Pharmacological Actions of Cannabinoids 312003). In these experiments, however, glutamatergic transmission was facilitated
by anandamide and/or capsaicin.
There is currently no support for the hypothesis thatR-(+)-WIN55212 inhibits
glutamate release in the hippocampus by acting on the non-CB 1 , non-CB 2 molec-
ular target that is thought to mediate its enhancement of GTPγS binding to central
neuronal membranes (see above). Thus, althoughR-(+)-WIN55212 does suppress
evoked EPSCs and paired pulse facilitation in CB 1 –/–CD1 mouse hippocampal
slices (Hájos et al. 2001), it does not enhance GTPγS binding to CB 1 –/–CD1 mouse
hippocampal membranes (Monory et al. 2002). Also, whilst CP55940 suppresses
evoked EPSCs in rat hippocampal slices (Hájos and Freund 2002a) and potassium-
evoked glutamate release from rat hippocampal synaptosomes (Köfalvi et al. 2003),
it does not share the ability ofR-(+)-WIN55212 or anandamide to enhance GTPγS
binding to CB 1 –/–C57BL/6 mouse brain membranes (Breivogel et al. 2001).
Peripheral Nervous System
Results from experiments with phenylephrine-precontracted rat isolated mesen-
teric and hepatic arteries suggest that∆^9 -THC can relax these vessels by acting
on capsaicin-sensitive perivascular sensory neurons to induce release of calci-
tonin gene-related peptide (Zygmunt et al. 2002). The underlying mechanism
is most probably CB 1 and CB 2 receptor-independent, as this relaxant effect of
∆^9 -THC was not prevented by 300 nM SR141716A or by 30 nM AM251 and as
the CB 1 /CB 2 receptor agonists HU-210 and CP55940 lacked detectable relaxant
activity, whereas cannabinol, which has relatively low activity as a cannabinoid
receptor agonist (Sect. 3.1), was equipotent with∆^9 -THC. The possibility, that
∆^9 -THC was acting through ionotropic or metabotropic glutamate receptors was
also excluded. Other observations made in this investigation were that∆^9 -THC-
and cannabinol-induced activation of CGRP release from rat arterial segments
could be prevented by capsaicin pretreatment and that∆^9 -THC- and cannabinol-
induced relaxations of precontracted arterial segments could be attenuated by the
noncompetitive TRPV1 antagonist ruthenium red. However, these cannabinoids
were most probably not acting through TRPV1 receptors in these experiments.
Thus, the competitive TRPV1 antagonist capsazepine did not attenuate the va-
sorelaxant effects of∆^9 -THC and cannabinol, and in contrast to both capsaicin
and anandamide,∆^9 -THC also relaxed phenylephrine-precontracted mesenteric
arterial segments that had been obtained from TRPV1–/–mice. In more recent ex-
periments, Jordt et al. (2004) have obtained evidence that∆^9 -THC and cannabinol
may have induced vasorelaxation by acting through ANKTM1, another member
of the transient receptor potential (TRP) family of ion channels that, unlike the
TRPV1 receptor, appears to be insensitive to anandamide and is implicated in
the detection of noxious cold. ANKTMI was found to be insensitive to HU-210,
CP55940 and 2-arachidonoyl glycerol.
It has also been proposed that the terminals of sympathetic neurons supplying
cardiovascular tissue express a non-I 1 , non-I 2 subtype of the putative imidazo-
line receptor that is both CB 1 receptor-like andα 2 -adrenoceptor-like and that
mediates inhibition of evoked noradrenaline release when activated (reviewed in