IOVS Journal of Virology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laine, K.
Right arrow Articles by Järvinen, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laine, K.
Right arrow Articles by Järvinen, T.
(Investigative Ophthalmology and Visual Science. 2002;43:3216-3222.)
© 2002 by The Association for Research in Vision and Ophthalmology, Inc.

Comparison of the Enzymatic Stability and Intraocular Pressure Effects of 2-Arachidonylglycerol and Noladin Ether, a Novel Putative Endocannabinoid

Krista Laine1,2, Kristiina Järvinen3, Raphael Mechoulam2, Aviva Breuer2 and Tomi Järvinen1

1 From the Departments of Pharmaceutical Chemistry and 3 Pharmaceutics, University of Kuopio, Finland; and the 2 Department of Medicinal Chemistry and Natural Products, Hebrew University, Jerusalem, Israel.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. The endogenous cannabinoids N-arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) are known to decrease intraocular pressure (IOP). Recently, a novel putative endogenous cannabinoid, noladin ether, was isolated in porcine and rat brains. In the present study, both the degradation of endogenous cannabinoids in ocular tissues and the effect on IOP of 2-AG and noladin ether were compared.

METHODS. The rates of enzymatic degradation for AEA, 2-AG, and noladin ether were determined in bovine cornea and iris-ciliary body homogenates. 2-AG and noladin ether were dissolved in either hydroxypropyl-ß-cyclodextrin (HP-ß-CD) or propylene glycol and administered unilaterally to the rabbit eye. IOPs were measured in the treated and untreated eyes. The CB1 receptor antagonist AM251 was administered topically 15 minutes before the cannabinoids to investigate whether CB1 receptors mediate the effect on IOP produced by 2-AG and noladin ether.

RESULTS. Noladin ether degraded more slowly than either 2-AG or AEA in the iris-ciliary body and cornea homogenates. The effect on IOP of 2-AG was biphasic (i.e., an initial increase in IOP followed by a reduction in the treated eye). Noladin ether decreased IOP immediately after topical administration, and no initial IOP increase was observed in the treated eye. The CB1 receptor antagonist AM251 (25 µg) blocked the effect on IOP of noladin ether but did not affect the action of 2-AG.

CONCLUSIONS. Topical administration of the novel putative endogenous cannabinoid noladin ether decreased IOP in rabbits. This IOP reduction was most probably mediated through the CB1 receptor. The effect on IOP of noladin ether differed from those of the known endogenous cannabinoids AEA and 2-AG, probably because of its more stable chemical structure.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Evidence for an endogenous cannabinoid system was obtained in 1988 when the first cannabinoid receptor was identified in rat brain.1 Presently, the endogenous cannabinoid system has been shown to include at least two major cannabinoid receptor subtypes, CB1 and CB2,1 2 in addition to two known endogenous ligands for cannabinoid receptors, N-arachidonylethanolamide (AEA)3 and 2-arachidonylglycerol (2-AG).4 5 Recently, a novel putative endogenous CB1 receptor ligand, noladin ether, was identified in porcine6 and rat7 brains. Chemically, noladin ether is the 2-glyceryl ether of arachidonyl alcohol and structurally resembles 2-AG (Fig. 1) .



View larger version (17K):
[in this window]
[in a new window]
  		Figure 1. The chemical structures of AEA, 2-AG, and noladin ether. Dashed box: the main differences in these structures from a degradation point of view.

 
Noladin ether has been shown to exhibit several cannabimetic actions that are typical for AEA and 2-AG, such as reduced locomotor activity, catalepsy, hypothermia, and antinociception.6 It has a demonstrated binding affinity for CB1 receptors in rat brain microsomal membranes, with an inhibition constant (Ki) of 21.2 ± 0.5 nM. A considerably lower binding affinity for CB2 receptors (Ki > 3 µM) has been reported for noladin ether in CB2-transfected COS cells.6 Noladin ether exhibits agonist activities toward cells expressing CB1 and CB2 receptors, as evaluated by estimating their capacities to induce Ca2+-currents.8

As with typical neurotransmitters, AEA and 2-AG are rapidly inactivated after their biosynthesis and release. Both endogenous cannabinoids are apparently transported into cells by a common carrier-mediated uptake mechanism.9 10 In cells, AEA is enzymatically hydrolyzed to arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH),11 whereas FAAH and the yet uncharacterized lipase activities are thought to be involved in the enzymatic hydrolysis of 2-AG to arachidonic acid.9 The cellular uptake of noladin ether has recently been suggested to occur through the endocannabinoid transporter.7

