410 G.A. Cabral and A. Staab
effect on mitogen-induced transformation. Both stimulated lymphocyte transfor-
mation at low concentrations but inhibited mitogenesis at high concentrations.
In contrast, cocaine neither affected mitogen-induced lymphocyte transformation
nor altered the effect of THC when added together with this cannabinoid. Human
lymphocytes and mouse splenocytes appeared to respond in similar patterns.
6.2
Endogenous Cannabinoids (Endocannabinoids)
The recognition that exogenous cannabinoids could alter immune functional ac-
tivities through cannabinoid receptors implicated the existence of an endoge-
nous functionally relevant ligand-receptor system. Devane et al. (1992) isolated
from porcine brain an arachidonic derivative, anandamide, in a screen for en-
dogenous ligands for the cannabinoid receptor with properties suggestive that
it acted as a natural ligand for the cannabinoid receptor in the brain. The dis-
covery and characterization of anandamide served as a catalyst for studies to
assess its role in signaling through the CB 1 receptor in the brain as well as in
the immune system. Valk et al. (1997) reported that anandamide acted through
the CB 2 receptor as a synergistic growth factor for hematopoietic cells. Derocq
et al. (1998), in a similar study using IL-3-dependent and IL-6-dependent murine
cell lines, postulated that anandamide exerted a growth-promotion effect. How-
ever, it was indicated that this growth-promoting effect was cannabinoid receptor-
independent.
De Petrocellis et al. (1998) reported that anandamide potently and selectively
inhibited the proliferation of human breast cancer cells in vitro. Anandamide
dose-dependently suppressed the proliferation of MCF-7 and EFM-19 human
breast carcinoma cells but did not affect the proliferation of several nonmam-
mary tumoral cell lines. The anti-proliferative effect of anandamide was ap-
parently not due to toxicity or to apoptosis of cells but was accompanied by
a reduction of cells in the S phase of the cell cycle. The stable analog of anan-
damideR-methanandamide and the synthetic cannabinoid HU-210 also inhibited
EFM-19 cell proliferation. The drug effects were blocked with the CB 1 antagonist
SR141716A, suggesting that anandamide blocked human breast cancer cell prolif-
eration through a CB 1 -like receptor-mediated inhibition of endogenous prolactin
action at the level of the prolactin receptor. Facci et al. (1995) reported that mast
cells, multifunctional bone marrow-derived cells found in mucosal and connective
tissues and in the nervous system that play an important role in tissue inflamma-
tion and neuroimmune interactions, expressed a peripheral cannabinoid receptor
with differential sensitivity to anandamide and palmitoylethanolamide. It was
found that they expressed the CB 2 receptor and that this receptor exerted neg-
ative regulatory effects on mast cell activation. Although palmitoylethanolamide
and anandamide bound to the CB 2 receptor, only the former down-modulated
mast cell activation in vitro. It was proposed that palmitoylethanolamide, unlike
anandamide, behaved as an endogenous agonist for the CB 2 receptor on mast
cells. The existence of an autacoid local inflammation antagonism (ALIA) pro-