Ocular Hypotensive Effects of an Intratracheally Delivered Liposomal Δ9-Tetrahydrocannabinol Preparation in Rats

Abstract

This study investigated the effect of an intratracheal (i.t.) administration of a liposome-entrapped Delta9-tetrahydrocannabinol (LTHC) preparation on intraocular pressure (IOP) in nonanaesthetized Brown Norway rats. The ocular hypotensive effects of i.t. LTHC were compared to that of intraperitoneal (i.p.) LTHC administration. All i.t. LTHC doses >0.05 mg/kg significantly decreased IOP (P < 0.05) within 30 min of administration, and doses of i.t. LTHC >0.1 mg/kg decreased IOP within 15 min of administration. A maximal reduction in IOP of 2.32 +/- 0.27 mmHg (n = 4) was seen with 1.0 mg/kg of i.t. LTHC. In comparison, no significant IOP drop was apparent prior to 30 min with all doses (0.01-1.0 mg/kg) of i.p. LTHC tested, although a similar maximum drop in IOP (2.15 +/- 0.12 mmHg; n = 8) was obtained with 1.0 mg/kg of LTHC. The ED(50) for i.t. and i.p. LTHC was 0.08 mg/kg and 0.12 mg/kg, respectively. The IOP-lowering effects of i.p. LTHC (0.2 mg/kg) were reduced by 14% and 80% by 0.25 mg/kg (n = 6) and 2.5 mg/kg (n = 6), respectively, of the CB1R antagonist, SR141716A. In conclusion, i.t. LTHC was superior to i.p. LTHC in producing a more rapid and potent decrease in IOP. The IOP-lowering effect of LTHC was blocked by the CB1R-selective antagonist, SR141716A, suggesting that CB1Rs contribute to the ocular hypotensive effect of Delta9-tetrahydrocannabinol.

TheIn VivoEffects of the CB1-Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice

“…The GAT229-induced increase in the duration of the IOP-lowering effect is in contrast to the relatively shortlived actions of acute orthosteric CB 1 activation by can-nabinoids, typically lasting only about 1-2 h after administration. [12][13][14]16,28,65,66 We found that whereas administration of 1% WIN alone reduced IOP for *1 h, the combination of subthreshold (0.25%) WIN with GAT229 reduced IOP for at least 6 h in normotensive mice. Duration of action is important when considering use as a clinically relevant therapeutic; drugs with short durations of action require frequent administration, which may lead to issues with patient compliance.…”

Indirect Sympatholytic Actions at β-Adrenoceptors Account for the Ocular Hypotensive Actions of Cannabinoid Receptor Agonists

“…IOP is the primary risk factor for glaucoma, a blinding neurodegenerative eye disease, and drugs that reduce IOP, so-called ocular hypotensives, are used in the treatment of glaucoma. Although the IOP-lowering ability of cannabinoid agonists is well established (Hepler and Frank, 1971;Liu and Dacus, 1987;Chien et al, 2003;Szczesniak et al, 2006), none have been developed for the treatment of glaucoma, largely because of a limited understanding of the mechanisms by which cannabinoids produce their effect on IOP.…”

Enhanced Solubility, Stability, and Transcorneal Permeability of Delta-8-Tetrahydrocannabinol in the Presence of Cyclodextrins

“…A number of pharmacological and histological studies strongly suggest direct role of ocular CB1 receptors in the lowering of the IOP by the cannabinoids (1,2). Additionally, Δ 9 -THC has also been reported to reduce glutamate and N-methyl-Daspartate-induced retinal ganglionic cell death through its CB1 agonist activity (1)(2)(3)(6)(7)(8)(9). Moreover, the antioxidant property of Δ 9 -THC protects neurons against oxidative stress associated with glutamate-induced excitotoxicity (2,8,9).…”

“…Additionally, Δ 9 -THC has also been reported to reduce glutamate and N-methyl-Daspartate-induced retinal ganglionic cell death through its CB1 agonist activity (1)(2)(3)(6)(7)(8)(9). Moreover, the antioxidant property of Δ 9 -THC protects neurons against oxidative stress associated with glutamate-induced excitotoxicity (2,8,9). Therefore, in contrast to currently available drugs, topical administration of Δ 9 -THC would not only reduce the IOP but would also protect the retinal ganglionic cells against glutamate and N-methyl-D-aspartate-induced neurotoxicity.…”