Jump to content

Recommended Posts

Cannabinoid Receptor Expression in Disease: Mechanisms and Their Therapeutic Implications

In diseases for which cannabinoid receptors are protective, knowledge of the mechanisms of receptor up-regulation could be used to design therapies to regionally increase receptor expression and thus increase efficacy of an agonist. Alternatively, inhibition of harmful cannabinoid up-regulation could be an attractive alternative to global antagonism of the system. Here we review current findings on the mechanisms of cannabinoid receptor regulation in disease and discuss their therapeutic implications.

 

This is interesting and has some easy to read tables.

Edited by in vivo
Link to post
Share on other sites
  • Replies 62
  • Created
  • Last Reply

Top Posters In This Topic

Top Posters In This Topic

Popular Posts

If CBD which does not bind to CB1 or CB2 yet is called a Cannabinoid then Thujone is just as much a Cannabinoid? I understand that CBD and Thujone does modulate the affinity of other Cannabinoids, li

This is great stuff !  Thank you.     I downloaded the first PDF and will read it and move on to the next.     I'm intensely interested in the medicinal effect of this herb...it's almost unbelieva

(I've edited this thread in an attempt make the purpose and direction of this conversation more clear.)   This post is an attempt at beginning a discussion that focuses on gaining a more developed u

Endocannabinoid tone versus constitutive activity of cannabinoid receptors
 

This review evaluates the cellular mechanisms of constitutive activity of the cannabinoid (CB) receptors, its reversal by inverse
agonists, and discusses the pitfalls and problems in the interpretation of the research data. The notion is presented that
endogenously produced anandamide (AEA) and 2-arachidonoylglycerol (2-AG) serve as autocrine or paracrine stimulators of
the CB receptors, giving the appearance of constitutive activity. It is proposed that one cannot interpret inverse agonist
studies without inference to the receptors’ environment vis-à-vis the endocannabinoid agonists which themselves are highly
lipophilic compounds with a preference for membranes. The endocannabinoid tone is governed by a combination of
synthetic pathways and inactivation involving transport and degradation. The synthesis and degradation of 2-AG is well
characterized, and 2-AG has been strongly implicated in retrograde signalling in neurons. Data implicating endocannabinoids
in paracrine regulation have been described. Endocannabinoid ligands can traverse the cell’s interior and potentially be stored
on fatty acid-binding proteins (FABPs). Molecular modelling predicts that the endocannabinoids derived from membrane
phospholipids can laterally diffuse to enter the CB receptor from the lipid bilayer. Considering that endocannabinoid signalling
to CB receptors is a much more likely scenario than is receptor activation in the absence of agonist ligands, researchers are
advised to refrain from assuming constitutive activity except for experimental models known to be devoid of
endocannabinoid ligands.

 

 

Recent studies are providing greater evidence that endocannabinoids
serve an autocrine or paracrine function to regulate
the cannabinoid receptors. The production and removal
of these endogenous agonists must be considered as intrinsic
to the local responses directed by both CB1 and CB2 cannabinoid
receptors. In many studies of cannabinoid receptor
inverse agonist effects, the capability of local production of
endocannabinoids was not investigated or even mentioned
as a consideration. This is partly because of the paucity of
selective inhibitors of synthetic and degradative enzymes for
endocannabinoids, coupled to the complexities of determining
endogenous levels of these and related lipid ligands. One
cannot interpret inverse agonist studies without reference to
the receptor’s environment vis-à-vis the endocannabinoid
agonists. The endocannabinoid levels are the results of a
combination of synthetic pathways, storage and inactivation
involving transport and degradation.

 

This is interesting. It seems to suggest that most CBD research is possibly flawed.

Edited by in vivo
Link to post
Share on other sites

I feel as though the pdf above, titled Cannabinoid Receptor Expression in Disease, is a potentially a useful tool and a practical way of approaching cannabinoid treatments. I make sense, to me, to think about the receptors that are nearest to the condition/disease that's being targeted. This seems to make sense because receptors that are physically nearest your target are more likely to interacting with it. This is what I was trying to drive towards in my first post. Cannabinoid Receptor Expression in Disease seems to be a bit easier to decipher at a glance than the ECS as an Emerging Target, so I'm going to add this one to the first post. 

