part of CB2R gene, we found that the promoters of CB2R KO mice were still active
and that a CB2R truncated version was expressed, indicating that the CB2R KO
mice with ablation of the C-terminal peptides of 131 amino acids was an incomplete
CB2R knockout (Liu et al. 2009 ). Another mouse CB2R KO mice that has been
generated with ablation of N-terminal peptide 156 amino acid (Deltagen, Inc.
San Mateo, CA) turned out to be an incomplete CBR KO mouse.
In summary, after over two decades since the cloning of CB2R gene 61, and
earlier studies that were not able to detect neuronal CB2Rs in healthy brains, the
functional presence of neuronal CB2Rs in the CNS has been controversial despite
data indicating functional neuronal expression of CB2Rs from our research data and
those of others. While there are still lingering doubts, data from our continuing
CB2R research will not only clear the remaining ambiguities and controversies but
will also certainly reinvigorate thefield as we have so much to do and learn so that
we can continue to move thefield forward. This is because we have created new
tools and reagents and generated critically needed microglia and dopamine
(DA) neuron specific CB2R conditional KO mouse models to study the functional
roles and the associated molecular pathways in microglia- and DA neuron- specific
Cx3cr1-Cnr2-Lox and DAT-Cnr2-Lox transgenic mice. Furthermore, using
cell-type specific conditional CB2R transgenic mice will also reveal CB1R func-
tional role in the absence of CB2Rs and to deduce the interaction between CB1Rs
and CB2Rs which are largely unknown.
10.6 Frame Work on the Molecular Basis
for the Therapeutic Potential of Cannabinoids
The role and interaction of CB1Rs with CB2Rs cannot be ignored in increasing
knowledge on the medicinal, legal and recreational use of cannabis. The proposed
therapeutic implications of targeting elements of the eCB system for the treatment
of neurological and mental illness may involve interaction between CB2Rs and
CB1Rs which remains one of the most abundant G-protein-coupled receptors
(GPCRs) in the brain. Therefore, significant advances with discoveries unravelling
such compelling knowledge and major breakthroughs about the elements of the
endocannabinoid system can be described as paradigmatic (Onaivi 2002 ). The
discovery that specific genes codes for cannabinoid receptors (CBRs) that are
activated by marijuana use and endocannabinoids (eCBs) (Onaivi et al. 2006 ), that
also activates CBRs have provided surprising new knowledge about cannabinoid
genomic and proteomic profiles as potential therapeutic targets. These remarkable
progress, new understanding and advances indicate that the molecular, cellular,
biochemical and behavioral responses to marijuana, which remains one of the most
widely used and abused drugs in the world, are coded in our genes and chromo-
somes. This increasing new knowledge from the decoding of the human genome
led to the acknowledgement that, many aspects of genetic risk factors in marijuana
10 Cannabinoid CB2 Receptor Mechanism ofCannabis sativaL. 235