This study investigated the distribution of CB1 and VR1 receptors in rat cultured hippocampal and sensory cells and in the myenteric plexus of various rodents. CB1 and VR1 receptor-immunoreactivity was observed in a subset of neurones and their processes. Primary sensory neurones expressed CB1 receptors on their soma and fibres. The vast majority of CB1 receptor-expressing hippocampal neurones were GABAergic but appeared to be VR1 receptor-immunonegative. Cannabinoid agonists inhibited the expression of cell surface CB1 receptors in a concentration-dependent, stereoselective manner. This inhibition of cell surface labelling was maximal at 16 h, did not require the activation of Gi/o-proteins and was abolished in the presence of SR141716A, a selective CB1 receptor antagonist. A new primary antibody pre-labelling protocol demonstrated that this inhibition reflects agonist-induced internalisation and suggests that internalised CB1 receptors are translocated from axons towards somatodentritic regions. In F-11 cells, shown here to naturally express CB1 receptors on their somatic membrane, cannabinoid-induced internalisation occurred within a relatively short period (30 min). In the guinea-pig and rat myenteric plexus, virtually all CB1 and VR1 receptor- immunopositive cells were cholinergic. Subpopulations of calbindin-, calretinin- and neurofilament protein-immunopositive neurones co-expressed either receptor type. The localisation of VR1 receptors in calcitonin gene-related peptide-positive fibres and the expression of CB1 receptors in their somata implies a role for VR1 receptors in neuropeptide release and identified CB1 receptor-containing secretory neurones. There was also a close association between CB1 and VR1 receptor-immunoreactivity and fibres labelled for synaptic protein, suggesting roles for these receptors in the modulation of neurotransmitter release. These results are consistent with the inhibition by cannabinoids of neurotransmitter release and gastrointestinal transit and peristalsis. Internalisation of CB1 receptors may be a mechanism by which neurones control sensitivity to endocannabinoids and regulate the development of tolerance to cannabinoid drugs. The co-localisation studies in the gut identified intrinsic sensory, interneuronal and motor neurones expressing CB1 and VR1 receptors.