Edited by in vivo
Link to post
Share on other sites
  • 3 weeks later...

I am quite slow to absorb all this..

 

but I am willing to try :)

 

correct me if I am wrong.. but I am sitting here thinking that the euphoric effect we all blame on the THC is not necessarily the thc itself affecting the brain but it is also the brains defense against a barrage of extra particles? ?

 

on a molecular level that's fascinating to try to wrap Mibrains around... to think that as the thc molecule binds to the receptor the receptor produces more fluids to counteract the addition of molecules and thereby literally floods the synaptic gaps with a.... what's the word.. a electronic agitator.

 

its no wonder we feel the effects the way we do when you consider on a molecular level we are actually overwhelming the receptors with not just the cannabis and all its molecules... but our bodies own defenses to those additional molecules...

 

as I understand cannabis the trychomes are the plants natural defense mechanism against predatory attacks.. so.. to think our body reacts to that in a similar fasion on a molecular level should not surprise me..

 

is the euphoria actually a miniature allergic reaction?

 

lost myself in my own thought process this morning :)

 

hope everyone is having a great day

 

thank you for posting this research and information it really is all very fascinating to try to digest...I pinned this thread also to allow other folks the ability to find this data easily if they so choose.

 

knowledge is power.

 

learn to read.

read to learn.

 

Peace.

Link to post
Share on other sites

First, I'd like to thank you for pinning these threads. I feel honored that others might make use of this information.

 

I am sitting here thinking that the euphoric effect we all blame on the THC is not necessarily the thc itself affecting the brain but it is also the brains defense against a barrage of extra particles?

 

CB1 receptors are primary thought to be associated with the psychotropic effects of THC. To put into perspective how closely interconnected CB1 receptors are to the reward mechanism in the brain: mice that are genetically modified to not have CB1 receptors don't self administer morphine. 

 

When it comes to the bodies reaction to being flooded with THC, it's important to note that the average life span of a cannabinoid receptor is 0.5 seconds. Their level of expression (the amount of receptors) is constantly in flux. When we flood our bodies with THC on a consistent basis, the level of expression of the receptors is reduced throughout the body. Some diseases are also associated with an increase or decrease in cannabinoid receptor expression. This is important because of cross signalling between receptors. The greater the density of cannabinoid receptors, the greater activation of these receptors (ie more psychotropic effects). Methods are being developed to adjust cannabinoid receptor expression for therapeutic gain. Some that come to mind include diet, unrelated compounds, and electro acupuncture.  

 

Aside from the level of cannabinoid receptor expression, another variable to consider is the way in which cannabinoid receptors function. This is where things get tricky. On the first page there's a pdf that discusses some of the functions displayed by G Protein-Coupled Receptors (GPCRs). Cannabinoid receptors are part of the GPCR super family. Over half of all pharmaceuticals work of off GPCRs and cannabinoid receptors are one of the most highly expressed of them. This is important because these receptors have more than one functional mechanism, and they can often directly interact with one another. What this means is that in addition to thinking about THC activating CB1 receptors, other receptors need to be taken into account. Some examples might include CB1 and CB2 forming functional heteromers, which means that activation of one automatically "turns down" the ability of the other to be activated. There are a number of GPCRs that form functional heteromers with cannabinoid receptors. Functional heteromers provide some targets that have the potential to increase psychotropic, as well as therapeutic effects. An example worth mentioning: fatty acid inhibitors can amplify the effects of CB1 receptors. Overall, I suspect that these variations in function have much to do with the difference in psychotropic effects, much the same way that they have differing therapeutic implications.

 

The consistent use of an exogenous agonist (like THC) does seem to appear to potentially lead to physiological issues. This is especially true wherever cannabinoid receptors are tonically active. Tonically active receptors are receptors that are always being exposed to particular levels of endogenous cannabinoids (natural cannabinoids in the body), rather than endogenous cannabinoids being produced on demand. An example of this would be the GI tract. The GI tract is lined with CB1 receptors that are tonically active. In some cases, when a body is exposed to high levels of exogenous cannabinoids (like THC) for long periods of time, it can lead to problems due to enzymes involved in the biosynthesis of endogenous cannabinoids getting "backed up".

