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Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy. We found that keratinocyte inhibition by either optogenetic or chemogenetic methods largely alleviated paclitaxel-induced mechanical hypersensitivity across acute and persistent time points from 2 days through 3 weeks. Furthermore, we found that paclitaxel exposure sensitized mouse and human keratinocytes to mechanical stimulation and enhanced currents of PIEZO1, a mechanosensitive channel highly expressed in keratinocytes. Deletion of PIEZO1 from keratinocytes alleviated paclitaxel-induced mechanical hypersensitivity in mice. These findings suggest that nonneuronal cutaneous cells contribute substantially to neuropathic pain and pave the way for the development of new pain relief strategies that target epidermal keratinocytes and PIEZO1.

Abstract: Few analgesics identified using preclinical models have successfully translated to clinical use. These translational limitations may be due to the unidimensional nature of behavioral response measures used to assess rodent nociception. Advances in high-speed videography for pain behavior allow for objective quantification of nuanced aspects of evoked paw withdrawal responses. However, whether videography-based assessments of mechanical hypersensitivity outperform traditional measurement reproducibility is unknown. First, we determined whether high-speed videography of paw withdrawal was reproducible across experimenters. Second, we examined whether this method distinguishes behavioral responses exhibited by naive mice and mice with complete Freund's adjuvant (CFA)-induced inflammation. Twelve experimenters stimulated naive C57BL/6 mice with varying mechanical stimuli. Paw withdrawal responses were recorded with high-speed videography and scored offline by one individual. Our group was unable to replicate the original findings produced by high-speed videography analysis. Surprisingly, ∼80% of variation was not accounted for by variables previously reported to distinguish between responses to innocuous and noxious stimuli (paw height, paw velocity, and pain score), or by additional variables (experimenter, time-of-day, and animal), but rather by unidentified factors. Similar high-speed videography assessments were performed in CFA- and vehicle-treated animals, and the cumulative data failed to reveal an effect of CFA injection on withdrawal as measured by high-speed videography. This study does not support using paw height, velocity, or pain score measurements from high-speed recordings to delineate behavioral responses to innocuous and noxious stimuli. Our group encourages the continued use of traditional mechanical withdrawal assessments until additional high-speed withdrawal measures are validated in established pain models., (Copyright © 2024 International Association for the Study of Pain.)

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown if keratinocytes contribute to touch evoked pain and hypersensitivity following tissue injury. Here, we used inhibitory optogenetic and chemogenetic techniques to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapeutic treatment. We found that keratinocyte inhibition largely alleviates paclitaxel-induced mechanical hypersensitivity. Furthermore, we found that paclitaxel exposure sensitizes mouse and human keratinocytes to mechanical stimulation through the keratinocyte mechanotransducer Piezo1. These findings demonstrate the contribution of non-neuronal cutaneous cells to neuropathic pain and pave the way for the development of new pain-relief strategies that target epidermal keratinocytes and Piezo1.

Epidermal keratinocytes mediate touch sensation by detecting and encoding tactile information to sensory neurons. However, the specific mechanotransducers that enable keratinocytes to respond to mechanical stimulation are unknown. Here, we found that the mechanically-gated ion channel PIEZO1 is a key keratinocyte mechanotransducer. Keratinocyte expression of PIEZO1 is critical for normal sensory afferent firing and behavioral responses to mechanical stimuli in mice., Competing Interests: AM, OI, FM, KS, AM, CS No competing interests declared, (© 2022, Mikesell et al.)

Our ability to quickly detect and respond to harmful environmental stimuli is vital for our safety and survival. This inherent acute pain detection is a "gift" because it both protects our body from harm and allows healing of damaged tissues [1]. Damage to tissues from trauma or disease can result in distorted or amplified nociceptor signaling and sensitization of the spinal cord and brain (Central Nervous System; CNS) pathways to normal input from light touch mechanoreceptors. Together, these processes can result in nagging to unbearable chronic pain and extreme sensitivity to light skin touch (allodynia). Unlike acute protective pain, chronic pain and allodynia serve no useful purpose and can severely reduce the quality of life of an affected person. Chronic pain can arise from impairment to peripheral neurons, a phenomenon called "peripheral neuropathic pain." Peripheral neuropathic pain can be caused by many insults that directly affect peripheral sensory neurons, including mechanical trauma, metabolic imbalance (e.g., diabetes), autoimmune diseases, chemotherapeutic agents, viral infections (e.g., shingles). These insults cause "acquired" neuropathies such as small-fiber neuropathies, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and post herpetic neuralgia. Peripheral neuropathic pain can also be caused by genetic factors and result in hereditary neuropathies that include Charcot-Marie-Tooth disease, rare channelopathies and Fabry disease. Many acquired and hereditary neuropathies affect the skin, our largest organ and protector of nearly our entire body. Here we review how cutaneous nociception (pain perceived from the skin) is altered following diseases that affect peripheral nerves that innervate the skin. We provide an overview of how noxious stimuli are detected and encoded by molecular transducers on subtypes of cutaneous afferent endings and conveyed to the CNS. Next, we discuss several acquired and hereditary diseases and disorders that cause painful or insensate (lack of sensation) cutaneous peripheral neuropathies, the symptoms and percepts patients experience, and how cutaneous afferents and other peripheral cell types are altered in function in these disorders. We highlight exciting new research areas that implicate non-neuronal skin cells, particularly keratinocytes, in cutaneous nociception and peripheral neuropathies. Finally, we conclude with ideas for innovative new directions, areas of unmet need, and potential opportunities for novel cutaneous therapeutics that may avoid CNS side effects, as well as ideas for improved translation of mechanisms identified in preclinical models to patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express TRPC5 , the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)