In this study, the enzymatic stabilities for 2-AG, AEA, and noladin ether were compared in bovine cornea and iris-ciliary body homogenates. It has already been demonstrated that various cannabinoids affect intraocular pressure (IOP) in rabbits12 13 14 15 and humans,16 particularly in patients with glaucoma who are resistant to conventional glaucoma therapies.17 For this reason, we examined the ability of noladin ether, the more enzymatically stable endocannabinoid, to decrease IOP in rabbits and compared its effect on IOP to those of 2-AG. Finally, we examined whether the effect on IOP of 2-AG and noladin ether were mediated through CB1 receptors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals
AEA was purchased from Deva Biotech (Hatboro, PA). 2-AG and arachidonic acid were obtained from Cayman Chemical (Ann Arbor, MI). Noladin ether (2-arachidonyl glycerol ether, HU-310) was synthesized as described earlier.6 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD, Encapsin, molecular weight [mw] = 1297.4, degree of molar substitution 0.4) was obtained from Janssen Biotech (Olen, Belgium), and the CB1 receptor antagonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) was purchased from Tocris Cookson (Bristol, UK). Propylene glycol was purchased from Oriola Oy (Espoo, Finland).

Preparation of Eye Homogenates for Degradation Study
Cornea and iris-ciliary body homogenates (20% wt/wt) were prepared as follows. Approximately 20 bovine eyes, obtained from a local abattoir (Atria Oy, Kuopio, Finland) were immediately rinsed with ice-cold 0.9% NaCl solution, and the corneas were dissected within 3 hours of death. Iris-ciliary bodies were detached from the eye as a single tissue sample. The removed eye tissues were cut into smaller pieces, weighed into separate centrifuge tubes and homogenized in tubes with four volumes of ice-cold isotonic 50 mM phosphate buffer (pH 7.4) using a homogenizer (model X-1020; Ystral, Ballrechten, Germany). The crude homogenates were centrifuged for 90 minutes at 9000g at 4°C (RC-26 Plus centrifuge; Sorvall DuPont, Newtown, CT). Pellets were discharged and supernatants were stored at -80°C until use. The protein concentrations, determined by using the Bradford method,18 were 7.1 mg/mL for cornea and 7.3 mg/mL for iris-ciliary body homogenates, respectively.

Degradation Study
The degradation rates for 2-AG, AEA, and noladin ether were determined in 10% bovine cornea and iris-ciliary body homogenates. An appropriate amount of test compound (initial concentrations were 0.7 mM for AEA and 2-AG and 0.1 mM for noladin ether) was dissolved in one volume of 50 mM isotonic phosphate buffer (pH 7.4) containing 0.1% ethanol. One volume of preheated cornea or iris-ciliary body homogenate was added, and the solution was incubated at 37°C in a water bath. At predetermined time intervals, 200-µL aliquots were withdrawn and immediately mixed with 400 µL ice-cold acetonitrile to terminate the reaction. After 5 minutes of centrifugation at 14,000 rpm (16,000g), the clear supernatant was assayed for remaining amounts of endogenous cannabinoid by HPLC.

HPLC Analysis
The analytical HPLC system (Hitachi Ltd., Tokyo, Japan) consisted of a pump (model L-7100), interface module (model L-7000), diode array detector (model L-7455; 200–400 nm, set at 211 nm) and a programmable autosampler (model L-7250). An endcapped reversed-phase column (125 mm x 4 mm, 5 µm; Purospher RP-18; VWR International, Niittyrinne, Finland), protected with an end-capped guard column (4 mm x 4 mm, 5 µm), was used for chromatographic separations.

Isocratic elutions for the hydrolysis studies in bovine iris-ciliary body and cornea homogenates were performed with a mobile phase mixture of 18% phosphate buffer (20 mM, pH 3.0) in acetonitrile at a flow rate of 1.2 mL/min. The concentrations of the eye drops were determined by a gradient method, in which the mobile phase consisted of 20 mM monobasic potassium phosphate buffer (20 mM, pH 7.0) in acetonitrile. The proportion of acetonitrile was linearly increased from 60% to 90% during a 15-minute period, maintained at a 5-minutes plateau, and subsequently returned to the initial concentration during the course of 6 minutes.