 

I'm not sure if i answered your question. I guess I would say that the evidence is leaning towards the likelihood that the various compounds interact with one another via known GPCR mechanisms, and/or independently to create differing effects. I don't know if the psychotropic effects can be attributed to the bodies defense mechanisms, but i think it's important to think about the mechanisms that are disrupted by constant exposure to exogenous cannabinoids.        

Edited by in vivo
Link to post
Share on other sites

that is great.

 

thank you !

 

you must work at a lab or something you seem to have an absolutely awesome awareness of the way cannabis acts... seems like you have been paying attention somewhere :)

 

I for one appreciate the feedback and loads of information... its going to take time for me to absorb.. but I love the resources.... thank you again !

Link to post
Share on other sites

I really should work at a lab. I wish that I did. (Hook me up with a discount?) If I had access to the equipment, I would do a ton of experiments.

 

I was basically blown off by the lab that I have used. I had recently been introduced to some of Russo's work and was so excited about the possibilities, that I'm pretty sure that they thought I was a just talking bunny muffin. I had two pages of questions and was shooting them off in a rapid fire fashion. "Give me all your knowledge yesterday!" is possibly how it came across. I have the type of personality that can come across as intense, especially when I'm excited.

 

I feel as though part of the reason I was blown off was because there is such a lack of demand for more complete cannabinoid and terpene profile testing services. I was the second person to ever ask according to the representative that I spoke with. This is a large part of what weighed into my decision to join this board. A combination of standardizing product, comprehension of physiological responses, and anecdotal reports, all shared online, could increase an individual's ability to successfully utilize this plant exponentially, in very little time. 

 

My hope is that once someone that's become familiar with the differing effects attributed to cannabinoids or terpenes (that are currently not being tested for here in MI), that they'll ask about these compounds and explain to their supplier why they feel they're important. That seems like my only chance to get access to more complete testing services, other than to get my own equipment.

 

I wish we had a non profit doing testing for MI.

 

Anyway, I appreciate your initial question, as well as your kind words.                 

Edited by in vivo
Link to post
Share on other sites

Endocannabinoids and Related Compounds: Walking Back and Forth between Plant Natural Products and Animal Physiology  

 

Introduction

These recent milestones of the exploitation of the plant with perhaps the oldest history of medicinal and recreational use by mankind are the result of four decades of intensive research. This process started with the identification and chemical synthesis of THC, the controlled study of its pharmacological properties, and the identification of its receptors in animal organisms and of their endogenous ligands, the endocannabinoids (Figure 1), and it continued with the progressive understanding of the physiological and pathological roles of this newly discovered signaling system and the appreciation of the potential therapeutic use not only of THC and endocannabinoids, but also of other plant cannabinoids. Despite this impressive sequence of achievements, whose aspects have been the subject of recent “historical” reviews 3, 4 and 5, there is much more to the original understanding of the THC mechanism of action than the discovery of the endocannabinoid system. The purpose of this article is not merely to highlight the past contribution of chemical biology to our current understanding of endocannabinoid regulation and function, but, more importantly, to discuss the several other discoveries that stemmed, and are still likely to originate in the future, from the finding of cannabinoid receptors and their endogenous ligands.

 

 

