In general, cannabinoid-induced pharmacological effects are effectively inhibited by the CB1 receptor antagonist SR141716A (71). Thus, significant blockade of THC-induced effects were observed in the mouse tetrad (72,73) and in the mouse tail-flick test for pain perception when supraspinal CB1 receptors were exposed to the antagonist (74). Also, THC- or anandamide-induced memory impairment was attenuated by SR141716A (75). In rats, SR141716A effectively antagonized tetrad-like central effects induced by anandamide (76). Moreover, anandamide-increased appetite was inhibited by SR141716A (77). More recently, 2-AG-induced effects have been included in studies on the CB1 antagonist. Thus SR141716A blocked the antiepileptiform effect of 2-AG, similarly to that of anandamide, in rat hippocampal slices (78,79). Hence we have evidence now that both exogenous and endogenous cannabinoid-induced effects can be blocked by the CB1 antagonist.
However, contrary to expectation, a number of anandamide-induced effects, although they are similar to THC-induced effects, could not be inhibited by the CB1 receptor antagonist. For example, in mice, anandamide-induced effects in the tetrad were antagonized by neither SR141716A (73,80) nor by LY320135 (Fride et al., unpublished observations). Further, SR141716A blocked the antinociceptive effects of THC in mice much more efficiently than those of anandamide (74). This phenomenon has been explained as a pharmacokinetic effect, since inhibition of anandamide-induced effects in the tetrad was accomplished when either a (nonspecific) FAAH inhibitor, phenylmethylsulphonyl fluoride (PMSF), was co-administered with anandamide in order to enhance its half-life, or when a stable analog was administered instead of anandamide (81) (see also review by Nakamura-Palacios and colleagues ). It is still not clear, however, why the CB1 antagonist should only reverse the effects induced by anandamide when its half-life is sufficiently prolonged (e.g., by phenylmethylsulphonyl fluoride, PMSF). Does anandamide act via (an)other receptor in addition to the CB1 receptor?
Observations on CB1 receptor knockout CB-/- mice support such possibility. Thus □9-THC-induced hypoalgesia in the tail-flick test was present, despite the gene deletion, in two knockout strains that were developed in different laboratories and from different parent strains (83,84). Since the tail-flick test is presumably measuring spinal pain perception, while the hot-plate test assays supraspinal mechanisms of pain (85), this observation suggests that mainly higher-level pain mechanisms are affected by CB1 receptor deletion. This is compatible with the observation that SR141716A, when injected intraperitoneally or intracerebrally, fully antagonized cannabinoid-induced analgesia, but only partially when injected at the spinal level (74). Since cannabinoid receptor-mediated pain has a spinal component (86), these data suggest a non-cannabinoid receptor mechanism at the spinal level in addition to the CB1 receptor-mediated transduction.
More recent experiments with the CB1 receptor knockout mice showed, surprisingly, that the CB1-/- mice display anandamide-induced CB1 receptor-mediated response including analgesia, catalepsy, and motor inhibition, despite the absence of CB1 receptors (87). This suggests that anandamide exerts some pharmacological effects that are similar to those induced by exogenous cannabinoids but that are not CB1 receptor-mediated.
In the next sections, evidence for endocannabinoid mechanisms of action other than via CB1 receptor activation will be outlined.
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