Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

Abstract

Human tissues express cannabinoid CB 1 and CB 2 receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB 1 /CB 2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; D 9 -tetrahydrocannabinol (D 9 -THC)) and Sativex (D 9 -THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB 2 receptors, and/or (v) adjunctive 'multi-targeting'.

A restricted population of CB 1 cannabinoid receptors with neuroprotective activity

“…Hence, from a translational point of view, it is tempting to speculate that the glutamatergic-neuron CB 1 receptor pool may constitute a therapeutic target to attenuate neurodegeneration in patients with HD. THC and other cannabinoids have a favorable drug safety profile and are already used in the clinic as antiemetic, anticachectic, antispastic, and analgesic compounds (36). Although exhaustive clinical studies are indeed necessary to assess whether cannabinoid-based medicines could be used for the management of neurodegenerative diseases, the findings reported here, by providing a specific neurobiological substrate for cannabinoidevoked neuroprotection in preclinically relevant models, may contribute to improving the development of therapeutic approaches aimed at targeting the glutamatergic-neuron CB 1 receptor population.…”

Astrocytes in endocannabinoid signalling

“…Involvement of astrocytes in endocannabinoid signalling in the brain pathology ECB signalling is altered in numerous neurological and neurodegenerative diseases, which has been proposed to result in the exacerbation or amelioration of certain brain disorders such as multiple sclerosis, post-traumatic stress disorder, traumatic brain injury and Parkinson's disease [57]. While brain disease mechanisms are largely considered to have a neuronal origin, increasing evidence suggests that disturbances of astrocyteneuron interactions are related to brain disorders [58,59].…”

Endocannabinoids in nervous system health and disease: the big picture in a nutshell

“…These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol), and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex) [46]. Pertwee [47] provides an up-to-date account of where the field stands and mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other types of pain, epilepsy, anxiety, depression, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis and hepatic, renal, intestinal and cardiovascular disorders.…”

“…As the bulk of this information derived mainly from preclinical research, there is a clear need for phase I clinical trials with healthy human subjects and phase II trials with patients. It will also be important to select the strategy that would be the one most likely to produce the greatest benefit-to-risk ratio in patients [47].…”