Previously Unknown Function Of A Cannabinoid Receptor Identified

[Norby]

http://neurosciencenews.com/cb2-cannabinoid-receptor-hippocampus-4147/

 

Study could improve our insights into brain diseases.

The cannabinoid type 2 receptor – also called “CB2 receptor” – is a special membrane protein. Its function is to receive chemical signals that control cellular activity. “Until now, this receptor was considered part of the immune system without function in nerve cells. However, our study shows that it also plays an important role in the signal processing of the brain,” explains Professor Dietmar Schmitz, Speaker for the DZNE-Site Berlin and Director of the Neuroscience Research Center of the Charité (NWFZ/NeuroCure). Schmitz coordinated the current study, which involved Berlin colleagues and also scientists from the University of Bonn and from the “National Institute on Drug Abuse” of the US.

As the researchers demonstrated in an animal model, the CB2 receptor raises the excitation threshold of nerve cells in the hippocampus. “Operation of the brain critically depends on the fact that nerve impulses sometimes have an exciting impact on downstream cells and in other cases they have a suppressing effect,” says Dr Vanessa Stempel, lead author of the current publication, who is now doing research in Cambridge, UK. “The CB2 receptor works like a set screw by which such communication processes can be adjusted.”

Component of the “endocannabinoid system”

The CB2 receptor is part of the endocannabinoid system (ECS). This family of receptors and signaling substances exists in many organisms including humans. It is a biochemical control system which is involved in the regulation of numerous physiological processes. Its name refers to the fact that chemicals derived from the cannabis plant bind to receptors of the ECS. So far, there are two known types of these receptors: The CB2 receptor has no psychoactive effect. Hence, the mind-altering effects triggered by the consumption of cannabis are ascribed to the “cannabinoid type 1 receptor”.

As the researchers demonstrated in an animal model, the CB2 receptor raises the excitation threshold of nerve cells in the hippocampus. Image is for illustrative purposes only.

Potential therapeutic applications

The results of the current study could contribute to a better understanding of disease mechanisms and provide a starting point for novel medications. “Brain activity is disturbed in schizophrenia, depression, Alzheimer’s disease and other neuropsychiatric disorders. Pharmaceuticals that bind to the CB2 receptor could possibly influence the activity of brain cells and thus become part of a therapy,” Professor Schmitz concludes.

About this neuroscience research

Source: Marcus Neitzert – DZNE
Image Source: The image is in the public domain.
Original Research: Abstract for “Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus” by A. Vanessa Stempe, Alexander Stumpf, Hai-Ying Zhang, Tuğba Özdoğan, Ulrike Pannasch, Anne-Kathrin Theis, David-Marian Otte, Alexandra Wojtalla, Ildikó Rácz, Alexey Ponomarenko, Zheng-Xiong Xi, Andreas Zimmer, and Dietmar Schmitz in Neuron. Published online March 18 2016 doi:10.1016/j.neuron.2016.03.034

Abstract

Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus

Highlights
•CB2Rs are expressed in hippocampal principal neurons
•CB2Rs mediate a cell type-specific self-inhibitory plasticity in CA3/CA2 PCs
•CB2Rs reduce the spike probability of CA3 PCs and alter gamma oscillations in vivo
•CB2Rs act complementary to presynaptic CB1Rs

Summary
Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.

“Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus” by A. Vanessa Stempe, Alexander Stumpf, Hai-Ying Zhang, Tuğba Özdoğan, Ulrike Pannasch, Anne-Kathrin Theis, David-Marian Otte, Alexandra Wojtalla, Ildikó Rácz, Alexey Ponomarenko, Zheng-Xiong Xi, Andreas Zimmer, and Dietmar Schmitz in Neuron. Published online March 18 2016 doi:10.1016/j.neuron.2016.03.034

[Greg Rx]

If you liked that, you will love this

The Brain's Medicine: Natural Marijuana-Like Chemicals Play Important Role in Placebo Effect

 

 

Placebos are inactive treatments that shouldn’t, in some sense, have a real effect. And yet they often do. But the chemical basis of the placebo effect, despite its enormous importance, is still largely a mystery. A study published this week in Nature Medicine shows thatcannabinoid receptors are involved in the placebo response to pain, which hasn’t been demonstrated before. The finding implies that the brain’s own endocannabinoids can fight pain, and actually do it via the same pathway as several compounds in the cannabis plant.

What’s the Context:

• For most drugs and treatments to be approved today, they must be favorably compared to ineffective placebos to prove that the therapeutics actually work. (This comparison is not simple, and whether certain drugs—like many antidepressants—are actually better than placebos is a matter of considerable debate.)
• The placebo effect has a impressive ability to confound expectations. For example, in a 1999 study researchers gave participants an inert substance but said it was a stimulant. The patients became stimulated and tense. Stranger still, they gave people a muscle relaxant, also calling it a stimulant. The patients still tensed up.
• Much of what we know about placebo chemistry comes from studies of pain. Pain tolerance, in contrast to more slippery traits like anxiety, can be relatively easily quantified—i.e., the length of time someone can withstand a painful sensation (which doesn’t cause lasting damage). The current study employed a tourniquet that painfully tightens around the arm like the cuff of a blood-pressure monitor until participants said it was “unbearable.”