Take Home Messages and Open Questions

From the data reviewed in this article it is clear that biological and pharmacological studies carried out with a chemical mind can reveal new physiological and pathological mechanisms and, eventually, solve clinical problems. The exciting walk from the psychotropic constituent of Cannabis to the understanding of the mechanism of its biological actions led to the discovery of the endocannabinoid system, a signaling apparatus whose function goes well beyond what could have been imagined from pharmacological studies on THC. The route from the endocannabinoids to the Capsicum pungent principle then led to the finding of endovanilloids, endogenous mediators whose role is yet to be fully understood. The discovery of endocannabinoids and endovanilloids paved the way for the finding of several other lipid signals, and it prompted, on the one hand, new strategies for the chemical synthesis of compounds with multiple pharmacological and therapeutic targets, and, on the other hand, the search for chemically similar compounds back in plants. Many open questions to which the meeting of chemistry and biology can provide an answer still remain. Just to name a few, these questions involve the understanding of the mechanisms and exact physiological meaning of the target and metabolic pathway promiscuity of fatty acid ethanolamides; the identification of the elusive protein(s) facilitating endocannabinoid membrane transport; the receptor “deorphanization” of the several tens of bioactive fatty acid amides that have been discovered, and their testing on the several TRP channels that have been identified so far, many of which are, like TRPV1, activated by plant natural products; the determination of the exact function and molecular targets of fatty acid ethanolamides in plants; and the understanding of the mechanism of action in animals of other phytocannabinoids, like the therapeutically promising cannabidiol. Thus, the exciting promenade from plant natural products to animal physiology and back might soon become a true treasure hunt.

 

Link to post
Share on other sites
  • 3 months later...

This is great stuff !  Thank you.  

 

I downloaded the first PDF and will read it and move on to the next.  

 

I'm intensely interested in the medicinal effect of this herb...it's almost unbelievable.

 

As a cancer survivor, apoptosis interests me most since the type of cancer I had was a result of a failure in the apoptosis mechanism due to a genetic mutation that I suspect was caused by exposure to environmental chemicals.  Apoptosis is the term for the suicide of white blood cells once they have done their job protecting the body from infection.  If apoptosis doesn't occur, the once beneficial white blood cells pile up, merge and begin to develop their own blood supply - and a tumor is born.  

 

Cancer patients are at risk of relapse and more cancers, so I feel that if I can find a way to keep apoptosis working in my body, I may actually be able to prevent a relapse or a different cancer. 

 

It seems that CBD is the ticket to encourage apoptosis and I am interested in the health benefits from juicing with the leaves and consuming the whole plant in order to get the holistic effect of it....to me, the THC is just a bonus.

 

Keep up the great work, Vivo !!

Link to post
Share on other sites
  • 1 month later...

I'd like to point out that it's not the fault of science, or most of those who work in it, that cannabis is still schedule 1. Please don't hold it against science. Science is the friend of anyone serious about cannabinoid based treatments. Believe it or not there is more to cannabis than simply getting stoned.

Link to post
Share on other sites

Cancer patients are at risk of relapse and more cancers, so I feel that if I can find a way to keep apoptosis working in my body, I may actually be able to prevent a relapse or a different cancer.

 

I just posted a new thread on the biology of cannabinoids and cancer treatments. It's in the cancer section. Other phytocannabinoids like beta-caryophyllene, alkylamides found in echinecea purpurea, and particularly honokiol and magnolol, all have similar potential in cannabinoid based cancer therapies.

Link to post
Share on other sites

I just posted some articles on magnolol and honokiol in their respective places. You may notice that they appear to be thought of as candidates in many similar conditions to those that we're treating with cannabinoids from cannabis. That's because magnolol and honokiol are also natural cannabinoids that are found in magnolia officinalis root bark. It's been used in Chinese medicine for 2000 years. I consider these, as well as other natural cannabinoids like beta-caryophyllene found in a number of sources, alkylamides from echinecea purpurea, yangonin from kava, and others.

 

Identifying additional sources of natural cannabinoids to incorporate into cannabinoid based treatments is advised and economical. There's no reason to believe that any 'entourage effect' would be limited to cannabinoids that originate in cannabis.   

 

I'm currently working with Iron Labs to quantify the magnolol and honokiol from extracts.

Edited by in vivo
Link to post
Share on other sites

in the last decade (2000–2010), our understanding of the endocannabinoid system has experienced a true revolution.

 

From here

 

 

I don't even like to search back further than around 2010 since our understanding have developed so much since then.

 

To me, this thread among other things is about self empowerment. It's about not believing that we need to wait for the gatekeepers to provide us with clinically available cannabinoids. Cannabinoids are relatively safe. We know how to cultivate and manipulate cannabis to procure the chemotypes we desire. We know about other natural sources of cannabinoids. We can learn which combinations of cannabinoids, terpenes, and flavonoids might be best suited to our needs. If we can blindly target ailments, imagine what could be done with a more systematic and scientifically based approach.

