[Cannabinoid applications in glaucoma]. / Aplicaciones de los cannabinoides en glaucoma.

INTRODUCTION: Glaucoma is a slowly progressive optic neuropathy that is one of the leading causes of legal blindness throughout the world. Currently there is a limited group of topical drugs for the medical treatment of glaucoma is currently limited, and research needs to be focused on new therapeutic horizons, such as the potential usefulness of the cannabinoid agonists for the treatment of glaucoma. AIM: To review the current scientific literature related to the beneficial effects derived from the different ways of administration of cannabinoids indicated for the glaucomatous optic neuropathy. DEVELOPMENT: Cannabinoid receptors have shown an intense expression in ocular tissues implicated in the regulation of the intraocular pressure, as well as inner layers of the retina. Through activation of CB1 and CB1 specific receptors and through other still unknown pathways, the cannabinoid agonists have shown both a clear hypotensive, as well as an experimentally proved neuroprotective effect on retinal ganglion cells. CONCLUSIONS: Some cannabinoid agonists (WIN 55212-2, anandamide) have demonstrated, in experimental studies, to act as «ideal drugs¼ in the management of glaucoma, as they have been shown to have good tolerability after topical application, efficiently reduce intraocular pressure, and behave as neuroprotectors on retinal ganglion cells. Further studies as regards the safety and clinical assays must be carried out in order to examine the effectiveness of these drugs for the treatment of glaucoma in our daily clinical practice.

Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids.

Several studies have shown anxiolytic effects of cannabinoids after systemic or central injections. The periaqueductal gray matter is a midbrain structure involved in the control of anxiety states. Intra-cerebral administration of cannabidiol, a phytocannabinoid, or anandamide, an endocannabinoid, into the dorsolateral portion of periaqueductal gray (dlPAG) promotes anxiolytic-like effects in several animal models of anxiety with bell-shaped dose-response curves. The reasons for these curves are still unclear, but since these drugs can also activate TRPV1 receptors and increase glutamate release, we hypothesized that, at high doses, cannabidiol and WIN 55,212-2, a CB1 receptor agonist, could activate TRPV1 receptors, facilitating glutamate neurotransmission and anxiety responses. To test this hypothesis male Wistar rats with cannulae aimed toward the dlPAG were submitted to the following intra-dlPAG treatments: Experiment 1. Vehicle (0.2 microL) or WIN 55,212-2 (3-30 pmol); Experiment 2. Capsazepine (CPZ, 10 nmol, a TRPV1 receptor antagonist) or vehicle followed, 5 min later, by vehicle or WIN 55, 212-2 (10 or 30 pmol); Experiment 3. CPZ (10 nmol) or vehicle followed, 5 min later, by cannabidiol (30 or 60 nmol). Ten minutes after the last injection the animals were tested in the elevated plus maze (EPM). WIN 55,212-2 and cannabidiol induced anxiolytic effects at lower doses that disappeared at the higher dose. Although CPZ+WIN 10 or CPZ+WIN 30 pmol groups were not different from control (CPZ+V), capsazepine prevented the decrease in open arm exploration caused by the higher of dose of WIN 55,212-2 (30 nmol) relative to the lower dose of WIN 55,212-2 (10 nmol) and, in the case of cannabidiol (60 nmol), increased open arm exploration (V+CBD 60 group versus CPZ+CBD 60 group). These results suggest that TRPV1 receptors in the dlPAG modulate anxiety and that activation of these receptors by high doses of cannabinoids could be involved in the bell-shaped dose-response curves observed with these compounds.

Implication of the endocannabinoid system in the locomotor hyperactivity associated with congenital hypothyroidism.

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB(1)) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB(1) receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB(1) receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.