Preparation of Eye Drop Solutions
2-AG and noladin ether were dissolved either in HP-ß-CD solutions or propylene glycol. The aqueous eye drop solutions were adjusted to pH 7.4 with 0.1 M sodium hydroxide solution, and the solutions were made isotonic with sodium chloride. Final eye drop concentrations in HP-ß-CD were 1.25 mg/mL (12.5% HP-ß-CD) and 2.5 mg/mL (25% HP-ß-CD) for 2-AG and 0.625 (6.25% HP-ß-CD) and 2.5 mg/mL (25% HP-ß-CD) for noladin ether.

2-AG was dissolved in propylene glycol to concentrations of 0.3125, 1.25, and 5 mg/mL and noladin ether to a concentration of 5 mg/mL. A 25% HP-ß-CD solution or propylene glycol was used as a control vehicle in the IOP studies. The CB1 receptor antagonist AM251 was dissolved in 45% HP-ß-CD to a concentration of 0.5 mg/mL.

Animals
Normotensive pigmented Dutch belted rabbits (2.4–3.6 kg, n = 6) or New Zealand White albino rabbits (3.0–4.0 kg, n = 6), of both sexes, were used as experimental animals. The rabbits were housed singly in cages under controlled illumination (12-hour light-dark cycle, with lights-on at 7:00 A.M.) and environmental conditions (temperature, 20.0 ± 0.5°C, 55%–75% relative humidity). The rabbits were given water and food ad libitum, except during the experiments. All animals were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

IOP Measurements
For each experiment, rabbits were placed in plastic restraining boxes that were located in a quiet room. A drop (25–50 µL) of test solution was instilled unilaterally into the left eye on the upper corneoscleral limbus. During installation, the upper eyelid was gently pulled slightly away from the globe. IOP was measured by using a pneumatonometer (Digilab Modular One; Bio-Rad, Cambridge, MA) for pigmented rabbits or a handheld tonometer (Tonopen XL; Mentor, Norwell, MA) for albino rabbits. Before each measurement, 1 or 2 drops of topical anesthetic (0.04% oxybuprocaine) was applied to reduce discomfort. For every determination, at least two readings were taken from each treated (ipsilateral) and untreated (contralateral) eye, and the mean of these readings were used. IOP was measured at 1 hour before administration, then at 0, 0.5, 1, 2, 3, 4, and 5 hours after application of the eye drops. IOP at the time of administration of the eye drops (0 hour) was used as a baseline value. All IOP studies begun at 8:30 A.M., and were set up according to a nonbblinded, randomized, crossover design. At least 72 hours of washout time was allowed for each rabbit between doses. In the CB1 antagonism experiments, AM251 was administered topically 15 minutes before the topical administration of either 2-AG or noladin ether.

Statistical Analysis
The IOP results are presented as a change in IOP (% of the baseline) mean ± SE of the mean. The statistical analysis was performed on computer (SPSS ver. 11.0 for Windows; SPSS, Inc., Chicago, IL), and a two-way analysis of variance (ANOVA) for repeated measures with Bonferroni correction was used to compare treated and untreated groups. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Degradation Rate of the Endocannabinoids in Eye Homogenates
The half-lives (t1/2, mean ± SD) of AEA and 2-AG in 10% bovine iris-ciliary body homogenate were 8.7 ± 3.8 minutes (n = 3) and 3.1 ± 0.9 minutes (n = 3), respectively. The corresponding t1/2 in 10% bovine cornea homogenate were 178.7 ± 21.2 minutes for AEA (n = 3) and 19.1 ± 2.6 minutes for 2-AG (n = 3), respectively. The hydrolysis of AEA and 2-AG followed pseudo first-order kinetics in the iris-ciliary body (Fig. 2) and cornea homogenates, and their main degradation products eluted at the retention time of a synthetic arachidonic acid standard (Fig. 3) .



View larger version (16K):
[in this window]
[in a new window]
  		Figure 2. Pseudo first-order plots for the enzymatic degradation of 2-AG ({circ}), AEA ({blacksquare}), and noladin ether ({blacktriangleup}) in 10% (wt/wt) bovine iris-ciliary body homogenate at 37°C (pH 7.4).

