Delivering Cannabis Pain Relief Directly to the Site

Marc Moulin November 13, 2018 0 comments

New research explores the frontiers of how cannabis brings source specific pain relief.

Chronic pain is a part of the everyday life of approximately twenty percent of Canadians. Further, half of those Canadians report that they have been experiencing chronic pain for at least ten years. This represents a significant proportion of their life. Unfortunately, in recent years, receiving chronic pain treatment has proved to be more difficult. The opioid epidemic has led to increased shaming of prescription opioid use. Subsequently, it has also resulted in some physicians hesitating to prescribe opioids to their patients. Positively, at least, these facts, combined with increasing scientific evidence supporting cannabis as a pain reliever, have led to increases in cannabis-related pain therapy. But, cannabis currently has no source specific pain relief mechanism. In other words – most cannabis medicine targets the whole body, rather than specific sections of it.

However, cannabinoid pain therapy is not without limitations. Because cannabinoid receptors are located throughout the entire body, pain relief can come with some unwanted effects. For example, while THC binding to CB1 receptors in the spinal cord dulls the pain pathway to the brain, THC binding to CB1 receptors in the brain also causes cognitive impairment. In other words – picture a patient with nerve pain in their back. Surely this patient shouldn’t have to forego driving a car simply because they have to take THC-rich medication simply to get by. Further – this patient also shouldn’t be forced back into opioid medication with its side effects.

Unquestionably, the ideal desired effect would be achieved independent of any side effects. Fortunately, advancing cannabinoid science suggests that this could eventually be possible. Researchers are currently exploring how “allosteric modulators” can change how effectively cannabinoids bind to specific receptor sites. Overall, this would lead to the ability to deliver source specific pain relief without the unwanted side effects.

cannabis, opioids, opioid epidemic, USA, legalization, cannabinoids, pain, pain relief, economics, prescription

[bsa_pro_ad_space id=25]

Orthosteric vs. Allosteric Binding Sites

Cannabinoid receptors belong to a family of receptors called G-coupled-protein receptors (GCPRs). Research has revealed that GCPRs have binding sites called orthosteric and allosteric binding sites. Here’s how they each work following their activation:

  • Orthosteric sites are the main binding sites for cannabinoids. For example, THC binding to the CB1 receptor. [1]Nussinov, R., & Tsai, C. J. (2012). The different ways through which specificity works in orthosteric and allosteric drugs. Current Pharmaceutical Design18(9), 1311-1316.
  • Allosteric sites bind with allosteric modulators to change the shape of the receptor to either uncover (positive allosteric modulator) or hide (negative allosteric modulator) additional orthosteric binding sites.

For example, research has shown that CBD is a negative allosteric modulator to CB1, interfering with how THC binds to the CB1 receptor.

CBD Acts as a Negative Allosteric Modulator of CB1

In a study published in the British Journal of Pharmacology (2015), the researchers investigated CBD as a negative allosteric modulator of CB1. This research is based on previous reports demonstrating that CBD acts as an antagonist to CB1 receptors. They subsequently found that CBD reduced the efficacy and potency of 2-AG and THC in cells expressing CB1 receptors. The CBD behaved like a non-competitive negative allosteric modulator of CB1 receptors. So, in other words, there was no direct binding of CBD with the orthosteric site of the CB1 receptor. [2]Laprairie, R. B., Bagher, A. M., Kelly, M. E. M., & Denovan‐Wright, E. M. (2015). Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. British Journal of … Continue reading

Therefore, the authors concluded that allosteric modulation, in combination with effects not mediated by CB1 receptors, could explain CBD’s mechanism of action. This is undeniably important. Moreover, while orthosteric sites tend to be uniform across CB1/CB2 receptors, allosteric sites may vary across the body as seen in other receptors.[3]Wenthur, C. J., Gentry, P. R., Mathews, T. P., & Lindsley, C. W. (2014). Drugs for allosteric sites on receptors. Annual Review of Pharmacology and Toxicology54, 165-184.

[bsa_pro_ad_space id=26]

Allosteric modulators could then exhibit more precise mechanisms of action and hold promise for the discovery of drugs which may have fewer side effects than those targeting the orthosteric site.  Research into novel allosteric modulators is underway, but direct applications are limited so far. [4]Nguyen, T., Li, J. X., Thomas, B. F., Wiley, J. L., Kenakin, T. P., & Zhang, Y. (2017). Allosteric modulation: an alternate approach targeting the cannabinoid CB1 receptor. Medicinal Research … Continue reading


Novel CB1 Positive Allosteric Modulators

Although some research has focused on improving the efficacy of exogenous cannabinoids, recent innovative research has demonstrated that novel CB1 allosteric modulators can enhance the effects of the body’s endogenous cannabinoids, such as anandamide.

In a study published in Neuropsychopharmacology (2015), the researchers showed that a novel positive allosteric modulator called ZCZ011 enhanced in vitro and in vivo binding of anandamide. ZCZ011 elicited CB1-mediated anti-nociceptive effects in neuropathic and inflammatory models of pain without corresponding cannabis-associated side effects.[5]Ignatowska-Jankowska, B. M., Baillie, G. L., Kinsey, S., Crowe, M., Ghosh, S., Owens, R. A., … & Zanato, C. (2015). A cannabinoid CB 1 receptor-positive allosteric modulator reduces … Continue reading

Suppressing Pain – Without Causing Dependency?

Moreover, research uncovered similar effects in a 2018 study published in Biological Psychiatry in which the researchers detailed the success of a positive allosteric modulator called GAT211. They evaluated GAT211 for anti-nociceptive efficacy and tolerance in neuropathic and inflammatory pain models in mice. GAT211 proved to be a safe and effective analgesic therapy overall. And, perhaps most significantly, those treated in the study avoided the undesirable side effects of tolerance, dependence, and abuse liability.[6]Slivicki, R. A., Xu, Z., Kulkarni, P. M., Pertwee, R. G., Mackie, K., Thakur, G. A., & Hohmann, A. G. (2018). Positive allosteric modulation of cannabinoid receptor type 1 suppresses pathological … Continue reading

Therefore, in another study, published in Neuropharmacology in 2019, the researchers aimed to assess the efficacy of CB1 allosteric modulators on easing the symptoms of Huntington’s Disease in mice models. An early change that occurs in Huntington’s Disease in a reduction in CB1 levels in the brain.

The researchers hypothesized that certain CB1 positive allosteric modulators could enhance the binding of endocannabinoids anandamide and 2-AG to the orthosteric binding site. They were correct.[7]Laprairie, R. B., Bagher, A. M., Rourke, J. L., Zrein, A., Cairns, E. A., Kelly, M. E., … & Denovan-Wright, E. M. (2019). Positive allosteric modulation of the type 1 cannabinoid receptor … Continue reading Accordingly, a positive allosteric modulator called GAT229 improved cell viability, improved motor coordination, delayed symptom onset, and normalized gene expression.

The Future of Source Specific Pain Relief

Overall, research into cannabinoid receptor allosteric modulation is in its infancy, as cannabinoid allosteric modulators were only discovered in 2005. Since then, these modulators have only proved to be viable in laboratory settings. Furthermore, how researchers might target specific sources of pain in humans with exogenous cannabinoids is unclear.

Regardless, allosteric modulation of cannabinoid receptors represents an exciting frontier in cannabinoid-based pain therapy. It could hold the key to enhancing the pain-relieving power of the endocannabinoid system. On top of this, it could minimize the unwanted effects common with cannabinoid medicine. Overall, only time will tell – but since the recent upsurge in studies on the potential of cannabis, it looks like researchers will now get answers sooner than later.