Many of the pharmacological effects of Delta(9)-tetrahydrocannabinol are me
diated through CB1 and CB2 cannabinoid receptors. However, with the discove
ry of endogenous cannabinoids, some discrepancies have arisen. Furthermore,
unlike the CB1 receptor, the sequences of the mouse and human CB2 receptor
are divergent, raising the possibility of species specificity. The gene fo
r the rat CB2 receptor was cloned, expressed, and its properties compared w
ith those of mouse and human CB2 receptors. Sequence analysis of the coding
region of the rat CB2 genomic clone indicates 90% nucleic acid identity (9
3% amino acid identity) between rat and mouse and 81% nucleic acid identity
(81% amino acid identity) between rat and human. The rat CB2 receptor was
stably expressed in human embryonic kidney-293 cells to examine its pharmac
ology. The rat CB2 showed low affinity for anandamide, an endogenous ligand
shown to act at the CB1 receptor. In contrast, high-affinity binding for S
R144528 (CB2-selective antagonist) as well as several cannabinoid receptor
agonists was observed. Coupling to adenylate cyclase was observed. Aspects
of the pharmacology of palmitoylethanolamide were also examined. It bound t
o CB1 and CB2 receptors with low affinity and stimulated GTP gamma S bindin
g in the cerebellum and CB2-expressing cell lines with low potency. The dat
a in this study suggest that the discrepancies in affinities between rat an
d human may represent species differences. The rat CB2 receptor genomic clo
ne will be a useful tool for studying the function and regulation of CB2 in
rats.