 


View larger version (15K):
[in this window]
[in a new window]
  		Figure 3. A representative HPLC chromatogram of a sample after a 5-minute incubation of AEA (A) and 2-AG (B) and after a 90-minute incubation of noladin ether (C) in 10% (wt/wt) bovine iris-ciliary body homogenate at 37°C (pH 7.4). (D) Sample after incubation with 10% iris-ciliary body homogenate only. AA, arachidonic acid.

 
Noladin ether degraded much more slowly in bovine iris-ciliary body (t1/2 = 430.0 ± 0.0 minute; n = 2) and cornea homogenate (t1/2 = 1128.7 ± 532.1 minutes; n = 2) than either AEA or 2-AG. Noladin ether did not degrade to arachidonic acid during the incubation time (120 minutes; Fig. 3 ). The iris-ciliary body homogenate contained low levels of arachidonic acid itself, as the HPLC chromatogram showed (Fig. 3D) . These endogenous arachidonic acid levels corresponded with the amounts found in the noladin ether samples (Fig. 3C) .

Effect on IOP
2-AG was administered topically, either in aqueous HP-ß-CD or propylene glycol vehicle. The effect on IOP of 2-AG in the treated eyes of pigmented rabbits are summarized in Table 1 . Topical administration of 2-AG in the HP-ß-CD vehicle induced a dose-dependent increase in IOP followed by a decrease that was, however, not statistically significant. The maximum IOP reduction (-15.4% ± 6.4%) produced by 2-AG in the HP-ß-CD vehicle was obtained at 2 hours after application (Table 1) . A similar dose-dependent IOP profile was obtained for 2-AG when it was administered in a propylene glycol vehicle (Table 1) .


View this table:
[in this window]
[in a new window]
  		Table 1. Changes in IOP in the Treated Eyes of Pigmented Rabbits after Administration of 2-AG in HP-ß-CD or Propylene Glycol Vehicle

 
In contrast, noladin ether decreased IOP in the treated eyes immediately after topical administration in normotensive pigmented rabbits (Table 2) . A maximum decrease in IOP was obtained at 2 hours after the topical administration of noladin ether, and it varied between -10.3% ± 1.5% and -17.3% ± 1.6%, depending on the dose and vehicle used. In albino rabbits, noladin ether also decreased IOP in the treated eyes immediately after administration. The maximal IOP reduction (-17.7% ± 2.7%) in albino rabbits was obtained at 3 hours post-dosing at a dose of 125 µg, when given in the propylene glycol vehicle (Table 3) . The differences between the IOP profiles induced by topical 2-AG and noladin ether treatments in the treated eyes of pigmented rabbits are illustrated in Figure 4 . Neither 2-AG nor noladin ether treatments significantly affected IOP in the untreated eyes (data not shown).


View this table:
[in this window]
[in a new window]
  		Table 2. Changes in IOP in the Treated Eyes of Pigmented Rabbits after Administration of Noladin Ether in HP-ß-CD or Propylene Glycol Vehicle

 

View this table:
[in this window]
[in a new window]
  		Table 3. Changes in IOP in the Treated Eyes of Albino Rabbits after Administration of Noladin Ether in Propylene glycol vehicle

 


View larger version (29K):
[in this window]
[in a new window]
  		Figure 4. (A) Changes in IOP (% ± SE, n = 6) in the treated eyes of normotensive pigmented rabbits after the unilateral topical administration of 62.5 µg 2-AG ({square}) or 25% HP-ß-CD vehicle ({blacksquare}) and (B) after the unilateral topical administration of 62.5 µg noladin ether ({circ}) or 25% HP-ß-CD vehicle (•). *Statistically significant from vehicle data at the 95% confidence level (P < 0.05, two-way ANOVA with Bonferroni correction).

