Anyone who’s accidentally touched a hot stove can understand that pain protects us. It’s a warning signal to remove our bodies from noxious stimuli (don’t keep your hand on a stove) and a powerful reminder to avoid them in the future (order take-out). While many acute forms of pain are clearly giving us helpful information about the safety of our environment, chronic pain can be uselessly debilitating.

Chronic pain affects millions of Americans every year. Currently, opioids are prescribed to treat pain in a short term setting. These drugs work by binding to opioid receptors in the brain to reduce the perception of pain. Opioids also act on the reward centers in the brain, which can lead to dependence and abuse. According to the CDC, opioids were involved in 28,648 deaths in 2014. In addition to supporting addiction treatment, a major priority in curbing opioid addiction should be to find alternative drugs for pain management.

So what are some possible alternatives to opioids? One major area of research is to target the primary sensory neurons that detect painful stimuli in the first place. These neurons, called nociceptors, transduce chemical, thermal, and mechanical pain into an afferent signal that lets you know you’re hurt. One group of ion channels that transduces pain signals is the Transient Receptor Potential (TRP) ion channel family. Two particular channels, TRPA1 and TRPV1, have been studied as potential targets for painkillers. However, antagonists that block their function also impair many normal sensory functions, like thermal sensation and protective, acute pain. Because of these side effects, clinical trials of these antagonists failed.

Luckily, the activity of TRPA1 and TRPV1 is complex, and there are more potential ways to reduce their pain signaling than simply turning them off. Dr. Xinzhong Dong and his lab, who also study itch, targeted the interaction of TRPA1 and TRPV1 to see if they could alter pain signaling in primary sensory neurons (Weng et al., 2015).

TRPA1 and TRPV1 can form a heteromer in sensory neurons, and this interaction is thought to be involved in the nociceptive pathway. Weng et al. identified a transmembrane protein, Tmem100, that modulates the TRPA1-TRPV1 complex in a way that increases the pain-related signaling from TRPA1.

To determine if Tmem100 actually affects the perception of pain, Weng et al. performed a barrage of behavioral assays to if pain responses were different in regular mice compared to mice in which Tmem100 had been genetically deleted in primary sensory neurons. Unlike the failed TRPA1 antagonist clinical trials, the results of theTmem100 knockout showed a decrease in mechanical hyperalgesia (an undesired pain) and preservation of important TRP functions like thermal and mechanical sensitivity.

To understand how Tmem100 affects the TRPA1-TRPV1 complex, Weng et al. electrically recorded from patches of membrane where TRPA1-TRPV1 and Tmem100 were located. They subjected the cells to chemicals that normally activate either TRPA1 or TRPV1, and found that TRPA1 was much more likely to respond to the stimulus when Tmem100 was also present.

Next, after showing that Tmem100 binds to both TRP channels, Weng et al. set out to structurally alter the protein. They found a sequence of the protein on the intracellular domain of Tmem100 that was positively charged and likely to be a binding site for TRPA1 and/or TRPV1. When the putative binding site was changed to an uncharged sequence, binding between the mutant protein, Tmem100-3Q, and TRPA1 was abolished, but binding with TRPV1 was unchanged.

Then, when Weng et al. recorded from membrane patches with the TRPA1-TRPV1 complex and the mutant Tmem100-3Q present, they found a surprising result: Instead of increasing the probability of TRPA1 activity like the wild type Tmem100, Tmem100-3Q actually decreased the probability of TRPA1 responding to noxious chemicals. Moreover, they didn’t even need the full transmembrane protein to achieve this reduction in pain signaling. Weng et al. created a cell permeable peptide (CPP) that mimics the new binding site of the Tmem100-3Q mutant and injected it into wild-type mice. In addition to recapitulating the electrophysiological effects of the Tmem100-3Q mutant, this injectable peptide reduced mechanical hyperalgesia in normal animals, while leaving mechanical and thermal sensitivity intact.

Taken together, these experiments identify Tmem100 as a modulator of TRPV1-dependent TRPA1 activity and introduce a mutant CPP as a viable therapeutic agent for local pain relief.



Don’t miss Dr. Xinzhong Dong discuss “Mechanisms of Itch and Pain” at 4 pm this Tuesday, March 8th in the CNBC Marilyn Farquar Seminar Room.



Weng, H. J., Patel, K. N., Jeske, N. A., Bierbower, S. M., Zou, W., Tiwari, V., … & Geng, Y. (2015). Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron, 85(4), 833-846.

Weyer, A. D., & Stucky, C. L. (2015). Loosening Pain’s Grip by Tightening TRPV1-TRPA1 Interactions. Neuron, 85(4), 661-663.

Rachel Cassidy is a first year student in the UCSD Neurosciences Graduate Program. She is currently rotating in Jeff Isaacson’s lab studying the circuitry of the auditory cortex.



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