A Counterpart to Pain

Abstract

Pain is not the only defense mechanism that alerts us to a physical hazard -the other is itch, an unpleasant sensation that is distinct from pain because it provokes the desire to scratch. Although pain and itch feel different, these two sensations share many qualities. Both are aversive sensations that evolved to protect us. Moreover, both can become pathological, developing into chronic debilitating conditions that ruin one's quality of life.Itch, in particular, represents the most common reason that a patient sees a dermatologist. It is estimated that ~10% of the general population and 30% of the elderly suffer from pruritis (the medical term for itch), which negatively affects sleep, mood, and quality of life, thereby presenting an enormous health burden (Weisshaar and Dalgard, 2009;Yosipovitch, 2008). Despite this prevalence, itch has received little attention, and the genetic underpinnings of itch sensitivity are virtually unknown. Here we discuss the limited number of genetic mutations in humans and in mice that have been found to affect itch sensitivity -either heightening or reducing it -and what such mutations tells us about how itch is detected and encoded in the nervous system. Why do we scratch?Scratching in response to a noxious agent is seen across vertebrates, who use this strategy to remove potential threats from the skin's surface, thereby minimizing exposure to harm. Even fish scratch, typically using tail fins or by rubbing against abrasive rocks (Stein, 1983). The highly conserved nature of this scratching response suggests that itch, like pain, confers an important evolutionary advantage. The basics of itchThe key difference between itch and pain is that itch is triggered by noxious stimuli at the very outermost aspect of the skin, whereas pain can be elicited from all cutaneous layers, ranging from superficial to deep, as well as most other regions of the body (Ross, 2011). Thus, the primary sensory neurons that detect pruritic stimuli are postulated to be a subset of dorsal root ganglia (DRG) and trigeminal neurons (perhaps 5%) that selectively innervate the dermis. Most itch fibers are likely to be a subset of unmyelinated, slowly conducting C-fibers, though recent studies suggest that some Aδ fibers may also be involved mediating itch (Ringkamp et al., 2011).What is the identity of these fibers? Remarkably, we do not yet know which sensory fibers mediate itch. Moreover, whether this subset of sensory neurons is specific for itch remains highly controversial. The best evidence that there exists a dedicated subset of peripheral sensory neurons that are selectively tuned to convey itch rather than nociception comes from experiments performing microneurography in humans. Using this technique, it is possible to isolate the activity of individual nerve fibers and identify those that respond to itch-inducing chemicals. Such experiments led to the discovery of C-fibers that are activated by pruritogens and whose activity corresponds to the sensation of itch in humans (Schmelz et al., 1997). Furt...