 
Antagonism of the Effect on IOP
To investigate whether the effect on IOP of either 2-AG or noladin ether were dependent on the CB1 receptors, pigmented rabbits were pretreated with the CB1 receptor antagonist AM251. The biphasic IOP effects of 2-AG (62.5 µg in 25% HP-ß-CD) were not influenced by AM251 (25 µg; Fig. 5A ). In contrast, the same dose of AM251 blocked the reduction of IOP induced by noladin ether (62.5 µg in 25% HP-ß-CD; Fig. 5B ). Topical administration of AM251 without the CB1 agonist did not have any recordable effect on the IOP of pigmented rabbits. Overall, the IOP changes varied between +3.3% ± 1.7% and -1.3% ± 1.9% after the topical administration of AM251 (25 µg) alone and were not statistically significant compared with the effect of treatment with 25% HP-ß-CD vehicle.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 5. (A) Effect of topically administered 2-AG (62.5 µg) on the IOP of rabbits with ({blacksquare}) or without ({square}) topical CB1 antagonist AM251 (25 µg) pretreatment. (B) Effect on IOP of noladin ether (62.5 µg) with (•) or without ({circ}) pretreatment with AM251 (25 µg) in rabbits. *Statistically significant difference between the treatments (P < 0.05, two-way ANOVA with Bonferroni correction).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Recently, a third putative endogenous cannabinoid, noladin ether, was isolated from porcine6 and rat brains.7 Noladin ether is chemically the 2-glyceryl ether of arachidonyl alcohol and thus differs from the previously identified endogenous cannabinoids AEA and 2-AG, which are the ethanolamide and glyceryl ester of arachidonic acid, respectively.

The present results demonstrate that noladin ether degraded at a significantly slower rate than either 2-AG or AEA in 10% bovine iris-ciliary body and cornea homogenates. The hydrolysis rates decreased in the order of 2-AG > AEA > noladin ether in both eye homogenates. These results can be explained by the fact that various esterases19 as well as FAAH-like enzyme activities20 21 are present in the eye, whereas relevant ocular enzymes for cleaving ether functional groups are probably not present. The higher hydrolysis rate for 2-AG, compared with AEA, may be because FAAH has been reported to hydrolyze 2-AG at a rate four times faster than AEA.22 In addition, these biological tissues are well known to be rich in enzymes that are capable of hydrolyzing esters. The main degradation product for AEA and 2-AG in the eye homogenates was arachidonic acid (Fig. 3) , but no arachidonic acid was formed from noladin ether during its incubation in 10% cornea and iris-ciliary body homogenates. The slow hydrolysis rate of noladin ether may raise the question of whether noladin ether is actually an endogenously produced cannabinoid receptor ligand in the ocular tissues studied. However, Fezza et al.7 have very recently suggested a shared cellular uptake for noladin ether with 2-AG and AEA, and its subsequent slow incorporation into phospholipids as an elimination mechanism in intact C6 glioma cells.

The topically administered AEA typically produces an initial IOP hypertension followed by a significant IOP reduction in the treated eye.12 23 This biphasic IOP profile for AEA is thought to be due to its rapid hydrolysis to arachidonic acid, which is subsequently biosynthesized to prostanoids that are responsible for effect on IOP.13 24 By contrast, synthetic cannabinoids, such as CP55940 and WIN55212-2, decrease IOP without an initial increase in IOP.15 25 When the effect on IOP of topically administered 2-AG and noladin ether were compared, 2-AG induced an initial IOP increase and subsequent reduction of IOP in rabbits, as reported earlier by Pate et al.14 The IOP profile of noladin ether differed from the profiles induced by other endogenous cannabinoids, because noladin ether decreased IOP immediately after topical administration without any initial elevation in IOP. On the basis of the differences in IOP profiles and degradation data (Fig. 3) , our results suggests that 2-AG is hydrolyzed, similar to AEA, to arachidonic acid in the eye, whereas noladin ether is eventually degraded to a metabolite other than arachidonic acid.

A CB1 receptor antagonist AM25126 was administered topically to study whether the IOP effects of 2-AG and noladin ether are mediated through the CB1 receptors in rabbits. AM251 blocked the IOP reduction caused by topical noladin ether but did not affect the IOP profile of 2-AG. This finding further strengthens the hypothesis that the CB1 receptors participate in the IOP effects of noladin ether. The effect on IOP of 2-AG is mediated through an alternative mechanism, most probably through its prostanoid metabolite(s). Earlier, we reported that the biphasic effect on IOP of topical AEA is not antagonized by the CB1 receptor antagonist SR141716A,25 which is also suggestive of an active prostanoid metabolite(s).