Painful Lessons: 

• Several previous studies (in 1999 and 2007) found that if you give somebody morphine only twice, and then the third time give them a placebo that they think is as strong pain-killer, their pain tolerance will shoot up almost as high as it was on the drug; this is the placebo effect in action. Let’s call this group A.
• Another control group was given morphine on three consecutive occasions, but the third time they were also knowingly given naloxone, a drug that blocks opiates like morphine and heroin from binding to opioid receptors in the brain and exerting an effect (for this reason naloxone can be used to treat heroin overdoses). As you might expect, naloxone prevented morphine from doing its thing and also squelched the placebo effect, as subjects expected the morphine not to work. Pain tolerance amongst these people was the same as that in the unmedicated control group.
• This is where it gets weird. Researchers then treated another group of people (let’s call them group C) just as they did those in group A, except for one important difference: on the third treatment, with placebo, people were also unknowingly administered naloxone. Unlike group A, the placebo effect on pain tolerance vanished: people did not have a significantly increased pain tolerance.
• These results suggest that after being “conditioned” with an opiate drug like morphine, people were capable of producing their own natural opiate-like chemicals that bind to some of the same receptors as morphine. These are called the brain’s endogenous opioids, a class that includes well-known natural painkillers like endorphins, which are released for example during exercise.
• Researchers had known opioids were involved in pain tolerance, but these studies were amongst the first to show they can be involved in the brain’s placebo response to pain.

Pot and Pain:

• Although naloxone blocks opiates like morphine, it has little to no effect upon less potent—but more widely used—drugs like non-steroidal anti-inflammatory drugs including ibuprofen. Given recent evidence that NSAIDs interact with cannabinoids and that their receptors are involved in pain tolerance, researcherFabrizio Benedetti decided to go a step further and see if cannabinoid receptors are involved in the placebo response to pain. (Spoiler alert: they are.)
• To test this proposition, Benedetti performed experiments very similar to those previously described. But instead of using naloxone to block opiods, he used a drug called rimonabant to block endogenous cannabinoids. (Rimonabant binds the cannabinoid receptors (CB1), boxing out the cannabinoids.)
• Benedetti first established average pain tolerance in unmedicated study participants. By giving a second group solely rimonabant, he ensured the drug had no impact on pain tolerance by itself.
• As before with morphine, patients in one group (“group 5”) were given an NSAID called ketorolac for two trials. One the third occasion they were given a placebo labelled a “strong painkiller”; their tolerance was much higher than normal. The placebo effect!
• The same was done to people in “group 6.” But on the third treatment, besides being given the painkiller placebo, they were also given rimonabant. And voila! Their pain tolerance was back to normal, on par with the tolerance of people not given any drug or placebo treatment.
• By binding to CB1, rimonabant must have blocked the action of the brain’s own cannabinoids, which the brain apparently is able to produce in order  to effectively combat pain in this instance.

So What:

• The study is the first to prove that the placebo response to pain involves the cannabinoid system, specifically CB1, the receptor to which the brain’s own natural cannabinoids bind. It’s also the receptor bound to by THC, the main psychoactive ingredient in cannabis.

The Future Holds:

• This study tested 82 people, large enough for meaningful results but not especially large or diverse, considering the wide variety of responses seen in placebos. Future studies are needed to fully understand the effect, which involves more neurotransmitters than just opioids and cannabinoids.

I wonder if this is why cannabis never does well in double blind studies.

[t-pain]

i just dont get why they go backwards to find the pharma pills.

 

1. cannabis thousands of years

2. ECS discovered

3. CB recepters discovered

4. CB1/2 research

5. ??????

6. lets find chemicals that activate cb1/cb2 and then make pills out of them

7. profit

 

where step5 should be actual research on figuring out everything about the ECS. or on receptors. or on everything.

 

they are skipping researching the human body and instead going straight to pill pushing.

 

its the same problem about researching marijuana. they take a premise that thc is bad because it makes you happy, then they isolate each individual part of the plant and try to make a pill out of each cannabinoid.

 

except for the fact that some of these cannabinoids might be toxic by themselves, or might have terrible side effects.

 

because they focused only on cb1/cb2 receptors and ignored all of the other chemical reactions happening within the body.

 

there is no research on these other (non cb1/cb2) reactions that regulate the bad side effects.

 

 

 

let me put it this way. THC travels all over the body. into many different cells. even passing the blood-brain barrier. what does thc do in each of these cells? no one knows.

[Wild Bill]

They've already had one cannabinoid-receptor-tweaking pharmaceutical pulled off the market because it caused severe depression and suicidal thoughts

 

I think you can buy a pill to treat that!

 

[MedicatedJester]

Holy crap, that article by GregRX was absolutely fascinating.

[Willy]

I think you can buy a pill to treat that!

 

 

Better Living thru chemistry!!