Cannabinoid Receptors
Two cannabinoid receptors have been identified so far, cannabinoid receptor 1 (CB1) from rat and human brain cDNA libraries, and cannabinoid receptor 2 (CB2) from human leukemic cell line (HL60) cDNA library Gerard et al., 1991; Matsuda et al., 1990 CB1 and CB2 are G-protein-coupled receptors (GPCRs). (Bruan et al., "Regulation of interleukin-12 production by G-protein-coupled receptors" 3(2) (2001, pages 99-107)
The CB1 receptor is mainly found in the central nervous system whereas the CB2 receptor is mainly found in the peripheral tissue, in particular in leucocytes, spleen and macrophages.
The peripheral cannabinoid receptor (CB2) is a G portein coupled receptor that is both positively and negatively couples to the mitogen-activated protein kinase (MAPK) and cAMP pathways, respectively, through a Bordetella pertussis toxin-senstive G protein. (Bouaboula et et., "Gi Protein Modulation Induced by a Selective Inverse Agonist for Periopheral Cannabinoid Receptor CB2: Implication for Intracellular Signalization Cross-Regulation.)
Agonists of the Cannabinoid Receptors
Agonists of the central cannabinoid receptor CB1 have been used for the prophylaxis and treatment of neurodegenerative disorders, in particular for the treatment of cerebral apoplexy and craniocerebral trauma. (U.S. Patent No. 6,525,087) Activation of the CB2 receptor has been shown to result in suppression of the immune system. (U.S. Patent No. 6,166,066)
Antagonists of the Cannabinoid Receptors
In addition to cannabimimetic agonists, receptor antagonists have also been described. The first of these was the orally active antagonist with high affinity for CB1 termed SR141616A. This compound was shown in rat brain membrane preparations (CB1 rich) to inhibit the binding of various receptor agonists with a Ki in the nM range while binding in splenocyte membranes (CB2 rich) was inhibited in the uM range. Rinaldi-Carmona M. et al., "SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350: 240-244. An antagonist for CB2 has also been described and termed SR144528.
Inverse Agonists of the Cannabinoid Receptors
Besides inhibiting the binding and function of cannabimimetic agents, the SR compounds act as inverse agonists in cell models displaying constitutive CB1 or CB2 activity. Thus, in certain cell types, treatment with SR compounds alone may cause changes in biological function by not only blocking the action of agonist, but also suppressing constitutive activity of CBRs as well as the activity of other G protein-coupled receptors. Bouaboula M et al., "Gi protein modulation induced by a selective inverse agonist for the periopheral cannabinoid receptor CB2: Implication for intracellular signalization cross regulation." Mol Pharmacol 55:473-480, 1999
THC and T cell development
There is evidence that THC has immunomodulatory effects like the inhibition of mitogen-induced T lymphocyte proliferation, Nahas et al., 1974, the inhibition of y-interferon production, Blanchard et al., 1986, and the suppression of induction of cytolytic function of cytotoxic T cells, Kelin et al., 1991.
For example, THC injection into mice suppressed the development of cell-mediated, Th1 immunity to infection with the intracellular, bacterial pathogen, Legionella Pneumophila (Lp) Newton et al., 1994 "Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by del-9-tetrahydrocannabinol injection" Infect. Immun., 62, 40115-4020
THC suppressed Th1 immunity by inhibiting the mobilization of IFNy and IL-12 as well as the expression of IL-12 receptors and increasing the expression of the Th2-promoting cytokine IL-4. For example, within hours following THC treatment and antigen challenge, serum IL-12 and IFNy mobilizaiton was decreased relative to drug vehicle controls and IL-4 was increased by drug treatment in spleen preparation. (Klein et al., 2000 "delta-9-tetrahydrocannabinol treatment suppresses immunity and early IFN-y, IL-12 and IL-12 receptor B2 responses to Legionella pneumophila infection. J. Immunol., 164, 6461-6466 )
THC and HIV
There is evidence that cannabinoid agonists may enhance HIV infection as shown by increased syncytia formation in MT-2 cells (which express both CB1 and CB2 cannabinoid receptors) when cultured in the presence of cannabinoid agonists and cell free HIV-1MN (Noe et al., "Cannabinoid Receptor Agonists Enhance Syncytia Formation in MT-2 Cells Infected with Cell Free HIV-1MN") MT-2 cells are naive CD4+ T cells.