In conclusion, the present study shows for the first time that the topical administration of the putative endogenous cannabinoid, noladin ether, decreases IOP in rabbits. The present results suggest that the effects on IOP of noladin ether are mediated through the ocular CB1 receptors, whereas the effects on IOP of 2-AG are most probably mediated by its arachidonic acid metabolites. These data also demonstrate that noladin ether is the first endogenous cannabinoid identified that does not degrade to arachidonic acid after topical administration.


   Acknowledgements
 
The authors thank Pirjo Halonen (University of Kuopio, Kuopio, Finland) for guidance with the statistical analysis of the data and James Callaway for comments regarding the language in the manuscript.


   Footnotes
 
Supported by the Academy of Finland, the National Technology Agency of Finland, the Kuopio University Foundation, the Emil Aaltonen Foundation, the Finnish Pharmaceutical Association, the National Institute of Drug Abuse (RM) and the Israel Science Foundation (RM).

Submitted for publication October 29, 2001; revised May 13, 2002; accepted May 29, 2002.

Commercial relationships policy: P (RM, AB); N (KL, KJ, TJ).

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Krista Laine, Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland; krista.laine{at}uku.fi.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Devane, WA, Dysarz, FA, III, Johnson, MR, et al (1988) Determination and characterization of a cannabinoid receptor in rat brain Mol Pharmacol 34,605-613[Abstract]
  2. Munro, S, Thomas, KL, Abu-Shaar, M. (1993) Molecular characterization of a peripheral receptor for cannabinoids Nature 365,61-65[Medline][Order article via Infotrieve]
  3. Devane, WA, Hanus, L, Breuer, A, et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor Science 258,1946-1949[Abstract/Free Full Text]
  4. Mechoulam, R, Ben-Shabat, S, Hanus, L, et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors Biochem Pharmacol 50,83-90[Medline][Order article via Infotrieve]
  5. Sugiura, T, Kondo, S, Sukagawa, A, et al (1995) 2-Arachidonylglycerol: a possible endogenous cannabinoid ligand in brain Biochem Biophys Res Commun 215,89-97[Medline][Order article via Infotrieve]
  6. Hanus, L, Abu-Lafi, S, Fride, E, et al (2001) 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor Proc Natl Acad Sci USA 98,3662-3665[Abstract/Free Full Text]
  7. Fezza, F, Bisogno, T, Minassi, A, et al (2002) Noladin ether, a putative novel endocannabinoid: inactivation mechanisms and a sensitive method for its quantification in rat tissues FEBS Lett 512,249-298[Medline][Order article via Infotrieve]
  8. Suhara, Y, Takayama, H, Nakane, S, et al (2000) Synthesis and biological activities of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, and its metabolically stable ether-linked analogues Chem Pharm Bull 48,903-907
  9. Beltramo, M, Piomelli, D. (2000) Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol Neuroreport 11,1231-1235[Medline][Order article via Infotrieve]
  10. Bisogno, T, Maccarrone, M, De Petrocellis, L, et al (2001) The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors Eur J Pharmacol 268,1982-1989
  11. Deutsch, DG, Chin, SA. (1993) Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist Biochem Pharmacol 46,791-796[Medline][Order article via Infotrieve]
  12. Mikawa, Y, Matsuda, S, Kanagawa, T, et al (1997) Ocular activity of topically administered anandamide in the rabbit Jpn J Ophthalmol 41,217-220[Medline][Order article via Infotrieve]
  13. Pate, DW, Järvinen, K, Urtti, A, et al (1996) Effects of topical anandamides on intraocular pressure in normotensive rabbits Life Sci 58,1849-1860[Medline][Order article via Infotrieve]
  14. Pate, DW, Järvinen, K, Urtti, A, et al (1997) Effects of topical alpha-substituted anandamides on intraocular pressure in normotensive rabbits Pharm Res 14,1738-1743[Medline][Order article via Infotrieve]
  15. Song, ZH, Slowey, CA. (2000) Involvement of cannabinoid receptors in the intraocular pressure-lowering effects of WIN55212-2 J Pharmacol Exp Ther 292,136-139[Abstract/Free Full Text]
  16. Hepler, RS, Frank, IM. (1971) Marijuana smoking and intraocular pressure J Am Med Assoc 217,1392
  17. Porcella, A, Maxia, C, Gessa, GL, et al (2001) The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies Eur J Neurosci 13,409-412[Medline][Order article via Infotrieve]
  18. Bradford, MM. (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding Anal Biochem 72,248-254[Medline][Order article via Infotrieve]
  19. Nakamura, M, Shirasawa, E, Hikida, M. (1993) Characterization of esterases involved in the hydrolysis of dipivefrin hydrochloride Ophthalmic Res 25,46-51[Medline][Order article via Infotrieve]
  20. Matsuda, S, Kanemitsu, N, Nakamura, A, et al (1997) Metabolism of anandamide, an endogenous cannabinoid receptor ligand, in porcine ocular tissues Exp Eye Res 64,707-711[Medline][Order article via Infotrieve]
  21. Bisogno, T, Delton-Vandenbroucke, I, Milone, A, et al (1999) Biosynthesis and inactivation of N-arachidonoylethanolamine (anandamide) and N-docosahexaenoylethanolamine in bovine retina Arch Biochem Biophys 370,300-307[Medline][Order article via Infotrieve]
  22. Goparaju, SK, Ueda, N, Yamaguchi, H, et al (1998) Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand FEBS Lett 422,69-73[Medline][Order article via Infotrieve]
  23. Pate, DW, Järvinen, K, Urtti, A, et al (1995) Ophthalmic arachidonyl ethanolamide decreases intraocular pressure in normotensive rabbits Curr Eye Res 14,791-794[Medline][Order article via Infotrieve]
  24. Laine, K, Järvinen, K, Pate, DW, et al (2002) Effect of the enzyme inhibitor phenylmethylsulfonyl fluoride on the IOP profiles of topical anandamides Invest Ophthalmol Vis Sci 43,393-397[Abstract/Free Full Text]
  25. Pate, DW, Järvinen, K, Urtti, A, et al (1998) Effect of the CB1 receptor antagonist, SR141716A, on cannabinoid-induced ocular hypotension in normotensive rabbits Life Sci 63,2181-2188[Medline][Order article via Infotrieve]
  26. Lan, R, Liu, Q, Fan, P, et al (1999) Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists J Med Chem 42,769-776[Medline][Order article via Infotrieve]



