While marijuana smoking is unlikely to become a safe and effective FDA approved treatment, cannabinoids will. The role of the endocannabinoids (EC) system and cannabinoid pharmacology is being studied intensely due to: 1) the affinity of cannabinoids with G-Coupled Proteins Receptors (GCPR), 2) the ubiquity of cannabinoid receptors CB-1 & CB-2 throughout the brain and body, and 3) the advantages of allosteric receptor modules for the development of novel treatments for pain, anxiety, obesity, cancer and neurodegenerative disorders.

It has been established that the acute effects of delta-9-Tetrahydrocannabinol (THC) is associated with moderate relief of pathologic pain via the activation of the CB-1 receptors, but not without producing numerous unwanted, centrally acting effects.

Recently the identification of allosteric modulators on the CB-1 has opened the door to the development of cannabinoid-based therapeutics due to the numerous advantages offered by targeting allosteric sites.

Why?

Binding of a pure positive allosteric modulator (PAM) to an allosteric site increases the affinity of the endogenous ligand for the orthosteric binding site and enhances the signaling by the endogenous ligand.

What Are Allosteric Modulators?

Allosteric modulators are compounds that bind selectively to allosteric sites on GCPR. There are three types of allosteric modulators:

  1. Positive allosteric modulators (PAMs) are allosteric ligands that bind to a site topographically distinct from the orthosteric site and enhance the affinity and/or efficacy of the orthosteric agonist.
  2. Negative allosteric modulators (NAMs) are allosteric ligands that decrease the affinity (cooperativity factor-α) and/or efficacy (modulation factor-β) of an orthosteric compound.
  3. Allosteric ligands that have no effect on the affinity and/or efficacy mediated by the orthosteric compounds are termed neutral or silent allosteric modulators (SAMs).

Recent research by Slivicki, et al., (2017) investigated whether the PAM on CB-1 signaling would suppress inflammatory and neuropathic pain without producing common cannabimimetic effects (intoxication, sedation, cognitive and memory deficits, and addiction). The investigation included:

  1. The pharmacological enhancement of endocannabinoid activity.
  2. The EC System and stress-induced modulation of pain.
  3. The EC system and medial prefrontal cortex (mPFC) dysfunction in pain states.
  4. Analysis of clinical failures utilizing the EC system for pain control.

As a result of this and similar investigations, it is clear that the EC system plays a key role in pain control. Preclinical models suggest that enhancing the EC signaling via activation of PAM may be an effective clinical strategy for mediating or blocking pain sensation. Yet gaps in our basic knowledge of the EC system and perhaps poor study design remain formidable challenges to advancing research toward clinical trials.

Why Does This Matter?

More than 100 million Americans suffer from chronic pain at a cost of around $600 billion a year in medical treatments and lost productivity, according to a report from the Institute of Medicine (IOM). Pharmaceutical companies and our NIH have tried to develop new pain treatments with very little to show for it. Treatment for this epidemic has changed little in 100 years.

In reality, patients with true chronic pain under the care of a highly trained specialist rarely abuse their medication or become addicts. Yet these drugs are inherently dangerous and often fall into the wrong hands.

Consequently, interest in pain control via the EC system has been the subject of a plethora of research aimed at developing an analgesic that does not cause tolerance, dependence, gastrointestinal dysfunction or cognitive impairment and provides such a narrow therapeutic window.

As Americans age and live longer, the prevalence of chronic pain will increase. Funding basic science and pain-specific research is desperately needed. Without viable alternatives to opioids, the future will indeed be painful.