 

Let's form a legion of patients and caregivers that know more about “one of the most important physiological systems involved in establishing and maintaining human health”, than most practicing physicians. Then let's educate them.

 

Editor’s Note: The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.

 

From here

Link to post
Share on other sites
  • 2 weeks later...

Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures — A short review

 

This is a bit dated, but there are some easy to read tables on the expression levels of CBRs throughout the body.

 

Here's another one:

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1995.tb20780.x/pdf

Edited by in vivo
Link to post
Share on other sites
  • 3 weeks later...

in vivo,

Do you have references that say why beta-caryophyllene, alkylamides found in echinecea purpurea, and particularly honokiol and magnolol are considered Cannabinoids? Or phytocannabinoids? If you consider beta-caryophyllene a Cannabinoid, what about the other 140 terpenes? Do you think there are the 85+ Cannabinoids + the 140+ terpenes, and they are all Cannabinoids?? Why do the experts all say there are 85 Cannabinoids?

Are you saying they are Cannabinoids just because they bind to CB1 or CB2 receptors? Would that make them Non-Classical Cannabinoids?

What about Cannabinoids that do not bind to receptors or inter react with them?

 

Didn't you forget wormwood, thujone

Meschler JP, Howlett AC (March 1999). "Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses". Pharmacol. Biochem. Behav. 62 (3): 473–80.

I am curious if they are true Cannabinoids or just Cannabinomimetics?

There are hundreds of synthetic compounds that have Cannabinomimetic responses, and they are not Cannabinoids.

Endogenous or Synthetic "cannabinoids" are at the most Non-Classical cannabinoids, because they do not come from Cannabis plants.

Alkylamides from Echinacea Are a New Class of Cannabinomimetics

CANNABINOID TYPE 2 RECEPTOR-DEPENDENT AND -INDEPENDENT IMMUNOMODULATORY EFFECTS

http://www.jbc.org/content/281/20/14192.full

These are CBD analogues:

http://www.ncbi.nlm.nih.gov/pubmed/15588739

All the best,

-SamS

Edited by hempsci
Link to post
Share on other sites

They're all posted on this board, but some of them aren't available for free anymore, so I uploaded them on scribd. Gertsch has a paper from 2010 that should be linked here as well titled "Phytocannabinoids Beyond Cannabis".
 

 This prompts us to define ‘phytocannabinoids’ as any plant-derived natural product capable of either directly interacting with cannabinoid receptors or sharing chemical similarity with cannabinoids or both.

 

http://www.scribd.com/UPMMJ

 

As you're well aware not all of Russo's and Gertsch's work is readily accepted, so terminology remains muddied. For my purposes I view them as either endocannabinoids, synthetics, or phytocannabinoids. In all reality the classifications for cannabinoids appear to be based on their chemical structure. "Beyond CB1 and CB2" linked in the first post of this thread covers this (Pertwee 2010). Shulgin also has a book that delves into the chemistry, but I don't have the reference handy.

 

Classical cannabinoids are dibenzopyran derivatives (THC, CBD, HU210).

Non-classical are bicyclic and tricyclic analogs of THC that lack the pyran ring (beta-caryophyllene, magnolol, honokiol, CP55940).

aminoalkylindole group (WIN55212)

eicosanoid group (AEA, 2-AG)

alkylamides (echinacea purpurea)

 

Thujones low affinity for CBRs and potential nuerotoxicity leaves me on the fence with it. I've got only limited experience with it making absinthe. I doubled up on the wormwood for the recipe and didn't distill it, so basically it was nasty stuff. I would be interested to learn about reports of bioassay from others. That it displaces ligands with a higher affinity/efficacy takes it off the table for CB1 activation, imo. But activation isn't necessarily always the goal. It might be of benefit to delve into the psychotropic effects of thujone in order to cross reference potential interactions with other terpenoids. One theory appears to be 5-HT3:

 

http://pubs.acs.org/doi/abs/10.1021/ed100620b

 

Another characteristic of thujone that might be worth considering is that it modulates GABA:

http://www.sciencedirect.com/science/article/pii/S0014299913000472

 

I guess the thing to keep in mind are the allosteric sites of CB1, and the way GPCRs modulate one another. Pertwee covers this in detail. Thujone is known to interact with GABA and 5-HT3 receptors, both of which interact with CB1. GABA and CB1 are actually presynaptically aligned in some regions of the brain.

