Loss of touch receptors leads to itch: Itch in response to light touch of the skin is an aging-associated problem. This phenomenon is called alloknesis and can become a major medical condition associated with dry skin. Feng et al. discovered that loss or dysfunction of Merkel cells causes scratching in mice (see the Perspective by Lewis and Grandl). Reduction of Merkel cell numbers results in reduced firing patterns and frequencies and changes the activation thresholds of slowly adapting afferent nerve fibers. Like hair cells, Merkel cells are lost with age. A painful scratch will temporarily alleviate itch because it induces enough activity through the remaining Merkel cells. Science , this issue p. 530 ; see also p. 492

Although both persistent itch and inflammation are commonly associated with allergic contact dermatitis (ACD), it is not known if they are mediated by shared or distinct signaling pathways. Here we show that both TRPA1 and TRPV1 channels are required for generating spontaneous scratching in a mouse model of ACD induced by squaric acid dibutylester (SADBE), a small molecule hapten, through directly promoting the excitability of pruriceptors. TRPV1 but not TRPA1 channels protect the skin inflammation, as genetic ablation of TRPV1 function or pharmacological ablation of TRPV1-positive sensory nerves promotes cutaneous inflammation in the SADBE-induced ACD. Our results demonstrate that persistent itch and inflammation are mediated by distinct cellular and molecular mechanisms in a mouse model of ACD. Identification of distinct roles of TRPA1 and TRPV1 in regulating itch and inflammation may provide new insights into the pathophysiology and treatment of chronic itch and inflammation in ACD patients.

As a protective mechanism, the cornea is sensitive to noxious stimuli. Here, we show that in mice, a high proportion of corneal TRPM8⁺ cold-sensing fibers express the heat-sensitive TRPV1 channel. Despite its insensitivity to cold, TRPV1 enhances membrane potential changes and electrical firing of TRPM8⁺ neurons in response to cold stimulation. This elevated neuronal excitability leads to augmented ocular cold nociception in mice. In a model of dry eye disease, the expression of TRPV1 in TRPM8⁺ cold-sensing fibers is increased, and results in severe cold allodynia. Overexpression of TRPV1 in TRPM8⁺ sensory neurons leads to cold allodynia in both corneal and non-corneal tissues without affecting their thermal sensitivity. TRPV1-dependent neuronal sensitization facilitates the release of the neuropeptide substance P from TRPM8⁺ cold-sensing neurons to signal nociception in response to cold. Our study identifies a mechanism underlying corneal cold nociception and suggests a potential target for the treatment of ocular pain.

Microglia, resident macrophages of the central nervous system (CNS), are essential to brain development, homeostasis, and disease. Microglial activation and proliferation are hallmarks of many CNS diseases including neuropathic pain. However, molecular mechanisms that govern the spinal neuro-immune axis in the setting of neuropathic pain remain incompletely understood. Here we show that genetic ablation or pharmacological blockade of transient receptor potential vanilloid type 4 (TRPV4) markedly attenuated neuropathic pain-like behaviors in a mouse model of spared nerve injury. Mechanistically, microglia-expressed TRPV4 mediated microglial activation and proliferation and promoted functional and structural plasticity of excitatory spinal neurons through releasing lipocalin-2. Our results suggest that microglial TRPV4 channels reside at the center of the neuro-immune axis in the spinal cord that transforms peripheral nerve injury into central sensitization and neuropathic pain, thereby identifying TRPV4 as a promising new target for the treatment of chronic pain.