Editor’s Note: The 2016 annual meeting of the Society for Neuroscience took place November 12-16, 2016, in San Diego, US. Part 2, below, of our coverage of the meeting is a summary of new findings on cannabinoids presented in a poster and at a related press conference. (See Part 1 here and Part 3 here).
Compounds found in the marijuana plant, Cannabis sativa, have been used for centuries to alleviate pain. Today, research is providing more details about how cannabinoids might be used to effectively treat chronic pain. But aside from plant or synthetic sources, there is another fount of cannabinoids: the brain. Now, researchers have shown that endogenous cannabinoid signaling can be harnessed to treat pain with the help of a compound that makes cannabinoid type 1 (CB1) receptors more sensitive to the body’s own natural cannabis-like signals.
The work was presented in a poster by Richard Slivicki, a graduate student in the laboratory of senior author Andrea Hohmann at Indiana University, Bloomington, US.
The cannabinoid approach
Research has shown that cannabis and its derivatives can effectively treat some pain conditions (see RELIEF related feature). But the drugs are limited by their psychoactive side effects, which mainly result from the plant ingredient tetrahydrocannabinol (THC) activating CB1 receptors. Researchers are aiming to find ways to reduce pain without producing these side effects, which can impair cognition and movement.
Hohmann also discussed the research in a press conference at the meeting. There, she explained that in addition to CB1’s “classical” binding site, where both endogenous cannabinoids and THC bind, the G protein-coupled receptor also contains a distinct “allosteric” site. “When a positive allosteric modulator binds to this separate site, it increases the amount of time that endocannabinoids stay associated with the receptor, so the net result is amplified endocannabinoid signaling,” she said.
The researchers used a model of chemotherapy-induced peripheral neuropathy (CIPN) to study the therapeutic effects of a positive allosteric modulator (PAM) of CB1 synthesized by collaborator Ganesh Thakur at Northeastern University, Boston, US. First, Slivicki treated mice with paclitaxel, a chemotherapy agent that produces neuropathic pain. Much like patients who develop CIPN, the mice developed hypersensitivity to mechanical and cold stimuli.
Next, the researchers treated the mice with the CB1 PAM or a compound that inhibits breakdown of endocannabinoids. “We found that both compounds reduced hypersensitivity relative to the control, but only the CB1 PAM remained efficacious over several weeks without producing tolerance,” Slivicki told PRF. The CB1 PAM delivered for several weeks nearly normalized pain sensitivity in the mice, and at higher doses, it returned the sensitivity of the animals to pre-injury levels, he said.
No serious side effects
Importantly, the CB1 PAM was capable of suppressing neuropathic pain without significant side effects. The researchers used behavioral measures to test for the so-called CB1 tetrad of effects that indicate receptor activation: catalepsy, motor ataxia, tail flick anti-nociception, and hypothermia. They found that wild-type mice did not display activity in the tetrad. “Our results suggest the PAM is not activating CB1 directly,” Slivicki said. “The idea is that only in a neuropathic state or with a disordered nervous system would this type of agent become useful, circumventing side effects and abuse liability found with commonly used pain medications,” he added.
CB1 receptors are expressed in brain circuits that are critical to pain processing, but cannabinoid signaling also participates in brain circuits that control cognition, emotion, and arousal as well. Unlike a dose of THC from inhaled or ingested cannabis, which activates CB1 receptors throughout the brain and body, a PAM works more specifically, Hohmann said in the press conference. “The advantage of an allosteric modulator is that it’s only boosting endocannabinoid signaling under conditions where endocannabinoids are already being released and engaging those receptors. It is therefore likely to show a more limited spectrum of unwanted side effects compared to THC, the active ingredient in cannabis.”
That might explain the lack of side effects seen with a CB1 PAM. “It’s quite clear that endocannabinoids are mobilized and synthesized on demand to produce adaptive changes in pain responses,” Hohmann said. By using strategies that boost endocannabinoids, “you’ll only affect signaling at locations where endocannabinoids are already working”—in this case, pain-processing circuits. The CB1 PAM could also allow patients using opioids to take lower doses, thereby reducing unwanted side effects.
The current work adds to an emerging body of evidence suggesting that this strategy of relying on allosteric modulation is viable (Ignatowska-Jankowska et al., 2015; Nguyen et al., 2016).
Another strategy to enhance endocannabinoid signaling is to inhibit the enzymes that degrade the messengers—namely, monoacylglycerol lipase (MGL), which hydrolyzes the endocannabinoid 2-arachidonoylglycerol(2-AG), and fatty acid amide hydrolase (FAAH), which metabolizes anandamide. Hohmann said of those efforts, “I see the therapeutic promise, but those enzymes also degrade other lipids that don’t bind to cannabinoid receptors,” so an unintended consequence of inhibiting them may be elevated levels of other lipids with functions that are not yet understood. In contrast, Hohmann said, “allosteric modulation should theoretically have very good selectivity for amplifying effects of endocannabinoids alone.”
A lack of access hinders research
Researchers at the press conference including Hohmann and moderator Margaret Haney, Columbia University Medical Center, New York, US, lamented the lack of research on cannabinoids, despite the fact that a majority of states have legalized medical or recreational use of marijuana. “Our scientific understanding of plant cannabinoids is in its infancy, as is our understanding of endogenous cannabinoids,” Haney said. “It has been very frustrating to be a cannabis researcher and watch society move ahead with no input from the scientific community. There has really been very little consideration of science on this topic.”
The dearth of research is not due to a lack of interest or even funding, but to the classification by the US government’s Drug Enforcement Administration (DEA) of cannabis and all its derivatives as Schedule 1 drugs—even including cannabidiol, a compound with no psychoactive or abuse-related effects. “I have to treat it like it’s heroin; it’s locked up in a triple drug-safe room. The regulations make studying the plant and its components extremely tricky,” Haney said. The agency recently moved to allow researchers access to plants from sources beyond the previously single government-run farm, but that hasn’t made things any easier, Haney said, because the DEA declined to remove the Schedule 1 classification (Drug Enforcement Administration, 2016; Drug Enforcement Administration, 2016). The restrictions severely limit access for researchers if not consumers, which will slow the development and application of effective cannabinoid therapeutics for pain.
Related content:
As Medical Cannabis Moves Mainstream, Can It Provide Pain Relief? RELIEF. January 10, 2016.
See here for a plain language summary of this article on RELIEF, PRF's sister site.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
Image credit: Society for Neuroscience
