Biomedical Engineering Reference
In-Depth Information
gland, heart, lung, and reproductive organs. CB
1
-receptor may form homodimeric complexes, and
heterodimeric complexes with m-opioid receptor or dopamine D2 receptor. Anandamide and 2-AG
may reach the receptor from the lipid phase of the membrane and not from the aqueous site.
In vitro
CB
1
-receptor seems to have constitutive activity or it may be under endocannabinoid
stimulatory tone. Several antagonists have also been shown to be inverse agonists but it is unclear
whether this has any
in vivo
signii cance.
Knock out mice that are lacking the receptor protein have been generated. They are generally
healthy and fertile with no apparent gross anatomical defects. However, they do have a number of
abnormalities, e.g., the dysregulation of the hypothalamus-pituitary-adrenal axis suggesting a role
of endocannabinoids in modulating neuroendocrine functions. Furthermore, they have a lighter and
leaner body phenotype and seem to have higher energy expenditure. In a number of experimental
settings these mice do also behave differently, e.g., in studies of alcohol dependence. CB
1
-receptor
knock out mice do not show hypothermia, hypoalgesia, and hypoactivity in response to THC. There
is evidence of splice variation of CB
1
-receptor of very low abundance but their biological signii -
cance is unclear. Activation of GPR55 can be blocked by the CB receptor antagonist Rimonabant
(refer to Figure 19.12), but not by the CB
2
-receptor antagonist SR 144528 (refer to Figure 19.13).
19.2.3 C
ANNABINOID
R
ECEPTOR
2
CB
2
-receptor also belongs to the 7TM-receptors and the human CB
2
-receptor has 44% homology
with human CB
1
-receptor. It seems to couple to the same G-proteins and signaling pathways as
does CB
1
-receptor. However, CB
2
-receptor is found primarily in the spleen, immune cells, tonsils,
and brain microglial cells where its expression can be induced by transformation of microglia to mac-
rophage-like cells. Furthermore, CB
2
-receptor is found in osteoblasts, osteocytes, and osteoclast where
it plays a critical role in the maintenance of normal bone mass. CB
2
-receptor knock out mice appear
healthy and fertile, but they have low-bone mass. In animal models of pain and inl ammation, these
CB
2
-receptor knock out mice have indicated a clear role for this receptor in modulating acute pain,
chronic inl ammatory pain, postsurgical pain, cancer pain, and pain associated with nerve injury.
19.2.4 O
THER
C
ANNABINOID
R
ECEPTORS
Since 2-AG and especially anandamide have a number of pharmacological effects that cannot be
fully explained by activation of the known cannabinoid receptors, it has been suggested that there
may exist more cannabinoid-like receptors. One such receptor may be the recently described GPR55
that is found in the brain and that can potently be activated by both THC, 2-AG, anandamide and the
cannabinoid receptor agonist CP 55,940 (refer to Figure 19.12). Another cannabinoid receptor ago-
nist, WIN 55,212-2, can however not activate GPR55. A number of agonists (e.g., CP 55,940, WIN
55,212-2, O-1812) and antagonists (e.g., Rimonabant, AM251, LY 320125) (refer to Figure 19.12)
have been developed. The biological signii cance of GPR55 is at present not known. Especially
anandamide can activate a number of other receptors and ion channels as mentioned above and this
may add to the confusion regarding the existence of additional cannabinoid receptors.
19.2.5 T
HERAPEUTIC
U
SE
AND
P
OTENTIAL
THC in capsules (Marinol, Solway Pharmaceutical) is used for treatment of nausea and vomiting
that are common side effects of chemotherapy, and for stimulation of appetite in AIDS patients.
In Canada, THC in the form of an extract of
cannabis sativa
called Sativex (GW Pharmaceuticals)
is provided as a mouth spray for multiple sclerosis patients who can use it to alleviate neuropathic
pain and spasticity. Sativex also contains other cannabinoids including cannabidiol that may add
to its function. Medicinal cannabis, i.e., marihuana or hashish prescribed by a doctor for increased
well being and alleviation of pain, spasticity, or loss of appetite by patients having AIDS, cancer,
and multiple sclerosis has been approved in the Netherlands and there is a strong lobby for approval
in certain states of United States.
