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Targeting Nicotine Receptors to Treat Chemotherapy-Induced Peripheral Neuropathy

September 17, 2019
By Julie Meade, Ph.D. Candidate in the Department of Pharmacology & Toxicology, School of Medicine, Virginia Commonwealth University, MCV Campus, Richmond, Virginia

Dr. TomaDr. Wisam Toma spends his time sneaking up on mice and poking them when they’re not looking.  His poking tool – a von Frey filament – looks like a toothbrush, but with only one bristle, as thin as a human hair. He holds his breath, leans forward, cranes his neck, puts his tool into position, and ever so gently, taps the sole of the mouse’s paw.  The mouse jumps and flails his paw violently. Dr. Toma records a positive response.

Dr. Toma’s mice flinch because they have been treated with paclitaxel, a common cancer chemotherapeutic that rapidly causes inflammatory pain, and later causes chemotherapy-induced peripheral neuropathy (CIPN).  CIPN produces numbness, tingling, burning, stabbing pain, that can last for the duration of chemo treatment, or for weeks, months, or years after completion of chemo. Like Dr. Toma’s paclitaxel mice, human cancer patients with CIPN can mistake a light touch as extremely painful.  Further, the ongoing numbness and tingling in chemo patients’ hands can make it difficult to perform tasks of daily life, like buttoning clothes. Imagine how hard it would be to text your friends when your hands constantly feel like pins and needles.

Dr. Toma is a postdoctoral pain researcher in the Department of Pharmacology & Toxicology at Virginia Commonwealth University. When he was a Ph.D. student at VCU, he helped establish the mouse model of CIPN he uses today. “I fell in love with the project and started working on it,” he said. That meant getting really good at poking mice.

New analgesics for neuropathy - CIPN and otherwise - are desperately needed. Current treatments for symptoms of neuropathy are only slightly better than placebo, come with side effects, and do not treat the underlying cause of neuropathy, Dr. Toma explained.  “One of the CIPN features that is replicated between human patients and preclinical models is the degeneration of nerve fibers in the skin,” Dr. Toma explained. By using a mouse with CIPN, we can test experimental analgesics specific for pain caused by this type of nerve fiber damage. More than look for new drugs that treat the perception of pain, we can take the analgesic development one step further and treat the underlying cause of the pain: the nerve fiber damage itself. “So by looking at these fibers when they are reduced by chemotherapy, when we use our candidate analgesics, we can see if these candidate analgesics prevent the degeneration of nerve fibers,” Dr. Toma said. 

One of Dr. Toma’s successful analgesics for CIPN was nicotine. This did not make sense to me. How could something that causes cancer treat chemo side effects?

Dr. Toma explained that mice with CIPN show improvement in pain tests when given nicotine. Most importantly, nicotine before and during paclitaxel treatment prevented nerve fiber degeneration, preventing future pain due to CIPN from ever having a chance to happen. “The doses of nicotine we used were not carcinogenic in vitro or in vivo,” he added. Dumbfounded by these results, I naively asked, “Should we smoke if we have pain?”

“No,” he replied, definitively. Unsurprisingly, cigarettes are not a safe alternative to Tylenol.  Nicotine is a non-selective agonist for nicotinic acetylcholine receptors (nAChRs).  nAChRs play roles in many physiological and cognitive processes, such as addiction, anxiety, focus, muscle contraction, gastrointestinal functions, and pain. “That is why we are looking for [nAChR subtype-selective] analogues to nicotine, that do not show abuse liability or withdrawal symptoms,” he said. 

“Current work on selective agonists to the α7 nicotinic receptor subtype shows that they are viable targets, with promising results for reversing and preventing neuropathy, and inflammation, as well,” Dr. Toma said, beaming, referring to his recent publication.  Typically, paclitaxel causes an inflammatory reaction, which activates immune cells.  These activated immune cells infiltrate healthy nervous tissue, causing the damage that leads to CIPN.  We don’t know the exact mechanism yet, but it looks like the α7-selective drug “R-47” is able to block this inflammatory response.  Mice given R-47 before paclitaxel did not have as much immune cell activation in their spinal cords.  Similar to the mice pretreated with nicotine, the paw nerve fibers of mice pretreated with R-47 looked healthy, and the mice did not flinch when poked lightly, despite receiving paclitaxel. 

Dr. Toma’s previous work with curcumin (found in the spice turmeric) gives further support to the idea of using α7-selective drugs for pain relief.  Curcumin, which works through α7, was able to reduce pain-like behavior in a different mouse model of inflammatory pain. 

Unlike nicotine or morphine, α7-selective modulators do not show drug abuse liability in laboratory tests.  And unlike gabapentin, which is sometimes prescribed to mask the symptoms of neuropathy, α7 modulators do not sedate the mice or impair their ability to do a balancing task.  Rather, these α7 modulators appear to treat the pain without psychoactive side effects.  α7 modulators like R-47 and curcumin need more preclinical testing, but it would be amazing if Dr. Toma’s work on these compounds could become the foundation for a new class of safe, non-addictive analgesics for neuropathy. 

Until then, it couldn’t hurt to eat more curry.

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