Intraocular pressure, ocular toxicity and neurotoxicity after administration of cannabinol or cannabigerol

doi:10.1016/0014-4835(84)90013-7

Experimental Eye Research

Volume 39, Issue 3, September 1984, Pages 251-259

https://doi.org/10.1016/0014-4835(84)90013-7 Get rights and content

Abstract

Cannabinol or cannabigerol was administered to cats topically in doses of 250, 500 and 1000 μg as a single drop or chronically via osmotic minipumps (20 μg hr⁻¹) over a period of 9 days. While cannabinol had a modest effect on intraocular pressure after a single dose, it caused a more significant reduction in ocular tension during chronic administration. Cannabigerol had similar effects, but the magnitude of response to its chronic administration was greater. Cannabinol but not cannabigerol caused conjuctival erythema and hyperemia. After systemic administration of cannabinol (20, 40 or 80 mg kg⁻¹) to rats, 8–13 Hz polyspike discharges appeared in the electrocorticogram during wakefulness and during rapid eye movement sleep episodes. Cannabigerol (10, 30 and 100 mg kg⁻¹) lacked this effect. These results indicate that chronic administration of these cannabinoids lowers ocular tension considerably. Like marihuana and delta-9-tetrahydrocannabinol, cannabinol produced both ocular toxicity and neurotoxicity. As cannabigerol lacked these toxicities, it appears that the ocular hypotensive effect of this cannabinoid is somewhat dissociable from both the adverse central and ocular effects accompanying marihuana intake.

References (21)

B.K. Colasanti et al.
Intraocular pressure, ocular toxicity and neurotoxicity after administration of Δ⁹-tetrahydrocannabinol or cannabichromene
Exp. Eye Res.
(1984)
K. Green et al.
Effect of Δ¹-tetrahydrocannabinol on aqueous dynamics and ciliary body permeability in the rabbit
Exp. Eye Res.
(1973)
K. Green et al.
A comparison of topical cannabinoids on intraocular pressure
Exp. Eye Res.
(1978)
R.S. Hepler et al.
Pupillary constriction after marihuana smoking
Am. J. Ophthalmol.
(1972)
F. Lipparini et al.
A neuropharmacological investigation of some trans-tetrahydrocannabinol derivatives
Physiol. Behav.
(1969)
J. Masur et al.
Induction by Cannabis sativa (marihuana) of rhythmic spike discharges overriding REM sleep electrocorticogram in the rat
Life Sci.
(1970)
J.H. Pirch et al.
Effects of acute and chronic administration of marihuana extract on the rat electrocorticogram
Neuropharmacology
(1972)
P.C. Will et al.
Polyethylene glycols as solvents in implantable osmotic pumps
J. Pharm. Sci.
(1980)
B. Colasanti et al.
Effects of delta-8-tetrahydrocannabinol on the voltage output of the EEG in the rat
B. Colasanti et al.
Electroencephalographic studies on the development of tolerance and cross tolerance to mescaline in the rat
Psychopharmacologia
(1975)

There are more references available in the full text version of this article.