 

The new synthetics that are designed to not cross the blood brain barrier are likely going to be quite valuable therapeutically, imo. Being able to selectively deliver cannabinoids to regions of the body without disrupting the brain will likely be of great benefit.  

Link to post
Share on other sites

They're all posted on this board, but some of them aren't available for free anymore, so I uploaded them on scribd. Gertsch has a paper from 2010 that should be linked here as well titled "Phytocannabinoids Beyond Cannabis".

 

 

http://www.scribd.com/UPMMJ

 

As you're well aware not all of Russo's and Gertsch's work is readily accepted, so terminology remains muddied. For my purposes I view them as either endocannabinoids, synthetics, or phytocannabinoids. In all reality the classifications for cannabinoids appear to be based on their chemical structure. "Beyond CB1 and CB2" linked in the first post of this thread covers this (Pertwee 2010). Shulgin also has a book that delves into the chemistry, but I don't have the reference handy.

 

Classical cannabinoids are dibenzopyran derivatives (THC, CBD, HU210).

Non-classical are bicyclic and tricyclic analogs of THC that lack the pyran ring (beta-caryophyllene, magnolol, honokiol, CP55940).

aminoalkylindole group (WIN55212)

eicosanoid group (AEA, 2-AG)

alkylamides (echinacea purpurea)

 

Thujones low affinity for CBRs and potential nuerotoxicity leaves me on the fence with it. I've got only limited experience with it making absinthe. I doubled up on the wormwood for the recipe and didn't distill it, so basically it was nasty stuff. I would be interested to learn about reports of bioassay from others. That it displaces ligands with a higher affinity/efficacy takes it off the table for CB1 activation, imo. But activation isn't necessarily always the goal. It might be of benefit to delve into the psychotropic effects of thujone in order to cross reference potential interactions with other terpenoids. One theory appears to be 5-HT3:

 

http://pubs.acs.org/doi/abs/10.1021/ed100620b

 

Another characteristic of thujone that might be worth considering is that it modulates GABA:

http://www.sciencedirect.com/science/article/pii/S0014299913000472

 

I guess the thing to keep in mind are the allosteric sites of CB1, and the way GPCRs modulate one another. Pertwee covers this in detail. Thujone is known to interact with GABA and 5-HT3 receptors, both of which interact with CB1. GABA and CB1 are actually presynaptically aligned in some regions of the brain.

 

The new synthetics that are designed to not cross the blood brain barrier are likely going to be quite valuable therapeutically, imo. Being able to selectively deliver cannabinoids to regions of the body without disrupting the brain will likely be of great benefit.

Understanding Chronic Pain as a Disease of the Brain

By Carole Alison Chrvala, PhD

Reviewed by Christopher Gharibo, MD, Medical Director of Pain Medicine, NYU Langone Medical Center Hospital for Joint Diseases, New York, NY

image

Take Note

The plasticity of the CNS is characterized by functional, structural, and chemical changes in the brain. These changes are associated with activation of the pain matrix in response to chronic pain.

Advances in brain imaging technology reveal that patients with chronic pain have altered pain modulatory circuits as well as structural abnormalities.

Imaging techniques have a promising role to play in the diagnosis of different chronic pain disorders and assessment of responses to current and new therapeutic interventions.

