H2218
   Abstract »    Full Text »    PDF »
Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase.
S. Batkai, M. Rajesh, P. Mukhopadhyay, G. Hasko, L. Liaudet, B. F. Cravatt, A. Csiszar, Z. Ungvari, and P. Pacher (2007)
Am J Physiol Heart Circ Physiol 293, H909-H918
   Abstract »    Full Text »    PDF »
[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor.
H. D. Burns, K. Van Laere, S. Sanabria-Bohorquez, T. G. Hamill, G. Bormans, W.-s. Eng, R. Gibson, C. Ryan, B. Connolly, S. Patel, et al. (2007)
PNAS 104, 9800-9805
   Abstract »    Full Text »    PDF »
Anandamide-Mediated CB1/CB2 Cannabinoid Receptor-Independent Nitric Oxide Production in Rabbit Aortic Endothelial Cells.
L. McCollum, A. C. Howlett, and S. Mukhopadhyay (2007)
J. Pharmacol. Exp. Ther. 321, 930-937
   Abstract »    Full Text »    PDF »
Endocannabinoids and Synaptic Function in the CNS.
Y. Hashimotodani, T. Ohno-Shosaku, and M. Kano (2007)
Neuroscientist 13, 127-137
   Abstract »    PDF »
Functional CB1 Receptors Are Broadly Expressed in Neocortical GABAergic and Glutamatergic Neurons.
E. L. Hill, T. Gallopin, I. Ferezou, B. Cauli, J. Rossier, P. Schweitzer, and B. Lambolez (2007)
J Neurophysiol 97, 2580-2589
   Abstract »    Full Text »    PDF »
A Novel Role of Cannabinoids: Implication in the Fever Induced by Bacterial Lipopolysaccharide.
K. Benamar, M. Yondorf, J. J. Meissler, E. B. Geller, R. J. Tallarida, T. K. Eisenstein, and M. W. Adler (2007)
J. Pharmacol. Exp. Ther. 320, 1127-1133
   Abstract »    Full Text »    PDF »
Cannabinoid receptors as novel targets for the treatment of melanoma.
C. Blazquez, A. Carracedo, L. Barrado, P. J. Real, J. L. Fernandez-Luna, G. Velasco, M. Malumbres, and M. Guzman (2006)
FASEB J 20, 2633-2635
   Abstract »    Full Text »    PDF »
Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation.
J. Palazuelos, T. Aguado, A. Egia, R. Mechoulam, M. Guzman, and I. Galve-Roperh (2006)
FASEB J 20, 2405-2407
   Abstract »    Full Text »    PDF »
Effect of Lipid Rafts on Cb2 Receptor Signaling and 2-Arachidonoyl-Glycerol Metabolism in Human Immune Cells.
M. Bari, P. Spagnuolo, F. Fezza, S. Oddi, N. Pasquariello, A. Finazzi-Agro, and M. Maccarrone (2006)
J. Immunol. 177, 4971-4980
   Abstract »    Full Text »    PDF »
The Endocannabinoid System as an Emerging Target of Pharmacotherapy.
P. Pacher, S. Batkai, and G. Kunos (2006)
Pharmacol. Rev. 58, 389-462
   Abstract »    Full Text »    PDF »
Sex and hormonal cycle differences in rat brain levels of pain-related cannabimimetic lipid mediators.
H. B. Bradshaw, N. Rimmerman, J. F. Krey, and J. M. Walker (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R349-R358
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882