layer of the cerebellum are all populated with
such endogenous cannabinoids (endocannabinoids)
particularly high concentrations of CB 1 receptors. 1,10
to be identified were N -arachidonoyl ethanolamine
In line with the analgesic properties of cannabinoid
(anandamide) in 1992 and 2-arachidonylglycerol in
receptor agonists, CB 1 receptors are also found on
1995 (Figure 1), 20-22 both of which are synthesised
pain pathways in the brain and spinal cord and at the
on demand in response to elevations of intracellular
peripheral terminals of primary sensory neurons. 11,12
calcium. 23 Anandamideisformedfrom N -arachidonoyl
Although the concentration of CB 1 receptors is
phosphatidylethanolamine in a process that is
considerably less in peripheral tissues than in the
catalysed by N -acyl phosphatidylethanolamine-
central nervous system, this does not mean that
selective
phospholipase
D
(NAPE-PLD).
The
peripheral CB 1 receptors are unimportant. Thus in
synthesis
of
2-arachidonylglycerol,
however,
some peripheral tissues, discrete regions such as
is thought to depend on the conversion of
nerve terminals that form only a small part of the
2-arachidonate-containing
phosphoinositides
to
total tissue mass are known to be densely populated
diacylglycerols
and
on
their
subsequent
with CB 1 receptors. Peripheral tissues in which
transformation to 2-arachidonylglycerol by the
CB 1 receptors are expressed on neurons include
action of two diacylglycerol lipase (DAGL) isozymes,
the heart, vas deferens, urinary bladder and small
DAGL α and DAGL β . 23,24 Following their synthesis and
intestine. 10,13
release, these endocannabinoids are removed from
their sites of action by cellular uptake and degraded
Both CB 1 and CB 2 receptors are coupled through
by
enzymes,
2-arachidonylglycerol
mainly
by
G i/o proteins, negatively to adenylyl cyclase and
monoacylglycerol lipase (MAGL) but also by fatty acid
positively to mitogen-activated protein kinase. 1,14 In
amide hydrolase (FAAH), and anandamide by FAAH
addition, CB 1 receptors are coupled to ion channels
and/or by palmitoylethanolamide-preferring acid
through G i/o proteins, positively toA-type and inwardly
amidase (PAA), cyclooxygenase-2, lipoxygenases
rectifying potassium channels and negatively to
and cytochrome P450. 5,23-25 Other ligands that may
N-type and P/Q-type calcium channels. 1,13,14 CB 1
be endocannabinoids are 2-arachidonylglyceryl
receptors can also couple to G s proteins to activate
ether (noladin ether), O -arachidonoyl ethanolamine
adenylyl cyclase, 15-17 the extent to which this occurs
(virodhamine), N -dihomo- γ -linolenoyl ethanolamine,
possibly being determined by the location of these
N -docosatetraenoyl
ethanolamine,
receptors or by cross-talk between CB 1 receptors
N -arachidonoyl
dopamine
(NADA)
and
and
co-localised
G-protein-coupled
non-CB 1
N -oleoyl dopamine (OLDA) (Figures 2 and 3). 5
receptors. 15,16,18,19 It may also be that CB 1 receptors
Endocannabinoids together with their receptors
can exist as two distinct subpopulations, one
constitute what is now usually referred to as the
coupled to G i/o proteins and the other to G s . 15 Details
‘endocannabinoid system’.
of additional signalling mechanisms that have been
proposed for cannabinoid CB 1 and CB 2 receptors
While it is generally accepted that endocannabinoids
can be found elsewhere. 1,14
do pass through cell membranes, one issue that is
currently very much a matter of debate is the question
The cloning of cannabinoid receptors was followed
of whether the cellular uptake of endocannabinoids
by the discovery that mammalian tissues produce
such as anandamide is mediated by a transporter. 25-27
compounds that can activate these receptors.The first
In contrast, FAAH is now well characterised. Indeed,
Figure 2 | Structures of the endogenous cannabinoid receptor agonists, N -dihomo- γ -linolenoyl
ethanolamine, N -docosatetraenoyl ethanolamine, NADA, oleamide, OLDA and virodhamine
OH
O
O
O
OH
OH
N
N
N
OH
H
H
H
N -Dihomo- γ -linolenoyl ethanolamine
N -Docosatetraenoyl ethanolamine
OH
O
O
O
NH 2
NH 2
N
OH
O
H
(Bold Link Text Denotes Compounds Available From Tocris)
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