 

Based largely on recent advances in neuroimaging and neurophysiology, we are beginning to understand that the experience of pain is a multifaceted process affected by somatosensory, emotional, cognitive, and genetic factors—as well as by structural changes in the brain.1 Chronic pain provokes changes in the central nervous system (CNS) that modify the sensory, emotional, and modulatory circuits that normally inhibit pain.2 A clear distinction exists between the effects of acute versus chronic pain on the brain, with chronic pain provoking structural changes in multiple regions of the brain that are involved in cognitive and emotional pain processing.3,4 These changes increase the risk of altered cognitive and emotional states characterized by fear, anxiety, or depression.2

 

Neurophysiologic studies confirm that the CNS has the ability, known as plasticity, to reorganize over time in response to an individual’s life experiences, thoughts, and actions. Among the factors that may contribute to reorganization of the CNS are comorbid health conditions such as depression and anxiety, as well as medication use.3 A sedentary lifestyle and low levels of social stimulation, which are frequently associated with chronic pain, may also contribute.3 The brain’s ability to reorganize in response to chronic pain is characterized by functional, structural, and chemical changes.2 Notably, it has been shown that specific areas of the brain, known as the pain matrix, are activated in response to pain. The pain matrix is thought to include the primary (S1) and secondary (S2) somatosensory cortices, insula, anterior cingulate cortex (ACC), amygdala, prefrontal cortex, thalamus, basal ganglia, and cerebellum.3,4 The insula, S1, S2, and lateral thalamus are involved in the sensory-discriminative aspect of pain processing, while the ACC plays a role in the perception of pain as an unpleasant event.3

 

Advances in anatomic, functional, and chemical neuroimaging confirm that chronic pain has profound effects on the brain.1 Neuroimaging studies may allow clinicians a glimpse at brain circuitry, effects of medications on neural networks, transitions from acute to chronic pain, identification of regions of the brain involved in the experience of chronic pain, brain plasticity, and neurochemical changes that occur in response to chronic pain.1 A wide variety of noninvasive methods are now available for neuroimaging that include magnetic resonance imaging, voxel-based morphometry (VBM), diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), magnetic encephalography, and near-infrared spectroscopy. These imaging techniques permit in vivo longitudinal evaluation of CNS plasticity and demonstrate the CNS reorganization that occurs in response to chronic pain, including connections in pain pathways and functional, anatomic, and chemical changes.1,4

 

For example, VBM and DTI provide anatomic images of the brain. Specifically, VBM measures the concentration of gray matter in different brain voxels,1 with evidence suggesting that gray matter is decreased in the ACC, thalamus, dorsolateral prefrontal cortex, cingulate cortex, and the insular cortex. All of these areas are associated with pain processing in patients with chronic pain.3,4 Reductions in gray matter have been documented in patients with diverse pain conditions, including fibromyalgia, migraine, and osteoarthritis.4

 

Correlations between changes in gray matter and the duration or severity of pain have also been reported. For example, greater decreases in gray matter have been associated with longer duration of pain.3,4 On the other hand, increased gray matter has been identified in the ACC, dorsolateral prefrontal cortex, amygdala, and brain stem following effective treatment to relieve chronic pain.3 Using DTI, anatomic changes also have been reported in the white matter of the brains of patients with complex regional pain syndrome.4 These alterations are thought to be associated with decreased tract myelination, reductions in parallel fiber organization, and impaired white matter connectivity.4

 

Functional imaging techniques include blood oxygen level-dependent (BOLD) fMRI to assess variations in the local concentration of deoxyhemoglobin, which is an indirect assessment of neuronal activity.1 Functional imaging has been extremely informative about changes in neural circuitry involved in the processing and modulation of pain. For example, persons with chronic pain demonstrate decreased pain-related activation in the pain matrix when they engage in tasks or activities that distract their attention from pain.3 Alternatively, functional imaging of patients who are directed to concentrate on their pain demonstrates an increase in the functional coupling of regions located in the pain matrix, which exacerbates pain.3 MRS studies have demonstrated changes in neurotransmitters among patients with chronic back pain, migraine, complex regional pain syndrome, and fibromyalgia.1

 

Our growing ability to obtain images of the brain in patients experiencing pain under different conditions has dramatically changed our traditional views and understanding of chronic pain and pain processing. These new findings hold the promise of significant improvements in our ability to diagnose and effectively treat chronic pain.1,3,4

 

 

Published: 04/16/2013

 

References:

 

Borsook D, Sava S, Becerra L. The pain imaging revolution: advancing pain into the 21st century. Neuroscientist. 2010;16:171-185.