This article has been cited by other articles:


Home page
 IOVSHome page
C. Nucci, V. Gasperi, R. Tartaglione, A. Cerulli, A. Terrinoni, M. Bari, C. De Simone, A. F. Agro, L. A. Morrone, M. T. Corasaniti, et al.
Involvement of the Endocannabinoid System in Retinal Damage after High Intraocular Pressure-Induced Ischemia in Rats
Invest. Ophthalmol. Vis. Sci., July 1, 2007; 48(7): 2997 - 3004.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
P. Pacher, S. Batkai, and G. Kunos
The Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pharmacol. Rev., September 1, 2006; 58(3): 389 - 462.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
Y. F. Njie, A. Kumar, Z. Qiao, L. Zhong, and Z.-H. Song
Noladin Ether Acts on Trabecular Meshwork Cannabinoid (CB1) Receptors to Enhance Aqueous Humor Outflow Facility
Invest. Ophthalmol. Vis. Sci., May 1, 2006; 47(5): 1999 - 2005.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
K. Nithipatikom, M. P. Endsley, M. A. Isbell, J. R. Falck, Y. Iwamoto, C. J. Hillard, and W. B. Campbell
2-Arachidonoylglycerol: A Novel Inhibitor of Androgen-Independent Prostate Cancer Cell Invasion
Cancer Res., December 15, 2004; 64(24): 8826 - 8830.
[Abstract] [Full Text] [PDF]

Home page
 Br. J. Ophthalmol.Home page
I Tomida, R G Pertwee, and A Azuara-Blanco
Cannabinoids and glaucoma
Br. J. Ophthalmol., May 1, 2004; 88(5): 708 - 713.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
A. B. El-Remessy, I. E. Khalil, S. Matragoon, G. Abou-Mohamed, N.-J. Tsai, P. Roon, R. B. Caldwell, R. W. Caldwell, K. Green, and G. I. Liou
Neuroprotective Effect of(-){Delta}9-Tetrahydrocannabinol and Cannabidiol in N-Methyl-D-Aspartate-Induced Retinal Neurotoxicity: Involvement of Peroxynitrite
Am. J. Pathol., November 1, 2003; 163(5): 1997 - 2008.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laine, K.
Right arrow Articles by Järvinen, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laine, K.
Right arrow Articles by Järvinen, T.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS