Alongside morphine, managing pain by using cannabinoid receptor agonists is as old as time immemorial.1 Indeed, medicinal preparations of the cannabis plant, which are taken by smoking, vaporization, transdermal application, and by oral ingestion, have been observed to produce “analgesic, anti-anxiety, anti-spasmodic, muscle relaxant, anti-inflammatory and anticonvulsant effects.”2 While cannabis preparations have been used for millennia for the treatment of pain, only recently have we begun to understand the endogenous cannabinoid signaling system responsible for these effects. This guide will explore the science behind phytocannabinoid — (or exogenous cannabinoids, such as from the cannabis plant) and endocannabinoid (EC) —mediated pain relief and its potential impact on medicine today.
Pain Perception (Nociception) Is A Major Function Of The ECS
By speculating and studying the effects of cannabis on various types of pain, we have established that pain perception and its relief is one of many major functions facilitated by the endocannabinoid system (ECS). Better understanding the multifactorial mechanisms by which this pain relief is achieved — through endogenous or exogenous cannabinoid signaling — is of benefit to patients and healthcare providers everywhere, given that managing chronic pain is no easy task (as evidenced by the opioid epidemic). While the devastating result of chronic opioid use can easily be seen by observing the consequences of opioid abuse in society today, cannabinoid-based therapy offers a novel approach to treating chronic pain in a much safer and, perhaps, more efficacious manner. The key factor that makes cannabis a safer, more appealing alternative to opioids for pain management is the fact that cannabis doesn’t cause respiratory depression like opioids do. Indeed, there has never been a fatal overdose from cannabis, whereas the number of opioid-related overdose deaths climbs daily. This is one of the main reasons cannabinoid therapies for pain is such a promising and potentially significant facet of modern medicine.
Overlap Between Endocannabinoid & Opioid Systems In Pain Perception
On a more general note, “agonist-activated cannabinoid receptors modulate nociceptive thresholds, inhibit release of pro-inflammatory molecules, and display synergistic effects with other systems that influence analgesia, especially the endogenous opioid system.”1 Thus, not only does the ECS play its own significant and unique role in pain control, but it is closely related with the functioning of other major systems, such as the endogenous opioid system. Indeed, cannabis has been shown to be incredibly effective at helping patients reduce or completely eliminate opioid intake altogether — and that’s no coincidence based on the science.3 As we dive further into what attributes of CB1 and CB2 make them uniquely responsible for pain control, this expansive system will become further elucidated.
Breaking Down Endocannabinoid Pharmacology
The pharmacology behind endocannabinoid (EC)-mediated analgesia can generally be broken down into CB1, CB2 and a third, non-cannabinoid receptor-mediated mechanism, just like many of the other therapeutic and psychomimetic effects of cannabis. Recent research has shown that the endocannabinoidome and its functioning cannot be explained solely by these two well-studied cannabinoid receptors. In a general sense, “ECs acting at CB1 negatively regulate neurotransmission throughout the nervous system, whilst those acting at CB2 regulate the activity of CNS immune cells. Signaling through both of these receptor subtypes has a role in normal nociceptive processing and also in the development resolution of acute pain states.”1 Since CB1 receptors are primarily distributed across the brain, while CB2 receptors are primarily located in immune cells, it stands to reason that the mechanisms by which they mediate pain signaling will be unique. Further breaking down these pathways into CB1, CB2, and non-cannabinoid receptor categories allows for a deeper understanding of how these mechanisms affect pain perception and control.
Pain-Control Via CB1: The Primary Analgesic Pathway
“The analgesic effects of cannabinoids and their ligands are primarily mediated by the cannabinoid receptor 1 (CB1) via inhibition of presynaptic gamma–aminobutyric acid (GABA) and glutamatergic transmission.”4 As mentioned earlier, CB1 mediated pain relief results from negatively modulating neurotransmission in the brain. This is because GABA is the primary neurotransmitter for suppressing neuronal excitability, and so when CB1 modulates levels of GABA (an inhibitory neurotransmitter) and inhibits the excitatory neurotransmitter glutamate, it’s considered to function as a negative regulator.
The Distribution Of CB1 Receptors In The Brain & Its Significance
CB1 receptors are ubiquitous in the anatomical areas of the brain that are responsible for pain processing and control, among other important biological functions. The CB1 receptor is a seven transmembrane G-protein coupled receptor (GPCR) and “its properties encompass a great deal of molecular, cellular and functional complexity.”5 Perhaps even more surprising and pertinent to the conversation around pain is the fact there exists 10 times as many CB1 receptors than mu-opioid receptors (the receptor that morphine acts upon) in the brain.6 This discovery alone certainly makes CB1 receptor mediated pain relief an attractive target in pain management — especially for chronic pain, where opioids are generally contraindicated. Examining which brain regions contain significant CB1 density is critical to identifying and understanding its role in mediating pain perception.
CB1 Receptors In The Periaqueductal Gray (PGA) Are A Key Area Of Interest
One of the key areas of interest for the CB1 receptor is the periaqueductal gray (PAG) along with the amygdala and cortex. The PAG is an area of the brain identified as being involved with highly aversive states such as nociception (pain perception) and anxiety. A 2009 study showed that stressful stimuli stimulated ECB (endocannabinoid) production in the PAG, and that CB1 agonist administration (or administration of drugs that “facilitated ECB related neurotransmission”) produced antinociceptive (painkilling) and antiaversive effects.7 Thus, this evidence clearly demonstrates the significance of CB1 as a novel target for cannabinoid and ECS mediated analgesia.
Pain Control Via CB2 Related Mechanisms
Unlike CB1 receptors, which are spread throughout the brain, CB2 receptors are widely distributed among the immune cells in the body. This receptor class is known to have powerful immunomodulatory effects that can mitigate the release of pro-inflammatory factors and cytokines from these immune cells and influence inflammatory pain processing.4 Since the immune system can release cytokines and factors that cause inflammation and pain, CB2 is of interest in pain control since it’s ubiquitous in immune regions of the body.8 In 1999, “Direct evidence of CB2-mediated anti-nociceptive effects was first reported… using the selective CB2 agonist, HU-308, which markedly decreased nociceptive behavior in the hind paw model of formalin treated rats”.9 A more recent knockout study (where certain genes are rendered inactive) in 2016 demonstrated how mice that lack the CB2 receptor display a highly inflammatory phenotype.8 The ability of the CB2 receptor to suppress secretion of these pro-inflammatory factors is fundamental to its role in both inflammatory and nociceptive pain perception and management. Furthermore, more recent research is also uncovering the presence of CB2 receptors in the sensory neurons in the brain and realizing their role in pain control, as well.10
Pain Control by Alternative, Non-Cannabinoid Receptor Mechanisms
While many pharmacological mechanisms of cannabinoid and endocannabinoid mediated analgesia can be explained in terms of either the CB1 or CB2 receptor, we now know the full picture is much more complex, and that it often involves non-cannabinoid receptors to exert its effects. The endocannabinoid anandamide is a good example to use to better illustrate this point. As the intricacies of the ECS are better understood, recognizing the role of these mechanisms will provide further exploration into pain control.
Vanilloid Receptor 1 (VR1) & Anandamide Blood Levels In Analgesia
High-blood levels of anandamide, one of the two well-known endocannabinoids, has been shown to play a key role in pain perception through a CB1-independent mechanism. “Anandamide acts in pain, depression, appetite, memory, and fertility (due to its uterine synthesis). Anandamide is synthesized enzymatically in brain areas that are important in memory and higher thought processes, and in areas that control movement.”1 In regards to its role in pain perception, it all comes down to the levels of anandamide in the blood (which can be modulated by enzymes the body makes to degrade anandamide or mechanisms by which its degradation is prevented) and a non-cannabinoid receptor called the Vanilloid Receptor (in this case, Vanilloid Receptor 1 or VR1). It is crucial to note here that the Vanilloid Receptor (VR) family is ion-gated, non-G protein coupled receptors that are completely different in structure and function from endocannabinoid receptors. While low concentrations of anandamide causes neurotransmitter inhibition from nociceptive primary sensory neurons by a CB1 receptor mediated mechanism, high concentrations of anandamide “increase the frequency of miniature excitatory postsynaptic currents recorded from substantia gelatinosa neurons by a VR1 receptor-mediated mechanism.”11
Thus, the concentration of anandamide determines which receptors it acts upon and what effects it will produce. “This may be an important presynaptic mechanism modulating pain perception at the spinal level. Indeed, nociceptive primary sensory neurons co-express CB1 and VR1 receptors to a high degree, giving further support to a complementary role for these receptors.”11 As such, modulating anandamide levels and preventing its enzymatic degradation has become an attractive target for analgesia, and can be achieved through the endogenous or exogenous modulation of the ECS.
Closing Thoughts On The ECS & Analgesia
The current modality surrounding the treatment of chronic pain is one that generally relies on opioids, and the dangers surrounding these prescriptions, including addiction and overdose, are unfortunately widespread. As the ECS becomes a growing target for research, understanding how the endocannabinoid receptors can help modulate pain is of the utmost importance. If this avenue can allow for the management of pain without crippling side effects and the risk of abuse/overdose, the importance of the ECS cannot be understated. Be it reaching a means to elevate blood anandamide levels naturally, or properly utilizing endocannabinoid receptors to trigger analgesia, the ECS provides an endogenous avenue to help mitigate pain safely and naturally, and cannabis is the key to further our understanding of this system.
- Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430692/.
- Cannabis sativa: The Plant of the Thousand and One Molecules. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740396/.
- Lucas, P. Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain. J. Psychoactive Drugs 44, 125–133 (2012).
- Barrie, N. & Manolios, N. The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease. Eur. J. Rheumatol. 4, 210–218 (2017).
- Busquets-Garcia, A., Bains, J. & Marsicano, G. CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity. Neuropsychopharmacology 43, 4–20 (2018).
- Sim, L. J., Selley, D. E., Xiao, R. & Childers, S. R. Differences in G-protein activation by mu- and delta-opioid, and cannabinoid, receptors in rat striatum. Eur. J. Pharmacol. 307, 97–105 (1996).
- Moreira, F. A. et al. Antiaversive Effects of Cannabinoids: Is the Periaqueductal Gray Involved? Neural Plast. 2009, (2009).
- The CB2 receptor and its role as a regulator of inflammation. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075023/.
- Hanus, L. et al. HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. U. S. A. 96, 14228–14233 (1999).
- Peripheral Nerve Injury Induces Cannabinoid Receptor 2 Protein Expression in Rat Sensory Neurons – PubMed. https://pubmed.ncbi.nlm.nih.gov/16084654/.
- Morisset, V. & Urban, L. Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord. J. Neurophysiol. 86, 40–48 (2001).