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

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.

Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1.SIGNIFICANCE STATEMENTThe chemotherapy-induced peripheral neuropathy is a major limiting factor affecting the chemotherapy patients. There is no effective treatment available currently. We demonstrate that zinc prevents paclitaxel-induced mechanical hypersensitivity via inhibiting the TRPV1 channel, which is involved in the sensitization of peripheral nociceptors in chemotherapy. Zinc transporters in DRG neurons are required for the entry of zinc into the intracellular side, where it inhibits TRPV1. Our study provides insight into the mechanism underlying the pain-soothing effect of zinc and suggests that zinc could be developed to therapeutics for the treatment of chemotherapy-induced peripheral neuropathy.

Cryo-EM reveals structural insights into a new class of chloride channels that underlies acid-sensitive anion currents.

Itch sensation provokes the scratch reflex to protect us from harmful stimuli in the skin. Although scratching transiently relieves acute itch through activation of mechanoreceptors, it propagates the vicious itch-scratch cycle in chronic itch by further aggravating itch over time. Although well recognized clinically, the peripheral mechanisms underlying the itch-scratch cycle remain poorly understood. Here, we show that mechanical stimulation of the skin results in activation of the Piezo2 channels on Merkel cells that pathologically promotes spontaneous itch in experimental dry skin. Three-dimensional reconstruction and immunoelectron microscopy revealed structural alteration of MRGPRA3 ⁺ pruriceptor nerve endings directed toward Merkel cells in the setting of dry skin. Our results uncover a functional miswiring mechanism under pathologic conditions, resulting in touch receptors triggering the firing of pruriceptors in the skin to drive the itch-scratch cycle.