Allosteric Modulation: The Versatility of Cannabinoid Receptors

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These are exciting times for a cannabinoid researcher; new information must constantly be integrated with the growing body of knowledge surrounding the endocannabinoid system. At times, that new information can even flip our understanding of the system on its head. One great example of that is embodied in the research surrounding allosteric modulation.

In our traditional understanding of the endocannabinoid system, there are two types of receptors: CB1 receptors, which are located primarily in the brain, and CB2 receptors, which are located throughout the central nervous system and immune system. CB1 receptors are known to be the primary cause of psychedelic effects from cannabis, so readers should not be surprised that THC bonds to those. In this model, receptors can either be activated or de-activated at varying degrees. For instance, a cannabinoid that barely activates a CB1 receptor would be a “weak/partial CB1 agonist”, while one that deactivates all CB2 receptors would be a “strong CB2 antagonist”. The first cannabinoids that were studied, such as THC, could adequately be described in such terms. However, as time went on, researchers began to suspect that cannabinoids could bond to our cannabinoid receptors at alternate sites, based on the knowledge that similar properties have been observed in other types of receptors.

What’s the difference? Everything. Consider the process of inhibition: normal (orthosteric) inhibitors can either trap the agonist to keep it from activating the receptor or can compete with the agonist for a bonding site (effectively reducing the number of receptors that can be activated by an agonist). Along with the supply of cannabinoids, this regulates receptor signaling. However, allosteric modulation occurs through cannabinoid bonding at an alternate site on the receptor. This allows the main receptor site to stay free to continue receiving normal, orthosteric signaling, while instead changing the receptor’s affinity or response to those agonists. The second part is the gold nugget here – allosteric modulation offers the promise of activating the CB1 receptor without any of the psychoactive effects. Indeed, research has illustrated that activation of the CB1 receptor can produce pain-numbing (antinociceptive) effects. However, to date, the psychoactivity of cannabis limits its medical utility. For instance, no one wants a heavily medicated airline pilot! If we could control how allosteric agents affect receptors, we could ideally pick and choose which effects of the receptor we would like to activate. This is the concept of the research behind Positive Allosteric Modulators (PAMs).

At this point in time, CB1 PAM research is in its infancy. The first series of CB1 PAMs illustrated the ability to improve receptor affinity for agonists but reduced signal transmission, which made them less useful. Next, in 2012, a research group was able to illustrate using a PAM to effectively boost the response to the body’s own cannabinoid, anandamide. However, just last month, researchers at VCU created a new type of CB1 PAM, known as “ZCZ011”, which has proven capable of acting independently.

In these studies, researchers used mice lacking enzymes that break down the body’s endocannabinoids, since this breakdown can lead to its own effects. To model pain, researchers chose the Chronic Constriction Nerve Injury (CCI) model of neuropathic pain as well as the Carrageenan Model of inflammatory pain. In the first, after using surgery to induce neuropathic pain, ZCZ011 was injected and the mice were tested for mechanical and thermal allodynia 75 minutes later – in other words, tests were run to see how painful physical stimuli such as pokes or cold temperatures were to rodents. In the second model, similar tests were run, but this time with swollen paws from inflammation induced by carrageenan, which causes swelling when injected. Researchers also tested the binding rate of both the body’s own endocannabinoid, anandamide, and a synthetic strong agonist, CP55,940, when administered at the same times as ZCZ011.

The results indicate that ZCZ011 may be a very practical and effective CB1 receptor-based painkiller. As expected, it increased CB1 receptor agonist binding while decreasing antagonist binding. This means that when applied with THC or other agonists, ZCZ011 would have a multiplying effect on the receptor signaling that occurs. However, given alone, ZCZ011 did not produce psychoactive effects in mice. No immobility, hypothermia, or locomotor depression was observed. In contrast, however, ZCZ011 completely blocked thermal and mechanical pain in neuropathic pain tests, suggesting it may serve as an effective painkiller in such conditions. Even in the carrageenan-induced swelling, ZCZ011 reduced thermal and mechanical pain. However, unlike enzyme inhibitors that allow cannabinoids to stay active longer, it did not affect overall levels of cannabinoids available in the brain.

Don’t expect ZCZ011 to be available to patients any time soon; further animal testing must be done to even begin human testing, and afterwards the FDA would have to approve/license its sale in the states. However, regardless of whether ZCZ011 specifically goes on to be a commonly used PAM, the concept of CB1 PAMs has now been proven. It is possible to activate CB1 receptor effects without psychoactivity. At this point in time, we can predict with good confidence that CB1 PAMs will eventually wind up in the hands of patients, which will mean that even patients in non-medical cannabis states will be able to benefit from cannabinoid research.


Works Cited

Bogna Ignatowska-Jankowska, Gemma Baillie, Steven Kinsey, et al. (2015) “A Cannabinoid CB1 Receptor Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with no Psychoactive Effects.” Published online 8 June 2015 <<>>.

 Elham Khajehali, Daniel T. Malone, Michelle Glass, et al. (2015) “Biased Agonism and Biased Allosteric Modulation at the CB1 Cannabinoid Receptor.” Molecular Pharmacology (2015) 88:368-379.