PubMed · 16026306
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María L López-Rodríguez. 2005. Cannabinoids.. https://doi.org/10.2174/1389557054368835
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BACKGROUND AND PURPOSE: The CB2 receptor has been proposed as a novel target for the treatment of pain, and CB2 receptor agonists defined in in vitro assays have demonstrated analgesic activity in animal models. Based on its in vivo analgesic efficacy, AM1241 has been classified as a CB2-selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported. EXPERIMENTAL APPROACH: In this study, AM1241 was characterized across multiple in vitro assays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB2 and CB1 receptors and its functional efficacies at the human CB2 receptor. KEY RESULTS: AM1241 exhibited distinct functional properties depending on the assay conditions employed, a unique profile in contrast to those of the agonist CP 55,940 and the inverse agonist SR144528. AM1241 displayed neutral antagonist activities in FLIPR and cyclase assays. However, when cyclase assays were performed using lower forskolin concentrations for stimulation, AM1241 exhibited partial agonist efficacy. In addition, it behaved as a partial agonist in ERK (or MAP) kinase assays. CONCLUSIONS AND IMPLICATIONS: The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB2 receptor. We postulate that functional efficacies displayed by protean agonists in various assay systems may depend on the levels of receptor constitutive activities exhibited in the assay systems, and therefore, efficacies observed in in vitro assays may not predict in vivo activities.
The results of recent clinical trials of medicinal cannabinoid drugs show that dizziness and vertigo are commonly reported adverse side-effects. Cannabinoid CB1 receptors were initially thought to be expressed in very low densities in the vestibular nucleus complex (VNC). Recent immunohistochemical studies have challenged this idea and suggested that CB1 receptors may exist in numbers similar to the granule cell layer of the cerebellum. This, together with evidence that brainstem CB1 receptors have a higher efficacy than those in many other parts of the brain and that application of cannabinoids can elicit potent electrophysiological effects in VNC neurons, suggests that CB1 receptors and their endogenous ligands may be important in central vestibular function. In this review, we consider the potential clinical significance of the endocannabinoid system for the development of vestibular disorders, the effects of recreational cannabis use and the therapeutic use of medicinal cannabinoids.
In order to assess the current knowledge on the therapeutic potential of cannabinoids, a meta-analysis was performed through Medline and PubMed up to July 1, 2005. The key words used were cannabis, marijuana, marihuana, hashish, hashich, haschich, cannabinoids, tetrahydrocannabinol, THC, dronabinol, nabilone, levonantradol, randomised, randomized, double-blind, simple blind, placebo-controlled, and human. The research also included the reports and reviews published in English, French and Spanish. For the final selection, only properly controlled clinical trials were retained, thus open-label studies were excluded. Seventy-two controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, and in the treatment of multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy and glaucoma.