Identify a new non-opioid-based target for the treatment of chronic pain


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A non-opioid-based target has been found to relieve chronic tactile pain and spontaneous pain in mice. Researchers at the Medical College of Wisconsin (MCW) found that blocking the canonical activity of transient receptor potential 5 (TRPC5) reversed tactile pain in mouse models of sickle cell disease, migraine, pain-related pain. chemotherapy and surgical pain.

TRPC5 is a protein that is expressed in mouse and human neurons that send pain signals to the spinal cord. The findings were published in Scientific translational medicine. The main and co-first authors of the manuscript, respectively, are MCW researchers Cheryl L. Stucky, Ph.D., professor, and Katelyn Sadler, Ph.D., postdoctoral fellow and former MCW postdoctoral fellow, Francie Moehring, Ph.D. ., all from MCW’s Department of Cell Biology, Neurobiology and Anatomy (CBNA). John McCorvy, assistant professor at CBNA, as well as graduate students and staff from Stucky and McCorvy Laboratories also participated. Learn more about the research and researchers here.

The MCW research team administered drugs that block TRPC5 activity in mice with sickle cell disease, migraine, chemotherapy-related pain, or surgical pain, and found that the drugs reversed tactile pain in all the models. Because each model differs in how long the accompanying pain lasts and how the tissue is injured, the researchers wanted to identify a converging factor that could be causing the pain (depending on the TRPC5) in each model. Using lipid mass spectroscopy, the team identified lysophosphatidylcholine (LPC) as a lipid that specifically rises to the site of injury in all of these pain models.

When TRPC5 inhibitors were tested in a mouse model of nerve damage, the drugs had no effect on pain. When the LPC levels of the model were examined, they did not change compared to the uninjured animals. The researchers believe that they selectively increase lipid impulse pain by activating or sensitizing TRPC5. The McCorvy Laboratory expressed human mouse forms or TRPC5 in non-native cells and, using high-throughput detection methods, determined that TRPC5 can be activated by specific doses of LPC. Stucky Laboratory tracked this finding and injected LPC into mice; animals injected with this lipid develop tactile pain and spontaneous pain.

To determine where TRPC5 inhibitors exert an analgesic effect, the researchers used the RNAscope technique to measure TRPC5 expression in sensory neurons that transmit pain signals to the spinal cord. Low levels of TRPC5 were found in mouse sensory neurons and high levels of TRPC5 in human sensory neurons. LPC was applied to mouse sensory neurons and, using electrophysiology, the team found that incubation with this lipid increased the mechanical sensitivity of these cells. When TRPC5 inhibitors were applied to sensory neurons removed from mice with and migraine, the mechanical sensitivity of these cells decreased.

“There are two TRPC5 inhibitors currently in clinical trials of kidney disease and depression,” Dr. Sadler said. “Pending the completion of Phase 1 safety testing, these drugs could be quickly followed for use in patients with chronic pain.”

From prescribing TRPC5 inhibitors broadly in all populations of pain patients, Sadler said, “Our identification of the relationship between LPC and TRPC5 could allow for the tailor-made application of TRPC5 drugs in pain types that are associated with elevations of this lipid. In other words, LPC could be a chronic pain type biomarker that could be treated with a TRPC5 inhibitor. “

“What excites me the most is that we found that TRPC5 is highly expressed in humans , and LPC has been shown to be elevated in patients with fibromyalgia and rheumatoid arthritis in other studies, Dr. Stucky said. This means that TRPC5 could be a new non-opioid target to relieve pain in chronic inflammation conditions that affect so many patients around the world. In addition, our finding that TRPC5 had no effect on painless touch means people can grab their cup of coffee, walk, get dressed, and pet their grandson without losing tactile perception. ”

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More information:
KE Sadler et al., “The canonical potential of transient receptor 5 mediates mechanical and spontaneous inflammatory pain in mice.” Scientific translational medicine (2021). … scitranslmed.abd7702

Citation: Identification of a New Non-Opioid-Based Target for the Treatment of Chronic Pain (2021, May 26) Retrieved May 26, 2021 at based-chronic-pain.html

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