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Editors Selection IGR 13-3
Basic Research: Endocannabinoids and outflow
Comment by David Woodward & Larry Wheeler on:
21832 Aqueous humor outflow effects of 2-arachidonylglycerol, Njie YF; He F; Qiao Z et al., Experimental Eye Research, 2008; 87: 106-114
Njie et al. (947) add a new pathway of altering aqueous humor outflow and describe the effects of the natural mammalian endocannabinoid 2-arachidonyl glycerol (2-AG) on the trabecular meshwork. Convincing evidence that 2-AG increases aqueous humor outflow is provided and this effect is extended by preventing enzymatic hydrolysis with LY 2183240, a MAG-lipase inhibitor. The expression of MAG-lipase was also confirmed in TM tissue by Western blotting. No indirect evidence for the conversion of 2-AG breakdown products to prostanoids was apparent, the effect of 2-AG alone being a short mono-phasic increase in outflow facility. The pharmacology was investigated by using a selective CB1 antagonist (SR 141716 A) and a selective CB2 antagonist (SR 144528). Both CB1 and CB2 receptor blockade completely abolished the effects of 2-AG on outflow facility. This may seem counter-intuitive. If CB1 and CB2 were essentially equally involved in mediating 2-AG effects on outflow facility, then one of the following scenarios would be readily envisaged. A combination of CB1 and CB2 antagonists would be needed to abolish the response to 2-AG, with each individual antagonist showing little effect. The effect of 2-AG would be partially blocked by one selective antagonist, complete blockade afforded by the addition of the second antagonist. Nevertheless, there is at least Basic Research one precedent for the pharmacological phenomenon reported by the authors, whereby both CB1and CB2 antagonism equi-effectively abolish the 2-AG response. Similarly, both broad-spectrum anti-serotonergics and histamine H1-antagonists are both extremely efficacious in preventing carrageen in induced rat paw edema. The authors postulate CB1/CB2 receptor heterodimerization as a possible explanation. Evidence in the pharmacology literature and other disciplines that seven transmembrane G-protein receptors can exist and function as homo- and/or hetero dimers. Heterodimerization was suggested in this paper to explain the results but not tested by using CB1/CB2 co-transfectants. Neither CB antagonist affected baseline outflow facility. This strongly implies that endogenous 2-AG production does not physiologically regulate outflow facility. The lack of effect of LY 2183240 alone also supports this observation. Finally, it should be noted that 2-AG is unstable and rapidly re-arranges to 1,(3)-AG. Although 2-AG is initially the singular molecular species, it disappears as re-arrangement proceeds, which results in 1,(3)-AG becoming the predominant species. It is, therefore, difficult to judge in experiments employing 2-AG whether it is the starting material, 1,(3) 2-AG, or both that produce the biological effect. In future experiments, the relative roles of 2-AG and 1,(3)-AG could be elucidated by employing the corresponding chemically and metabolically stable analogs, serinolamide and N-propanediol respectively.
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