Results from a series of experiments in mice and in human neurons suggest that an ion channel protein known as transient receptor potential canonical 5 (TRPC5), represents important contributor to tactile and spontaneous hypersensitivity to pain after inflammation. The studies, by researchers at Medical College of Wisconsin (MCW), indicate that inhibitors of the non-opioid-based target could represent a new therapeutic approach against inflammatory pain in humans.

The newly reported work, headed by Cheryl L. Stucky, PhD, a professor in the MCW Department of Cell Biology, Neurobiology and Anatomy (CBNA), showed how blocking TRPC5 alleviated chronic touch pain and spontaneous pain in mouse models of disorders including sickle cell disease, migraine, chemotherapy-related pain, and surgical pain.

TRPC5 is expressed in both mouse and human neurons that send pain signals to the spinal cord, Two TRPC5 inhibitors are already in early clinical trials, for treating kidney disease and for treating depression. “Pending successful completion of Phase 1 safety tests, these drugs could potentially be fast tracked for use in chronic pain patients,” stated Katelyn Sadler, PhD, who is co-first author of the team’s published study in Science Translational Medicine. The paper is titled “Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice.” Sadler and Francie Moehring, PhD, also at the CBNA, are co-first authors of the study.

TRPC5 is a new, non-opioid based target for chronic pain management. [Stucky Lab, Medical College of Wisconsin]

The ability of organisms to detect non-painful and painful pressure is critical for the development, protection and survival, but touch sensation can be distorted by tissue damage or disease, the authors explained. This can result in innocuous light touch being perceived as painful, while painful touch becomes more intense, and spontaneous pain can also arise even when there is no apparent stimulus “Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury,” the authors wrote. “The molecular basis of these sensations is not fully understood, and therefore, few adequate, non-addicting therapies exist.”

The team’s newly reported research has identified TRPC5 as a potential therapeutic target for injury-related tactile and spontaneous pain. For their studies, the researchers administered drugs that block TRPC5 activity to mice with sickle cell disease, migraine, chemotherapy-related pain, or surgical pain. They found that the drugs reversed touch pain in all of the models.

But because each model differs in terms of how long the accompanying pain lasts and how the tissue is injured, the researchers also wanted to identify a convergent factor that could be driving pain—in a TRPC5-dependent fashion—in each model. Using lipid mass spectroscopy, the team identified lysophosphatidylcholine (LPC) as a lipid that is elevated specifically at the site of injury, in all of the pain models.

Conversely, the TRPC5 inhibitors had no effect on pain in a mouse model of nerve damage, and the researchers showed that in this model, LPC levels were unchanged compared with levels in the non-injured animals. This finding prompted the researchers to reason that it is selective elevation of the lipid LPC that drives pain in the affected mouse models, by activating or sensitizing TRPC5.

Investigators in the lab of co-author John McCorvy, PhD, an assistant professor at CBNA, expressed the mouse or human forms of TRPC5 in non-native cells, and using high-throughput screening approaches, determined that TRPC5 could be activated by using specific doses of LPC. The Stucky Lab followed up on this finding, and showed that mice given LPC injections developed touch pain and spontaneous pain.

“Using pharmacologic and genetic tools, we found that TRPC5 mediates persistent pain after inflammatory and neuropathic injury in mice,” the authors wrote. “Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC).”

To determine where TRPC5 inhibitors were exerting an analgesic effect, the researchers then used the RNAscope technique to measure TRPC5 expression in the sensory neurons that convey 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 sickle cell disease and migraine, the mechanical sensitivity of these cells decreased. The team’s studies confirmed that 75% of human sensory neurons express TRPC5, the activity of which is directly modulated by LPC.

“On the basis of these data, we suggest that LPC might be a potential marker for the tailored application of TRPC5 inhibitors, which have high translational potential as non-opioid–based therapies for tactile and spontaneous pain,” the researchers concluded. “TRPC5 inhibitors might effectively treat spontaneous and tactile pain conditions characterized by elevated LPC.”

“What I’m most excited about is that we found TRPC5 is highly expressed in human sensory neurons, and LPC has been shown to be elevated in patients with fibromyalgia and rheumatoid arthritis in other studies,” said Stucky. “This means that TRPC5 could be a new, non-opioid target for alleviating pain in chronic inflammatory pain conditions that affect so many patients worldwide. Furthermore, our finding that TRPC5 had no effect on non-painful touch means that people can pick up their coffee cup, walk, dress themselves and caress their grandchild without losing tactile perception.”

Arthritis, fibromyalgia, diabetes, multiple sclerosis, and migraine, are among conditions that characterized by elevated levels of LPC, which may make their pain treatable with TRPC5 inhibitors, the team noted. “Our identification of the relationship between LPC and TRPC5 could allow for the tailored application of TRPC5 drugs in types of pain that are associated with elevations of this lipid,” said Sadler. “In other words, LPC could be a biomarker for types of chronic pain that could be treated with a TRPC5 inhibitor.”

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