Jump to content

Effects Of Cannabinoids And Cannabinoid-Enriched Cannabis Extracts On Trp Channels And Endocannabinoid Metabolic Enzymes

Recommended Posts




BACKGROUND AND PURPOSE Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system.


EXPERIMENTAL APPROACH The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested.



CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors.



These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.


LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7





Link to comment
Share on other sites

2116 Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 17 Editorial


New Developments in the Medicinal Chemistry of Vanilloid TRPV1 and Related Receptors


With 462 reviews over the past decade, Transient Receptor Potential (TRP) channels arguably represent one of today’s most

extensively reviewed pharmacological targets. The vanilloid (capsaicin) receptor TRPV1 itself has been subject to 271 reviews

and was featured in several books since its molecular cloning in 1997. One may ask, somewhat sceptically, why to add another

review to this pile? My answer is two-fold. First, our knowledge on TRP channels is rapidly evolving and thus the literature

needs constant critical re-evaluation. Second, this special issue is unique in that it attempts to form a coherent picture of the

field from the gating physiology of TRP channels through disease-related changes in TRP channels expression to preclinical

and clinical studies with compounds targeting TRPV1 for pain relief to emerging therapeutic targets (e.g. TRPA1, TRPV3 and

TRPM8) that are co-expressed with TRPV1 on nociceptive neurons.


Despite recent advances in our understanding of the mechanisms that cause and maintain pain, chronic pain still represents a

major treatment challenge to healthcare providers. The American Pain Society estimates that at least 50 million Americans are

affected by chronic pain, rendering many patients partially or totally disabled. Chronic pain already costs the country billions of

dollars in health care expenses and lost productivity and the situation will certainly worsen as the population continues to age.

Unfortunately, most analgesic drugs on the market today either provide unsatisfactory pain relief or their use is saddled by dangerous

side-effects. Clearly, there is a great need for novel, potent analgesic drugs with improved safety and tolerability.


The discovery of temperature-sensitive TRP channels (so-called “thermoTRP”s) in nociceptive neurons has spawned extensive

research efforts to understand the role of these channels in the initiation and maintenance of pain conditions and to identify

potent and selective small molecule antagonists that can be exploited for therapeutic purposes. Since these channels are strategically

located at the periphery where the pain pathway begins, it is hoped that TRP antagonists will be devoid of the sideeffects

that plague the clinical use of centrally-acting analgesic agents. Of note, the expression of thermoTRP channels is not

restricted to nociceptive neurons. Indeed, there is good evidence that the therapeutic potential of thermoTRP blockers extend

beyond pain and include airway disorders (e.g. chronic cough, asthma and chronic obstructive pulmonary disease), overactive

bladder, skin diseases (e.g. skin-derived pruritus, acne and alopecia or hirsutism), and cancer, just to name a few examples.


Of TRP channels that are present in nociceptive neurons, the vanilloid (capsaicin) receptor TRPV1 has attracted the most

attention so far partly due to the well-documented clinical potential of capsaicin to relieve pain. This explains the focus of this

special issue on TRPV1. Desensitization to capsaicin is a unique approach to lasting pain relief. After an initial excitatory response

(that can be minimized by topical analgesic agents like lidocaine), TRPV1-expressing neurons develop a long-lasting

(weeks in animal experiments and several months in clinical studies) refractory state in which the neurons are silent regardless

of the nature of the noxious stimulus. This is important since capsaicin-sensitive neurons express a broad range of channels that

are involved in pain perception. Importantly, all of these channels are silent during capsaicin desensitization.


Desensitization to systemic capsaicin (or its ultrapotent analogue, resiniferatoxin) administration is an extremely powerful

approach to mitigate pain in animal models.


Systemic desensitization is, however, not feasible in human patients for fear of potentially fatal side-effects (e.g. respiratory

arrest) if capsaicin is inadvertently injected into the circulation. In controlled clinical trials, capsaicin-containing creams gave

disappointing results due to a combination of limited efficacy and poor patient compliance. To circumvent these problems, occlusive

high capsaicin concentration patches (Qutenza) and site-specific capsaicin injections (Adlea) were developed. In clinical

trials, Qutenza showed significant pain relief compared to placebo in patients with post-herpetic neuralgia. Importantly,

Qutenza was devoid of any serious side-effect, inclusive body temperature regulation.


Resiniferatoxin (RTX) is an attractive alternative to capsaicin with improved desensitization to irritancy ratio. In patients

with overactive bladder, intravesical RTX treatment restored continence (or at least reduced the number of incontinent episodes)

with no significant adverse effects. Site-specific RTX injections (e.g. intraarticular administration in osteoarthritis patients)

represent another therapeutic approach that should be tried in the future. RTX can also be used as a “molecular scalpel”

to achieve permanent pain relief in cancer patients.


TRPV1 antagonists offer a novel mechanism of action for the potential treatment of a wide range of painful conditions. The

pharmaceutical industry showed great success in the identification and development of potent small molecule TRPV1 antagonist

candidates. At least twelve compounds entered Phase I clinical testing and five of these agents have progressed into Phase

II ‘proof-of-concept’ studies. The results of these trials are keenly awaited. If the promise of these compounds from preclinical

and Phase I work is confirmed by the proof-of-concept studies, TRPV1 antagonists may represent the first mechanistically

novel class of analgesic drugs for many years. The high expectations, however, were recently replaced by cautious optimism.

The key issues with some TRPV1 antagonists are hyperthermia (e.g. AMG517) and a potential for scalding injury (e.g. MK-

2295) due to impaired noxious heat detection.


In summary, desensitization of capsaicin-sensitive neurons by agonists and pharmacological blockade of TRPV1 by antagonists

are two fundamentally different and complimentary therapeutic approaches for pain relief. Only localized pain is amenable

to topical and/or site-specific capsaicin therapy. By contrast, small molecule TRPV1 antagonists may be administered per

os to alleviate more generalized pain. The balance between the beneficial actions and adverse effects of TRPV1 antagonists

must be carefully and pragmatically evaluated in order to determine if these drugs could emerge as the next generation of pain

killers. Regardless of the outcome, the tremendous experience obtained with therapeutic targeting of the TRPV1 receptor

should greatly facilitate on-going efforts to capitalize on the additional TRP channels (e.g. TRPA1, TRPV3, TRPV4, and

TRPM8) as well as somatostain-4 receptors that are present in nociceptive neurons.



Current Topics in Medicinal Chemistry, 2011, Vol. 11, No. 17 2117


Arpad Szallasi

Guest Editor – Currents Topics in Medicinal Chemistry

Departments of Pathology

Monmouth Medical Center

Long Branch, NJ and

Drexel University College of Medicine

Philadelphia, PA


Link to comment
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.

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.

  • Create New...