Marijuana is the most widely used illicit drug in the United States. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana, has been reported to be immunosuppressive and to alter the functional activities of macrophages. THC and various cannabinoids inhibit macrophage migration and phagocytosis, dampen production of chemokines, alter processing of antigens, down-regulate production of pro-inflammatory cytokines, and alter the systemic balance of cytokines from a Th1 pro-inflammatory to a Th2 anti-inflammatory profile. Now that an endogenous cannabinoid (endocannabinoid) system has been identified as having two receptor types, several signal transduction pathways, three prominent endocannabinoids, and specific pathways for the synthesis, cellular uptake and metabolism of the endocannabinoids, it is our premise that exogenous cannabinoids such as THC alter this endogenous system. Thus, definition of the effects of cannabinoids on macrophage function is important in view of initiatives to use marijuana as a medicinal for treatment of chronic disabling diseases, including AIDS. The objective of this study is to define the role of endogenous and exogenous cannabinoids in the modulation of macrophage function. The central hypothesis to be tested is that endocannabinoids exert their actions through cannabinoid receptors. However, we propose further that while endocannabinoids and exogenous cannabinoids act through these receptors, the consequences of such interactions are distinctive. That is, in contrast to exogenous cannabinoids, the effects of endocannabinoids may be localized and of short duration. This distinction may articulate a mode by which exogenous cannabinoids superimpose effects over the endocannabinoid system. In order to test these hypotheses, three Specific Aims will serve as guidelines to the research. First, it is proposed to define the effects of endocannabinoids on signature functional activities attributed to macrophages when in defined states of activation. The effects of arachidonylethanolamide (anandamide), 2-arachidonylglycerol (2-AG), and noladin ether will be assessed. Second, it is proposed to compare the in vitro effects endocannabinoids to those of THC. Third, it is proposed through a series of select experiments to determine whether in vitro effects are operative in vivo. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005832-14
Application #
7406647
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Avila, Albert
Project Start
2007-06-01
Project End
2012-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
14
Fiscal Year
2008
Total Cost
$285,248
Indirect Cost
Name
Virginia Commonwealth University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Raborn, Erinn S; Jamerson, Melissa; Marciano-Cabral, Francine et al. (2014) Cannabinoid inhibits HIV-1 Tat-stimulated adhesion of human monocyte-like cells to extracellular matrix proteins. Life Sci 104:15-23
Cabral, Guy A; Griffin-Thomas, LaToya (2009) Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med 11:e3
Cabral, G A; Griffin-Thomas, L (2008) Cannabinoids as therapeutic agents for ablating neuroinflammatory disease. Endocr Metab Immune Disord Drug Targets 8:159-72
Cabral, G A; Raborn, E S; Griffin, L et al. (2008) CB2 receptors in the brain: role in central immune function. Br J Pharmacol 153:240-51
Marciano-Cabral, Francine; Cabral, Guy A (2007) The immune response to Naegleria fowleri amebae and pathogenesis of infection. FEMS Immunol Med Microbiol 51:243-59
Cabral, G A; Marciano-Cabral, F (2005) Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol 78:1192-7
Marciano-Cabral, Francine; Han, Kathy; Powell, Eric et al. (2003) Interaction of an Acanthamoeba human isolate harboring bacteria with murine peritoneal macrophages. J Eukaryot Microbiol 50 Suppl:516-9
Burnette-Curley, D; Cabral, G A (1995) Differential inhibition of RAW264.7 macrophage tumoricidal activity by delta 9tetrahydrocannabinol. Proc Soc Exp Biol Med 210:64-76
Cabral, G A; Toney, D M; Fischer-Stenger, K et al. (1995) Anandamide inhibits macrophage-mediated killing of tumor necrosis factor-sensitive cells. Life Sci 56:2065-72
Pettit, D A; Showalter, V M; Abood, M E et al. (1994) Expression of a cannabinoid receptor in baculovirus-infected insect cells. Biochem Pharmacol 48:1231-43

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