- Demonstrated that a novel compound alleviates inflammatory and neuropathic pain in mice without producing tolerance or signs of abuse liability.
- Supports the hypothesis that compounds that act as positive allosteric modulators of the cannabinoid-type 1 receptor may offer effective and safe treatment for hard-to-treat types of pain.
NIDA-supported researchers report progress in developing medications that relieve chronic pain and do not, like opioids, lose effectiveness with continued use or carry risks for abuse and addiction. Dr. Andrea G. Hohmann, graduate student Richard A. Slivicki, and colleagues at Indiana University, Bloomington, successfully tested a compound that enhances the natural analgesic activity of the endocannabinoid system.
The endocannabinoid neurotransmission system is a component of the body’s natural mechanisms for controlling pain. Cannabinoid neurotransmitters (endocannabinoids) produce analgesic effects by stimulating cannabinoid-type 1 receptors (CB1Rs). Some drugs, notably marijuana’s ingredient tetrahydrocannabinol (THC), infiltrate this system to also activate CB1Rs. These drugs produce analgesia, but also produce unwanted side effects, including cognitive and mood changes and, in some people, addiction.
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Dr. Hohmann and Mr. Slivicki propose that compounds that act as positive allosteric modulators (PAMs) of CB1Rs can strengthen endocannabinoids’ analgesic effects without producing unwanted THC-like side effects. PAMs are molecules that bind to receptors at sites (allosteric sites) that are distinct from the receptors’ typical activation sites (orthosteric sites) (see Figure 1). PAMs render receptors more responsive to activation by naturally occurring neurotransmitters; hence, CB1R PAMs may amplify the effects of endocannabinoid activation of CB1R, including analgesia. At the same time, because PAMs do not themselves activate receptors, CB1R PAMs may avoid the unwanted effects of cannabinoid pharmaceuticals, which bind to the orthosteric site and activate receptors throughout the brain.
The Indiana researchers investigated the analgesic and other effects of a CB1R PAM called GAT211, which was synthesized in the laboratory of Dr. Ganesh Thakur at Northeastern University. Mr. Slivicki, in experiments with mice, found that GAT211 suppressed pain responses in protocols that simulate human inflammatory pain and neuropathic pain:
- Inflammatory pain: A single injection of GAT211 enabled animals to tolerate more mechanical pressure on a paw that had been exposed to an inflammation-causing chemical agent (complete Freud’s adjuvant).
- Neuropathic pain: Daily injections of GAT211 enabled animals to tolerate more cold and mechanical pressure on a paw that had been exposed to a neuropathy-causing agent (paclitaxel) (see Figure 2). This analgesic effect was sustained with no loss of effectiveness over 19 days of treatment, equivalent to more than 2 years in the human life span.
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Moreover, GAT211 did not produce reward or dependence. Mice did not prefer a chamber that they associated with the receipt of GAT211 over one in which they had received vehicle solution. Nor did mice that had been treated with GAT211 for an extended period show signs of withdrawal when the researchers administered a compound that prevented CB1R activation. In contrast, mice treated with a THC-like cannabinoid drug exhibited profound physical withdrawal signs when exposed to the same CB1R blocker. In addition, when GAT211 was given together with other compounds that also increase activity in the endocannabinoid system, the combination treatment produced an enhanced therapeutic reduction of neuropathic pain.
Dr. Hohmann says there is an urgent need to identify effective analgesics that lack abuse potential, because chronic pain is a major factor contributing to the current epidemic in opioid addiction. She says, “I believe that CB1 allosteric modulators have the potential to change the face of pain management as we know it.”
The study was supported by NIH grants DA041229, DA009158, DA021696, and DA024628.
Slivicki, R.A.; Xu, Z.; Kulkarni, P.M. et al. Positive allosteric modulation of cannabinoid receptor type 1 suppresses pathological pain without producing tolerance or dependence. Biol Psychiatry. 2017 Jul 8. pii: S0006-3223(17)31761-4. doi: 10.1016/j.biopsych.2017.06.032. [Epub ahead of print]
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NIDA. (2018, June 14). Novel Compound Alleviates Hard-to-Treat Pain in Mice. Retrieved from https://www.drugabuse.gov/news-events/nida-notes/2018/06/novel-compound-alleviates-hard-to-treat-pain-in-mice