French and Danish researchers have taken us closer to understanding why specific compounds in cannabis might alleviate tremor disorders in some patients.
After showing that a cannabinoid analog called WIN55,212-2, a compound very similar to the cannabinoids found in cannabis, lessened tremor symptoms in mice, the researchers discovered that natural endocannabinoids produced in the spine act against tremor by activating spinal astrocytes, which are a kind of star-shaped, non-neuronal cell, adding new layers to our knowledge of the nervous system.
"Astrocytes for a long time were overlooked because they signal in different ways than neurons," Eva Maria Maier Carlsen, a researcher at the University of Copenhagen and first author of a paper published March 18 in Nature Neuroscience told The Academic Times. "Neurons are very precise with a short signaling duration, whereas astrocytes are longer lasting and more diffuse. Most of what we know about them is from the brain, so putting them in the spinal cord is also part of the novelty of this study."
In the study, Carlsen and her colleagues first demonstrated that WIN55,212-2 reduced trembling in mice that had previously been injected with the stimulant harmaline, which they used to simulate the essential tremor seen in human patients. When they injected WIN55,212-2 into the spinal cords of those mice, trembling dropped off within half an hour. "It was dampening it, but it was not removing it completely," Carlsen added.
To understand why this occurred, the team used an electrode to stimulate spinal cord slices from mice. Their data implicated astrocytes from a part of the spinal cord called the ventral horn. "The spinal column is functionally divided into a ventral and a dorsal horn," Carlsen said. The dorsal horn is generally an input for sensory information, while the ventral horn is generally an output for motion.
They discovered that endocannabinoids prompted astrocytes to release molecules known as purines, which in turn dampened the excitation of neurons. In effect, Carlsen explained, the astrocytes amplified the signal from the endocannabinoids. To cap it off, the team showed that their cannabinoid analog failed to suppress tremor in mice whose spinal astrocytes lacked type 1 cannabinoid receptors.
All of this suggests astrocytes could be crucial to understanding how endocannabinoids impact the nervous system. According to Carlsen, this squares with the latest findings on that kind of cell, which was once marginalized. "From a more classical neural perspective, it's quite new and novel that astrocytes can modify neuronal signaling," she said.
Astrocyte research first took off during the 1990s, when scientists showed they were capable of signaling. The latest studies have further illuminated their subtle yet crucial functions throughout the brain.
"It adds a complete new layer to the signaling of the brain that needs to be appreciated," Carlsen said. "A lot of research is going into mapping and making models of how the brain works — and leaving out a whole element makes it difficult."
Carlsen emphasized that the researchers do not have proof that tremor disorders always involve astrocytes. "We're going in and hacking a system," she said. "Whether or not that's part of the course of tremor, we don't know."
Carlsen's coauthor, Jean-François Perrier, explained that their study built on prior research suggesting that cannabinoids reduced tremors in multiple sclerosis. For her part, Carlsen emphasized that much of the evidence remains anecdotal.
"My impression is that [cannabis] does not work for all patients," Carlsen said. "When it works, it really works well for them. To me, that highlights the need to understand how the system works, so that they can try to find out which patients will benefit and who will not."
In the United States, research on cannabis remains heavily restricted — for example, scientists are effectively limited to examining a low-THC variety grown at the University of Mississippi. Even as some scientists in the U.S. and abroad have highlighted the potential risks of cannabis, the limitations now in place have made studying the substance a challenge.
"Denmark is one of the easier countries to do it," Carlsen said, before noting that cannabis research remains difficult even there and in other countries with less stringent restrictions: "It's very, very tricky — waiting years to get approval for a clinical trial."
"The cannabis literature is very patchy, and sometimes is contradictory as well," Perrier added.
Perrier emphasized the difficulty of studying astrocytes in humans, as well as the inherent limitations of mouse models. "Mice are not humans, so we can hope that there's a similar mechanism, but as long as it's not really demonstrated, we cannot be sure," he said.
The researchers hope that patients will ultimately benefit from their findings.
"I think having this focus of treatment in the spinal cord could have some potential, so that we get better at targeting the spinal cord if we are aiming at treating motor symptoms," Carlsen said. "That way, you don't mess up the brain."
"The obvious hope is that some doctors will be inspired to do clinical trials on humans for treating tremor with cannabinoids," she added. "And then I would hope that people get more interested in astrocytes, because they're really cool."
The paper, "Spinal astroglial cannabinoid receptors control pathological tremor," published March 18 in Nature Neuroscience, was authored by Eva Maria Meier Carlsen, Sarah Falk, and Jean-François Perrier, University of Copenhagen; and Urszula Skupio, Laurie Robin, Antonio C. Pagano Zottola, and Giovanni Marsicano, Neurocentre Magendie and University of Bordeaux.