#5 Lex Pelger's Endocannabinoid System & Cannabinoids: 2-AG

#5 Lex Pelger's Endocannabinoid System & Cannabinoids:  2-AG

2-AG is the shorthand name for the second endocannabinoid ever discovered. The team of Dr. Mechoulam first isolated 2-Arachidonoylglycerol in 1995 from the guts of a dog. It occurs at higher levels in the brain than anandamide though it has less affinity for binding to the cannabinoid receptors. And if you catch a cannabinoid scientist at a bar during a conference, she might be heard to mutter that 2-AG may well be more important than anandamide - though more research is needed on this still mysterious molecule.

The hemp activist Bill Althouse describes 2-AG as the Paul Revere wandering through every little town of your wellness centers, alerting the troops to get ready to fight, a reboot that resets your system and looks for new problems.

When they first administered 2-AG to mice, they saw the same tetrad of effects that one sees from THC: pain reduction, immobility, reduction of spontaneous activity and a lower rectal temperature. Like anandamide, 2-AG is also synthesized on demand and it functions as a retrograde synaptic messenger to calm the brain. In certain synapses of the brain, it might even take the combined power of anandamide and 2-AG to engage the CB1 receptor fully.

Since 2-AG binds to both the CB1 receptor and the CB2 receptor more strongly than anandamide, it’s been called the true natural ligand for both receptors and has been implicated in a remarkably long list of biological responses.

Because it’s rapidly produced when needed, 2-AG acts as a fast signaller within a cell. In addition, since it’s a molecule permeable to the membrane, it’s also released to the extracellular fluid to become an intracellular mediator.

That’s especially important in long-term potentiation. That’s when the strength of a synapse is increased by its frequent stimulation. See the work of Eric Kandel for more on the biochemical basis of memory. Long-term potentiation underlies what we know of how memories are stored in the brain and it turns out that 2-AG appears to be necessary for the extinction of memories. That might not seem like a good thing until you consider that the removal or dampening of memories of the trauma that caused PTSD would be a treatment.

Another area of neuroprotection are the many studies that showed 2-AG to lower neuronal excitation. By keeping the brain from over-firing, it protects it. This paper by Panikashvili showed the protection of 2-AG in a mouse brain injury. Surprisingly, the injection of 2-AG caused a significant reduction in brain edema, reduced cell death in the hippocampus area, and improved the recovery after closed head injury. In a mouse model trial for multiple sclerosis, activating the cannabinoid receptors caused less spasticity and tremors.

[could also insert here about anxiety and drug addiction - but doesn’t seem like the right place]

For the importance we’ve learned so far, we’ll turn to the beginning of life. A group in Portugal learned that during pregnancy, 2-AG is essential to the formation of a placenta. Other research found out that the levels of 2-AG in a mouse’s brain peaks right after birth and that the endocannabinoid is a key component of milk. For this reason, there might be a clinical application for infants with failure to thrive and suckle. 

Also, with inflammation being one of the hottest topics in medical schools, the relation of 2-AG to inflammation and tissue injury is very intriguing. In diseases like endotoxic shock, severe congestive heart failure and arthritis, more 2-AG is found floating around in the blood - a response to the body’s lack of homeostatic balance.

In a series of studies that seem particularly cruel, 2-AG was also found to increase as a response to insult. If you hold someone upside down for thirty minutes (hemodynamic stress) or shock their system with a parabolic flight (the Vomit Comet) or the psychological awfulness of a Trier social stress test, the levels of 2-AG circulating in the blood go up in protective response. In patients with severe depression, they had less 2-AG in their bloodstream.

2-AG and anxiety

The endocannabinoid system has been shown to be involved in the regulation of anxiety. Several investigators have reported that the administration of SR141716A induced anxiety-like responses in experimental animals at least under certain conditions. Recently, Patel et al. demonstrated that hypothalamic 2-AG content decreased upon exposure to acute restraint and increased after 5 days of restraint. 2-AG within the hypothalamus may have an important role in dampening the hypothalamic–pituitary–adrenal axis under normal conditions. It was also reported that chronic stress downregulated the expression of the CB1 receptor and reduced the amount of 2-AG in the hippocampus and increased 2-AG levels in the limbic forebrain and amygdala. These results suggest that 2-AG is involved in the modulation of anxiety, yet the details remain to be clarified.

2-AG, the reward system, and addiction 

Another possible role of the endocannabinoid system in the brain is in the reward system. Treatment of young mice with SR141716A reduced ethanol preference. A reduction in ethanol preference was also observed among CB1 receptor−/− mice and no effect of SR141716A was apparent in these mice. These observations point to the possible involvement of endocannabinoids in addiction to alcohol. As for 2-AG, several investigators have demonstrated that chronic treatment of animals with drugs such as nicotine, cocaine, morphine, ethanol and Δ9-THC resulted in an increase or decrease in the levels of 2-AG in the whole brain or certain areas of the brain. Exposure of neuronal cells to ethanol in vitro also led to an increase in the level of 2-AG. Notably, Yamaguchi et al. demonstrated that the administration of 2-AG suppressed both jumping and forepaw tremors, signs of withdrawal, in morphine-dependent mice challenged with naloxone, as in the case of the administration of Δ8-THC or HU210. These observations suggest that 2-AG plays a part in drug addiction and withdrawal. Apparently, however, sufficient information has not yet been accumulated as to this important issue. Further studies are needed to unveil the functions of 2-AG in the reward system and drug and alcohol preference.

And in an additional complication of interest, it seems that the metabolites of 2-AG might also be active. That is to say, if an enzyme cuts this lipid in half, those pieces seem to have downstream effects as well.

With levels higher than anandamide and strong implications of its involvement in some of the most important systems of the body, research suggesting a key role for 2-AG in biological systems is increasing every year. 

For the importance we’ve learned so far, we’ll turn to the beginning of life. A group in Portugal learned that during pregnancy, 2-AG is essential to the formation of a placenta. Other research found out that the levels of 2-AG in a mouse’s brain peaks right after birth and that the endocannabinoid is a key component of milk. For this reason, there might be a clinical application of infants with failure to thrive and suckle. 

Also, with inflammation being one of the hottest topics in medical schools, the relation of 2-AG to inflammation and tissue injury is very intriguing. In diseases like endotoxic shock, severe congestive heart failure and arthritis, more 2-AG is found floating around in the blood - a response to the body’s lack of homeostatic balance.

In a series of studies that seem particularly cruel, 2-AG was also found as a response to insult. If you hold someone upside down for thirty minutes (hemodynamic stress) or shock their system with a parabolic flight (the Vomit Comet) or the psychological awfulness of a Trier social stress test, the levels of 2-AG circulating in the blood go up in protective response. In patients with severe depression, they had less 2-AG in their bloodstream.

And in an additional complication of interest, it seems that the metabolites of 2-AG might also be active. That is to say, if an enzyme cuts this lipid in half, those pieces seem to have downstream effects as well.

With levels higher than anandamide and strong implications of its involvement in some of the most important systems of the body, research suggesting a key role for 2-AG in biological systems is increasing every year.