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Role of cannabinoids in glaucoma: Lowering intraocular pressure or neuroprotection
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Glaucoma is a complex neurodegenerative disease that constitutes a cluster of different neuropathological changes. Primary open- and closed-angle glaucomas are the main cause of blindness associated with increased intraocular pressure and consequent damage to retinal ganglion cells and optic nerve. On the contrary, normal-tension glaucoma is triggered by other factors, including molecular, biological, environmental, and, importantly, aging. Growing evidence supports the presence of endogenous cannabinoid and cannabinoid receptor subtypes in different regions of the eye, indicating the role of cannabis in the pathogenesis of glaucoma. The use of cannabinoids as a treatment option for glaucoma is not approved yet in the absence of supporting clinical studies and due to unwanted side effects. However, it offers a promising therapeutic intervention in the progression and onset of glaucoma either by lowering IOP and/or neuroprotection.
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Citation Excerpt :
Importantly, acute and chronic administration of CBN has also been shown to reduce IOP in animal models. The electrocorticogram (ECoG) spikes observed with systemic administration of CBN were significantly less potent in comparison to Δ9-THC [45]. In agreement with these observations, herein, we demonstrated that CBN has an encouraging effect as a neuroprotectant as well as on reducing the ocular tone in our glaucoma models.
Glaucoma is characterized by progressive damage of the retinal ganglion cells (RGCs), resulting in irreversible vision loss. Cannabinoids (CBs) ameliorate several factors that contribute to the progression of glaucoma, including increased intraocular pressure (IOP), degeneration of RGC and optical nerve (ON) damage. However, a direct correlation of specific CBs with the molecular events pertaining to glaucoma pathology is not well established. Therefore, this study aims to evaluate the role of cannabinol (CBN) on RGC protection, modulation of IOP, and its effects on the level of extracellular matrix (ECM) proteins using both in vitro and in vivo models of glaucoma.
When exposed to elevated hydrostatic pressure, CBN, in a dose-dependent manner, protected differentiated mouse 661W retinal ganglion precursor-like cells from pressure-induced toxicity. In human trabecular meshwork cells (hTM), CBN attenuated changes in the ECM proteins, including fibronectin and α-smooth muscle actin (α-SMA), as well as mitogen-activated protein kinases (phospho-ERK1/2) in the presence or absence of transforming growth factor-beta 2 (TGF-β₂) induced stress. Ocular pharmacokinetic parameters were evaluated post-intravitreal (IVT) CBN delivery in vivo. Furthermore, we demonstrated that IVT-administered CBN improved pattern electroretinogram (pERG) amplitudes and reduced IOP in a rat episcleral vein laser photocoagulation model of glaucoma.
CBN promotes neuroprotection, abrogates changes in ECM protein, and normalizes the IOP levels in the eye. Therefore, our observations in the present study indicate a therapeutic potential for CBN in the treatment of glaucoma.
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Citation Excerpt :
Δ9THC, Δ8THC, and CBG reduce ocular pressure without altering aqueous humor production but enhancing aqueous humor outflow [56,57]. It has also been shown that CBN exhibits similar hypotensive properties and that CBG does not exhibit the adverse effects (e.g., ocular toxicity) due to Δ9THC or CBN [58]. The underlying physiological mechanisms of the differences in eye toxicity between these cannabinoids are intriguing.
While natural Δ⁹-tetrahidrocannabinol (Δ⁹THC), cannabidiol (CBD), and their therapeutic potential have been extensively researched, some cannabinoids have been less extensively investigated. The present article compiles data from the literature that highlight the health benefits and therapeutic potential of lesser known phytocannabinoids, which we have divided into varinic, acidic, and “minor” (i.e., cannabinoids that are not present in high quantities in common varieties of Cannabis sativa L). A growing interest in these compounds, which are enriched in some cannabis varieties, has already resulted in enough preclinical information to show that they are promising therapeutic agents for a variety of diseases. Every phytocannabinoid has a “preferential” mechanism of action, and often targets the cannabinoid receptors, CB₁ and/or CB₂. The recent resolution of the structure of cannabinoid receptors demonstrates the atypical nature of cannabinoid binding, and that different binding modes depend on the agonist or partial agonist/inverse agonist, which allows for differential signaling, even acting on the same cannabinoid receptor. In addition, other players and multiple signaling pathways may be targeted/engaged by phytocannabinoids, thereby expanding the mechanistic possibilities for therapeutic use.
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After the description of its chemical structure and synthesis in 1964, research on cannabigerol (CBG) progressed slowly, mainly due to its low concentration in the Cannabis plant. In fact, CBG is rapidly converted into its metabolites tetrahydrocannabinol (THC), cannabichromene (CBC), and cannabidiol (CBD). In recent years, a constellation of studies shone light onto CBG’s pharmacology and its potential medical applications. Literature highlights its numerous pharmacological properties ranging from adrenergic, serotoninergic, cannabinergic and transient receptor potential (TRP) actions, to the modulation of enzymes, such as cyclooxygenase, monoacyl glycerol lipase (MAGL), N-acylethanolamine acid amidase (NAAA) and phospholipase-A2 (PLA2). Possible medical applications of CBG found voice in several scientific publications some of which inspired the initiation of patents to protect its therapeutic uses. Current literature offers evidence of its potentials as an antiinflammatory and anticancer agent, to only cite a few, addressing interest on this phytocannabinoid as a potential starting material for new therapeutic agents. CBG owns a broad pharmacological activity, and the knowledge of its precise mechanism of action, as well as its still unknown clinical efficacy and possible adverse effects would unquestionably benefit from further research.
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In recent years, discovery of the cannabinoid receptors in the ocular tissues has opened up the possible utility of tetrahydrocannabinol (THC) and other cannabinoids in the management of several ocular diseases and conditions. The biopharmaceutical characteristics of THC, however, do not favor transmembrane diffusion. Additional physiological barriers, atypical of ocular drug delivery, makes THC delivery to the ocular tissues through the topical route even more challenging. Thus, careful formulation design and consideration is needed to translate the potential of THC into the preclinical and clinical settings. This chapter reviews some of the ocular conditions that can be impacted by THC, and the barriers to its delivery through the topical route. Strategies to improve ocular penetration of THC have also been discussed.

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Experimental Eye Research

Abstract

References (21)

Intraocular pressure, ocular toxicity and neurotoxicity after administration of Δ⁹-tetrahydrocannabinol or cannabichromene

Exp. Eye Res.

Effect of Δ¹-tetrahydrocannabinol on aqueous dynamics and ciliary body permeability in the rabbit

Exp. Eye Res.

A comparison of topical cannabinoids on intraocular pressure

Exp. Eye Res.

Pupillary constriction after marihuana smoking

Am. J. Ophthalmol.

A neuropharmacological investigation of some trans-tetrahydrocannabinol derivatives

Physiol. Behav.

Induction by Cannabis sativa (marihuana) of rhythmic spike discharges overriding REM sleep electrocorticogram in the rat

Life Sci.

Effects of acute and chronic administration of marihuana extract on the rat electrocorticogram

Neuropharmacology

Polyethylene glycols as solvents in implantable osmotic pumps

J. Pharm. Sci.

Effects of delta-8-tetrahydrocannabinol on the voltage output of the EEG in the rat

Electroencephalographic studies on the development of tolerance and cross tolerance to mescaline in the rat

Psychopharmacologia

Cited by (43)

Health benefits, pharmacological properties, and metabolism of cannabinol: A comprehensive review

Role of cannabinoids in glaucoma: Lowering intraocular pressure or neuroprotection

Cannabinol modulates neuroprotection and intraocular pressure: A potential multi-target therapeutic intervention for glaucoma

Pharmacological potential of varinic-, minor-, and acidic phytocannabinoids

Potential Medical Uses of Cannabigerol: A Brief Overview

Ocular Delivery of Tetrahydrocannabinol