Scientists test a compound that acts on cannabinoid receptors in the peripheral nervous system meant to relieve pain without typical side effects of marijuana usage.
For millennia, people have been using naturally derived cannabis for a plethora of reasons including remedies for illnesses, recreation, and pain. Many US states have legalized or decriminalized marijuana usage due to its relatively low risk. For some people the “high” or psychoactive effects of marijuana cause issues such as anxiety, drowsiness, or increased heart rate, preventing them from taking advantage of potential medicinal benefits. Scientists hope to find a way around this and create a cannabis drug that is as beneficial as the natural plant without those unwanted side effects.
A group of scientists at Washington University in St. Louis looked to CB-13, a synthetically derived cannabis drug that operates in the peripheral nervous system—rather than the central nervous system, which can stimulate psychoactive responses—to test its effects on pain in mice. The results, published in Pain, showed that short term dosing with CB-13 significantly reduced mechanical and thermal pain. However, the findings are equivocal regarding how well the drug sidestepped unwanted side effects.
Cannabinoids are compounds that activate two different receptors on neurons: cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. CB1 receptors are known to reduce pain. When CB1 receptors in the central nervous system (CNS) are activated, it causes psychoactive effects in humans and may also create a tolerance to the drug. Previous studies have shown CB-13 has a greater affinity for CB1 receptors but is restricted to the peripheral nervous system (PNS), so scientists hypothesized that it should relieve pain without causing unwanted side effects associated with cannabis.
In this study, led by the lab of Robert Gereau, the Dr. Seymour & Rose T. Brown Professor of Anesthesiology at WashU, mice’s paws were injected with complete Freund’s adjuvant (CFA), which causes inflammatory pain. Some were then dosed with CB-13 to test its analgesic effects. Mice received a poke or heat stimulus to their paw to test mechanical and thermal sensitivity. The mice were then given different doses and/or repeated dosing to test efficacy, tolerance, and behavioral effects.
After mice were injected with CB-13, there was a reduction in mechanical and thermal hypersensitivity. But with repeated dosing, the scientists found that by day seven, the analgesic effects of CB-13 were reduced, and they observed behaviors associated with activation of the CNS. Both the behavioral effects and increased tolerance suggest that the CNS was engaged with high and/or repeated dosing of CB-13.
The scientists also used electrophysiology and calcium imaging in dorsal root ganglia (DRG) to further examine the effects of CB-13. DRG are a group of cells next to the spinal cord that are associated with relaying sensory information in the PNS. Neurons in DRG are targeted in anesthesiology research because they are believed to play a central role in pain and pain relief.
The electrophysiology and calcium imaging results suggested that CB-13 reduces sensitization and excitability in DRG neurons, further confirming CB-13’s potential role in pain relief. Yet while CB-13 may have produced analgesic effects, future studies will focus on designing compounds that can better avoid untoward effects while directly engaging the PNS and relieving pain.
Alexa Toliver is a Neuroprep Postbacc Scholar in the lab of Robert Gereau, PhD.