Borsook D. A future without chronic pain: neuroscience and clinical research. Cerebrum. 2012 May/June. [Epub 2012 Jun 27]

Henry DE, Chiodo AE, Yang W. Central nervous system reorganization in a variety of chronic pain states: a review. PM R. 2011;3:1116-1125.

Schweinhardt P, Bushnell MC. Pain imaging in health and disease—how far have we come? J Clin Invest. 2010;120:3788-3797.

 

 

http://www.medpagetoday.com/resource-center/pain-management/brain/a/38479

Link to post
Share on other sites

So do you feel that all 140 Cannabis terpenes are phytocannabinoids? Either Non-Classical or Classical? Or do they have to as said below, interreact with the CB1, CB2, CB3, and/or the other dozen posulated CB receptors?

-Hempsci

 

"This prompts us to define ‘phytocannabinoids’ as any plant-derived natural product capable of either directly interacting with cannabinoid receptors or sharing chemical similarity with cannabinoids or both."

 

 

 

They're all posted on this board, but some of them aren't available for free anymore, so I uploaded them on scribd. Gertsch has a paper from 2010 that should be linked here as well titled "Phytocannabinoids Beyond Cannabis".

 

 

 

http://www.scribd.com/UPMMJ

 

As you're well aware not all of Russo's and Gertsch's work is readily accepted, so terminology remains muddied. For my purposes I view them as either endocannabinoids, synthetics, or phytocannabinoids. In all reality the classifications for cannabinoids appear to be based on their chemical structure. "Beyond CB1 and CB2" linked in the first post of this thread covers this (Pertwee 2010). Shulgin also has a book that delves into the chemistry, but I don't have the reference handy.

 

Classical cannabinoids are dibenzopyran derivatives (THC, CBD, HU210).

Non-classical are bicyclic and tricyclic analogs of THC that lack the pyran ring (beta-caryophyllene, magnolol, honokiol, CP55940).

aminoalkylindole group (WIN55212)

eicosanoid group (AEA, 2-AG)

alkylamides (echinacea purpurea)

 

Thujones low affinity for CBRs and potential nuerotoxicity leaves me on the fence with it. I've got only limited experience with it making absinthe. I doubled up on the wormwood for the recipe and didn't distill it, so basically it was nasty stuff. I would be interested to learn about reports of bioassay from others. That it displaces ligands with a higher affinity/efficacy takes it off the table for CB1 activation, imo. But activation isn't necessarily always the goal. It might be of benefit to delve into the psychotropic effects of thujone in order to cross reference potential interactions with other terpenoids. One theory appears to be 5-HT3:

 

http://pubs.acs.org/doi/abs/10.1021/ed100620b

 

Another characteristic of thujone that might be worth considering is that it modulates GABA:

http://www.sciencedirect.com/science/article/pii/S0014299913000472

 

I guess the thing to keep in mind are the allosteric sites of CB1, and the way GPCRs modulate one another. Pertwee covers this in detail. Thujone is known to interact with GABA and 5-HT3 receptors, both of which interact with CB1. GABA and CB1 are actually presynaptically aligned in some regions of the brain.

 

The new synthetics that are designed to not cross the blood brain barrier are likely going to be quite valuable therapeutically, imo. Being able to selectively deliver cannabinoids to regions of the body without disrupting the brain will likely be of great benefit.  

 
Link to post
Share on other sites

I think that any compound that's only found in cannabis is likely to directly interact with the ECS. I'd go a step further than that to suggest that practically all herbal remedies with a long history of use and a largely unknown pharmacological understanding is likely to directly interact with the ECS. It's kind of a big deal. 

 

If you want to elucidate these interctions you've got to look beyond CB1 and into how GPCRs modulate one another.   

Link to post
Share on other sites

Join the conversation

You can post now and register later. If you have an account, sign in now to post with your account.

Guest
Reply to this topic...

×   Pasted as rich text.   Paste as plain text instead

  Only 75 emoji are allowed.

×   Your link has been automatically embedded.   Display as a link instead

×   Your previous content has been restored.   Clear editor

×   You cannot paste images directly. Upload or insert images from URL.

Loading...



×
×
  • Create New...