Two professors from Harvard Medical School combined their respective skills to find an optimal treatment for pain. Cannabinoids were initially absent from one researcher’s focal point, but CBD hit the correct targets for better pain management. An optimal pair of pain signals became central in their collaborative research, proving the promiscuous nature of CBD.
Clifford Woolf, M.B., B.Ch., Ph.D. of Boston Children’s Hospital, teamed up with Bruce Bean, Ph.D. of Harvard Medical School to find a drug that treats pain. More specifically, their search was for a drug that orchestrates an iconic duet. The neurobiologists desired one pharmaceutical to turn up a specific signal, and Dr. Bean already knew that CBD shut down another (sodium ions.) (1)
THC versus CBD and pain
We discussed the relationship that a different pair of signals has with CB1 receptor agonists in the gut’s (vagus) nerve. THC manages pain by regulating cellular potassium and calcium switches that send signals up and down nerves. Otherwise, CB1 agonists like THC inhibits acetylcholine, which further shunts sensitivity at nerve endings.
Cannabinoids manage pain by moderating a symphony of sensory signals. (1, 2) Unlike THC, though, CBD does not directly agonize CB (cannabinoid) receptors. And mechanisms that CBD targets to treat pain were not fully identified in the research. (2) Professors Woolfe and Bean quantified the current and flow of potassium ions in mice under different conditions to assess pain responses.
A paper co-authored by Ken Mackie in 2008 identified the function of a purported third binding site for cannabinoids. (3) THC and CBD have opposing effects on the receptor known as GPR55, which affects a specific type of potassium signal — M current. CBD, therefore, performs one-half of the duet via the third cannabinoid receptor.
A particular heat-detecting channel likely exists on the sodium side of CBD’s pain management duet. Ionic sodium helps transport sensations from the base of a major facial nerve to its control board in the brain stem, for example. And CBD reverses this type of pain signal in part by desensitizing TRPV1 — sodium ions are one of TRPV1’s less discussed targets. (4-6)
Pain management with CBD and toxic receptors
Another example of TRPV1 desensitization is the pleasant feeling of a hot shower. CBD is more dynamic than hot water and spicy peppers, though. As such, the cannabinoid hits several targets in the body. Earlier, Dr. Bean discovered that tiny doses of CBD inhibit a toxic receptor, TTX. And sodium channels are blocked by TTX inhibition and not solely TRPV1 desensitization. (1)
In mice neurons, small doses of CBD act as a more efficient painkiller than an equal dose of bupivacaine. Of course, CBD is an imperfect drug due to its lack of selectivity. (2) In conclusion, CBD targets multiple sensory signals to induce analgesia.
Let us know in the comments if you or someone you know uses CBD for pain management. Do you want a follow-up study on CBD and toxic receptors in human neurons?
Zhang HB, Heckman L, Niday Z, et al. Cannabidiol activates neuronal Kv7 channels. Elife. 2022;11:e73246. Published 2022 Feb 18. doi:10.7554/eLife.73246
Zhang HB, Bean BP. Cannabidiol Inhibition of Murine Primary Nociceptors: Tight Binding to Slow Inactivated States of Nav1.8 Channels. J Neurosci. 2021;41(30):6371-6387. doi:10.1523/JNEUROSCI.3216-20.2021
Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A. 2008;105(7):2699-2704. doi:10.1073/pnas.0711278105
Gambeta E, Chichorro JG, Zamponi GW. Trigeminal neuralgia: An overview from pathophysiology to pharmacological treatments. Mol Pain. 2020;16:1744806920901890. doi:10.1177/1744806920901890
Anand U, Jones B, Korchev Y, et al. CBD Effects on TRPV1 Signaling Pathways in Cultured DRG Neurons. J Pain Res. 2020;13:2269-2278. Published 2020 Sep 11. doi:10.2147/JPR.S258433
Binshtok, A., Bean, B. & Woolf, C. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature449, 607–610 (2007).