Pharmacological Actions of Cannabinoids 29– It is not sensitive to activation by the established CB 1 /CB 2 receptor agonists,∆^9 -
THC, CP55940 or HU-210 (Breivogel et al. 2001; Di Marzo et al. 2000; Monory
et al. 2002).- It is not coupled to adenylate cyclase, at least in the cerebellum of CB 1 –/–CD1
mice (Monory et al. 2002). - It differs from the CB 1 receptor in its central distribution pattern (Breivogel et
al. 2001; Monory et al. 2002). - SR141716A and SR144528 do not appear to be competitive antagonists for this
putative receptor (Breivogel et al. 2001; Monory et al. 2002). - There are no specific binding sites for [^3 H]CP55940 on CB 1 –/–C57BL/6 mouse
brain membranes (Breivogel et al. 2001).
Ithasalsobeenfoundthat[^3 H]R-(+)-WIN55212 undergoes selective binding to
CB 1 –/–C57BL/6 membranes obtained from brain areas in whichR-(+)-WIN55212
enhances [^35 S]GTPγS binding (cerebral cortex, hippocampus and brain stem)
(Breivogel et al. 2001). Furthermore, CB 1 –/–C57BL/6 brain areas that are unre-
sponsive toR-(+)-WIN55212-induced enhancement of [^35 S]GTPγS binding seem
to lack [^3 H]R-(+)-WIN55212 binding sites (Breivogel et al. 2001). It is notewor-
thy, however, that some WIN55212-sensitive brain areas of CB 1 –/–C57BL/6 mice
(midbrain and diencephalon) and of CB 1 –/–CD1 mice (cerebellum) also seem
to lack [^3 H]R-(+)-WIN55212 binding sites (Breivogel et al. 2001; Ledent et al.
1999; Monory et al. 2002). Although CB 1 –/–C57BL/6 mouse brain does contain
specific binding sites for both [^3 H]SR141716A and [^3 H]R-(+)-WIN55212, these
two binding site populations have different distribution patterns (Breivogel et al.
2001). This is further evidence that SR141716A lacks affinity for the proposed
R-(+)-WIN55212/anandamide receptor.
A pharmacological property that the proposedR-(+)-WIN55212/anandamide
receptor may share with the CB 1 receptor is the ability to mediate antinociception,
catalepsy and hypokinesia. Thus, whilst∆^9 -THC produced these effects only in the
wild-type mice, anandamide was essentially as potent and effective in producing
these effects in CB 1 –/–as in CB 1 +/+C57BL/6 mice (Di Marzo et al. 2000). Indeed,
this putative new receptor may well prove to be a novel target for anti-spasticity
and analgesic drugs (Brooks et al. 2002). The presence of specific binding sites
for [^3 H]SR141716A on CB 1 –/–C57BL/6 mouse brain membranes may explain the
ability of SR141716A both to inhibit [^35 S]GTPγS binding to such membranes
(Breivogel et al. 2001) and to reduce milk intake and survival of newborn CB 1 –/–
C57BL/6 mice (Fride et al. 2003).
Central TRPV1-Like Receptors
Evidence has emerged for the presence of G protein-coupled, non-CB 1 recep-
tors on glutamatergic axonal terminals in the hippocampus with which at least
some cannabinoid receptor agonists can interact to inhibit glutamate release. More
specifically, results from electrophysiological experiments with hippocampal slices