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Ouch!

Elizabeth Eyler Makes Sense out of Sensation

December 2009 - The summer before I started graduate school, while interning at the McCormick Foods Company in Shanghai, I learned that there is more than one Chinese word for hot. There is one word to warn someone that the soup is steaming hot, and another to convey that that soup is spicy hot, conveniently eliminating the need to clarify which hot you are referring to. Yet our single English word for both temperature-hot and spicy-hot reflects a fundamental aspect of how we perceive these two sensations. To us they both feel hot.

So perhaps it is no surprise that the receptor in our cells that responds to hot temperatures (over 42*C) is also activated by capsaicin, the spicy-hot compound found in chili peppers. This receptor, the TRPV1 ion channel, was first identified by Mike Caterina in 1997 during his postdoctoral work at the University of California, San Francisco. Now an associate professor of biological chemistry at Johns Hopkins, Caterina and his lab continue to study the TRPV ion channels and their roles in sensory function.

TRPV1—pronounced trip vee one—is one of a subset of “thermoTRPs” that respond to a range of temperatures from hot to cold. In addition to responding to distinct temperature ranges, the different thermoTRP channels also respond specifically to different substances, including growth factors, natural plant compounds, and synthetic chemicals. Caterina notes that there is often an intuitive relationship between the compounds that activate a given TRP channel and the temperature to which it responds: the same type of TRP channel may be activated by both hot temperatures and compounds that feel hot to us, while another type may be activated by cool temperatures and cool-feeling compounds. For instance, this is true for TRPV1, which is activated by both heat and capsaicin, and for TRPM8, which is activated by cold temperatures and cool-feeling menthol.

In addition to mediating temperature sensation, thermoTRPs also play a role in pain perception—another fact that I discovered in Shanghai, although at the time I had never heard of a thermoTRP. While adding ingredients to a spice mixture, I managed to brush a tiny amount of capsaicin oil from my fingertips to my eyelids. The subsequent, painful burning sensation led me to spend much of the rest of the afternoon rinsing out my eyes in the bathroom sink and vigorously scrubbing my hands with all of the soap I could find.

Standing over the sink that afternoon in Shanghai, I readily would have believed that thermoTRPs are enriched in neurons and nerve fibers specialized to detect painful stimuli and to relay pain signals from the body to the brain. However, I never would have dreamed that an active area of pain research is to use TRPV1 activators to reduce pain rather than enhance it. TRPV1 activation, as I experienced, is often quite painful. In addition, during conditions of inflammation, nerve injury, or chronic pain, TRPV1 can contribute to increased sensitivity to other painful and ordinarily non-painful sensations. For example, if your arm is inflamed and TRPV1 is activated, a pin-prick might become a very painful experience instead of only a mildly painful one, and even a fingertip lightly brushing the inflamed area might feel painful. However, in addition to enhancing pain sensation by activating TRPV1 channels, strong TRPV1 activators like capsaicin can also desensitize TRPV1 channels over time and contribute to pain relief.

Topical creams and gels containing capsaicin, such as Zostrix and Icy Hot Arthritis Therapy, are already available over-the-counter to provide temporary relief for conditions like arthritis and muscle pain. However, one of the limitations of capsaicin creams is the pungency of capsaicin, which often causes a burning feeling and irritation where the cream is applied. Synthetic compounds that activate TRPV1 and that may help avoid these side effects are being studied as possible pain relievers, and some are currently in clinical trials for ailments including migraine, joint and muscle pain, and HIV-associated sensory neuropathy.

However, synthetic antipain drugs may still cause side effects of their own. Xinzhong Dong, an assistant professor of neuroscience at Hopkins, explains that these side effects can occur because the target molecules for these drugs are often also involved in processes other than pain and outside of pain-sensing neurons, elsewhere in the brain or in other tissues in the body. Dong’s lab studies the molecular mechanisms of pain and touch, focusing on genes that are expressed specifically in dorsal root ganglia (DRG) pain-sensing neurons and not anywhere else in the body. One hope is that research into these very specifically expressed genes will aid in the identification of new drug targets that specifically alleviate pain while limiting side effects.

One common side effect for patients who are taking powerful painkillers like morphine is itchiness that cannot be relieved by antihistamines. This is also a common side effect of the anti-malarial drug chloroquine, and this antihistamine-resistant itching can be so severe that patients stop taking their medication. Interestingly, some of the genes being studied in Dong’s lab appear to be expressed only in certain subsets of DRG neurons, suggesting that these different subsets may be responsible for different types of sensations, such as gentle touch, pain, or even different kinds of itching. Researchers in Dong’s lab are currently trying to determine whether there is a subset of chloroquine-sensitive “itch neurons” that is distinct from histamine-responsive neurons, and if so, whether the receptors for different kinds of itching and pain can really be separated. If this is the case, an improved understanding of how to separate the itch and pain responses could lead to new drugs that specifically alleviate pain by targeting molecules found only in pain-sensing neurons without targeting those involved in other processes, like itching.

The fact that many of the channels involved in pain are expressed outside of pain-sensing neurons may have implications for our overall understanding of sensation, however. Traditionally, research on pain and sensation has focused primarily on sensory neurons, including DRG neurons, and the role of sensory neurons in detecting and responding to environmental signals like heat or touch. However, Caterina’s lab and others have recently and unexpectedly discovered that functional, heat-responsive ion channels are present not only in sensory neurons but also in skin cells. This has led researchers to speculate that skin cells might also be participating in sensory function. “One of the big questions in the field is whether we have thought too narrowly about who might be a sensory cell,” says Caterina. “The deeper you get into a problem, the more you realize that it’s a more complicated problem than you once thought.”

- Elizabeth Eyler

The author is a 5th year graduate student in the Biochemistry, Cell, and Molecular Biology (BCMB) graduate program and works in the Meffert lab.

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