Investigators at the department of neuroscience at the faculty of health and medical sciences at the University of Copenhagen have discovered the mechanism of action of a synthetic cannabinoid derivative on spinal astrocytes for reduction of pathological tremors. Pathological tremors can be idiopathic or triggered by injuries, neurodegenerative disease and motor disorders. The authors show cannabinoids can reduce tremors by regulating the release of purines that regulate the transmission of electrical signals at synapses. The team reported its results in the March 18, 2021 online issue of Nature Neuroscience.
Medical cannabis refers to cannabis and cannabinoids that are prescribed by physicians for their patients. There is limited clinical research to define the safety and efficacy of using cannabis to treat diseases and the use of cannabis for medical purposes is a subject of much debate.
Patients who self-medicate report an improvement of tremor symptoms with cannabinoid-containing drugs. In fact, the anti-tremor effect of cannabis has been confirmed in both clinical studies and an animal model of multiple sclerosis.
First author Eva Carlsen, who is a post-doctoral research associate at University of Copenhagen, told BioWorld Science that "we see that an injection of the synthetic cannabinoid WIN55,212-2 into the spinal cord turns on the astrocytes in the spinal cord and prompts them to release adenosine, which then reduces nerve activity and thus involuntary shaking." Cannabinoid (CB) receptors are ubiquitously expressed on axon terminals and astrocytes and natural endocannabinoids produced in the spine act against tremor by activating spinal astrocytes which are star-shaped, non-neuronal cells.
Since both voluntary and spontaneous movements are triggered when the spinal cord's motor neurons are activated, the researchers focused on the spinal cord. Movement is initiated when the motor neurons connecting the spinal cord with the muscles sends impulses to the muscles which leads to a contraction. Carlsen added that involuntary shaking occurs when the motor neurons send out conflicting signals at the same time.
In the study, the authors investigated the role of endogenous cannabinoids in the ventral horn of the spinal cord, a region responsible for limb movements. They found that depolarization of spinal interneurons released endogenous cannabinoids that activated astrocytic CB1 receptors, causing release of purines, which in turn dampened the excitation of neurons.
The authors induced muscle tremors in mice, and activated spinal cannabinoid receptors by intrathecal lumbar administration of the highly potent cannabinoid agonist WIN55,212-2. Thirty minutes after injection, tremor was strongly reduced in all tested animals.
Pretreatment of these animals with a cannabinoid antagonist nullified the anti-tremor effect of WIN55,212-2. Furthermore, WIN55,212-2 failed to suppress tremor in mice whose spinal astrocytes lacked type 1 cannabinoid receptors.
According to Carlsen, targeting spinal astrocytes "constitutes a highly targeted approach for delivering cannabinoids and will avoid affecting the neurons in the brain responsible for our memory and cognitive abilities." The authors hope that strategy would bypass potential adverse effects of medical cannabis. However, Carlsen also noted that there was no solid evidence that cannabis would work in treating pathological tremors in all patients and it would be necessary to "identify which patients will benefit and who will not."
Carlsen further stressed that the current study elucidated "the crucial functions of astrocytes throughout the brain and demonstrated that astrocytes were integral parts of neuronal networks involved in motor control." The study found that a key function of astrocytic endocannabinoid signaling was to decrease pathological tremor. Under normal physiological conditions, during motor activity, 10-Hz oscillations are carried from the motor cortex to the spinal cord, but these oscillations are not apparent in contracting muscles. In pathological situations, these tremors become visible, and the cerebellum or basal ganglia are important for their limitation. According to Carlsen, this study showed that spinal astrocytes provided a filter that can act on most forms of tremor.
In the future, the authors hope to do clinical tests on patients suffering from essential tremor to determine whether the new approach has the same effect on humans as on mice.
Ultimately, Carlsen hopes that these results "will provide insight into the signaling of astrocytes and endocannabinoids and the influence on behavior and will inspire new approaches to treatment of tremor and develop our understanding of how and when cannabis should be used."