Scaling pain threshold with microRNAs.

P ain is not something universally enjoyed, especially chronic pain involving nerve damage, referred to as neuropathic pain (1). Pain perception can be modulated in a variety of ways—for example, by focusing attention on the painful stimulus. On page 1168 of this issue, Peng et al. (2) report that pain threshold in dorsal root ganglion neurons (DRG), which relay peripheral sensory information to the central nervous system, can be modulated by mechanisms involving a specific cluster of microRNAs (miRNAs). Remarkably, the same cluster also regulates the threshold of neuropathic pain in DRG neurons that would not be involved in pain under normal conditions. The study provides important new insights into molecular mechanisms that control pain threshold, both in normal and pathological conditions. Among the multitude of miRNAs expressed in the nervous system, the miR183/96/182 miRNA cluster (henceforth, miR-183 cluster) is expressed in DRG (3). The cluster is also found in a few other sensory organs. In addition, DRG expression of miR-183 is reduced in models of chronic pain (4–6). Experimentally, the key feature of the study by Peng et al. is the generation of a mouse line that permits the selective excision of the miR-183 cluster. This line was crossed with other mouse strains, allowing the conditional elimination of the cluster either in all DRG neurons, or in a subpopulation of DRG pain-responsive neurons (so-called nociceptors), or in another subpopulation of DRG neurons exquisitely sensitive to touch, called low-threshold mechanoreceptors. Through free nerve endings in the skin, nociceptors detect potentially harmful stimuli like heat or noxious chemicals. These endings have a high threshold for mechanical stimuli, whereas mechanoreceptors respond to light touch, NEUROSCIENCE