use whether as medicine or recreationally, including age of initiation, continuation
and problem use undoubtedly interacts with environmental factors such as epige-
netics and availability of marijuana along with the individual’s genotype and
phenotype. Therefore, the eCB signaling system has been described as a wide-
spread, neuromodulatory system in the brain and is also widely utilized in the
periphery to modulate metabolic functions and the immune system (Hillard et al.
2012 ).
These rapid advances in understanding the biological actions of marijuana,
phytocannabinoids, cannabinoids and eCBs, are unraveling the genetic basis of
marijuana use with implication not only for the recreational use but also for the
therapeutic potentials for human health and disease. Thus, because of the ubiquitous
distribution and role of the eCB system in the regulation of human physiological
processes, drugs that are targeted to different aspects of this system are already
benefiting cancer subjects and those with AIDS and metabolic syndromes
(Jesudason and Wittert 2008 ). So the cloning, identification and characterization of
some of elements of the eCB system including the CB1 and CB2 receptors which
are encoded byCNR1andCNR2genes, respectively, have been mapped to human
chromosome 6 and 1 respectively. Intensive research and further progress and
milestones has continued after the cloning of human, Chimpanzee, dog, rat, mouse,
and other species CB1R and CB2R genes. From the perspectives described above
and from the other chapters described in this book, new and interesting components
of other elements of the eCBs system are emerging as potential therapeutic targets
being uncovered using animal models of disease. However it is important to note
that pharmacological actions of CB1Rs and CB2Rs in the central nervous system
(CNS) may be more diverse and complex than previously recognized (Onaivi et al.
2012 ) with their differential distribution patterns and species and subtype differ-
ences in mammalian cannabinoid receptors. Furthermore, the nature of the inter-
action between CB1Rs and CB2Rs has not been well studied and characterized
(Onaivi 2009 ; Onaivi et al. 2012 ), but emerging evidence suggests that CB1Rs and
CB2Rs may work independently and/or cooperatively in different neuronal popu-
lations to regulate diverse physiological and biological functions in mental and
neurological disorders. For example, using the brain stimulation reward paradigm in
the rat, opposing effects of CB1Rs and CB2Rs in modulating brain stimulation was
demonstrated, with CB1Rs mediating stimulation and CB2Rs mediating brain
inhibition (Onaivi et al. 2012 ). We have also studied the interaction between the
endocannabinoid and vanilloid systems. Briefly, a possible interaction between the
cannabinoid and vanilloid signaling system has been suggested as depicted in
Fig.10.3. We tested the hypothesis that capsaicin directly and indirectly activate
endocannabinoid and endovanilloid systems to produce physiological and behav-
ioral responses in vivo. It appears that possible therapeutic benefits may be
exploited from the interactions of the endocannabinoid (CBRs) with endovanilloid
TRPV1 receptors. The advances in biotechnology and molecular biology and
availability of precise tools and protocols using in vitro and various transgenic
animals, are being used to explore and identify the involvement of elements of the
eCBs system in models of CNS function and dysfunction. Specifically conditional
236 E.S. Onaivi et al.