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The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2 ) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2. [ABSTRACT FROM AUTHOR]

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel that is gated by noxious heat, capsaicin and other diverse stimuli. It is a nonselective cation channel that prefers Ca2+ over Na+. These permeability characteristics, as in most channels, are widely presumed to be static. On the contrary, we found that activation of native or recombinant rat TRPV1 leads to time- and agonist concentration–dependent increases in relative permeability to large cations and changes in Ca2+ permeability. Using the substituted cysteine accessibility method, we saw that these changes were attributable to alterations in the TRPV1 selectivity filter. TRPV1 agonists showed different capabilities for evoking ionic selectivity changes. Furthermore, protein kinase C–dependent phosphorylation of Ser800 in the TRPV1 C terminus potentiated agonist-evoked ionic selectivity changes. Thus, the qualitative signaling properties of TRPV1 are dynamically modulated during channel activation, a process that probably shapes TRPV1 participation in pain, cytotoxicity and neurotransmitter release. [ABSTRACT FROM AUTHOR]

Temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels are critical contributors to normal pain and temperature sensation and therefore represent attractive targets for pain therapy. When these channels were first discovered, most attention was focused on their potential contributions to direct thermal activation of peripheral sensory neurons. However, recent anatomical, physiological, and behavioral studies have provided evidence that TRPV channels expressed in skin epithelial cells may also contribute to thermosensation in vitro and in vivo. Here, we review these studies and speculate on possible communication mechanisms from cutaneous epithelial cells to sensory neurons. [ABSTRACT FROM AUTHOR]

This article presents evidence that dTRPA1, an ion channel of the Transient Receptor Potential (TRP) family, is critical for thermotaxis behavior in Drosophila larvae. The rationale underlying this study is that one invertebrate TRP channel (dTRPA1) and six vertebrate TRP channels have been demonstrated electrophysiologically to undergo channel opening in response to heat or cold, over a range of temperatures that is distinct for each channel. In addition, gene disruption experiments have shown that TRPV1 is essential for normal heat-evoked pain sensation and thermal hyperalgesia in mice, while a Drosophila mutant lacking another TRP channel, Painless, shows impairment in avoidance responses to noxious heat or mechanical stimuli. Guided by these findings, and by the prior demonstration that Drosophila larvae and adults exhibit thermotaxis use in vivo short interfering RNA to disrupt expression of candidate thermosensory TRP channels, either individually or in combination, in Drosophila embryos. In particular, they focused on the genes encoding the Drosophila TRPV, TRPM and TRPA, as members of these TRP subfamilies are known thermoTRP. Simultaneous knockdown of a transgene encoding a neuronally expressed green fluorescent protein provided an efficient positive control for this procedure.

Transient receptor potential vanilloid 4 (TRPV4), a cation channel responsive to hypotonicity, can also be activated by warm temperatures. Moreover, TRPV4-/- mice reportedly exhibit deficits in inflammation-induced thermal hyperalgesia. However, it is unknown whether TRPV4 or related transient receptor potential channels account for warmth perception under injury-free conditions. We therefore investigated the contribution of TRPV4 to thermosensation and thermoregulation in vivo. On a thermal gradient, TRPV4-/- mice selected warmer floor temperatures than wild-type littermates. In addition, whereas wild-type mice failed to discriminate between floor temperatures of 30 and 34°C, TRPV4-/- mice exhibited a strong preference for 34°C. TRPV4-/- mice also exhibited prolonged withdrawal latencies during acute tail heating. TRPV4-/- and wild-type mice exhibited similar changes in behavior on a thermal gradient after paw inflammation. Circadian body temperature fluctuations and thermoregulation in a warm environment were also indistinguishable between genotypes. These results demonstrate that TRPV4 is required for normal thermal responsiveness in vivo. [ABSTRACT FROM AUTHOR]

Vanilloid receptor 1 (TRPV1) has been proposed to be the principal heat-responsive channel for nociceptive neurons. The skin of both rat and mouse receives major projections from primary sensory afferents that bind the plant lectin isolectin B4 (IB4). The majority of IB4-positive neurons are known to be heat-responsive nociceptors. Previous studies suggested that, unlike rat, mouse IB4-positive cutaneous afferents did not express TRPV1 immunoreactivity. Here, multiple antisera were used to confirm that mouse and rat have different distributions of TRPV1 and that TRPV1 immunoreactivity is absent in heat-sensitive nociceptors. Intracellular recording in TRPV1-/- mice was then used to confirm that TRPV1 was not required for detecting noxious heat. TRPV1-/- mice had more heat-sensitive neurons, and these neurons had normal temperature thresholds and response properties. Moreover, in TRPV1-/- mice, 82% of heat-responsive neurons did not express immunoreactivity for TRPV2, another putative noxious heat channel. [ABSTRACT FROM AUTHOR]

Six of the mammalian transient receptor potential (TRP) ion channel subtypes are nonselective cation channels that can be activated by increases or decreases in ambient temperature. Five of them can alternatively be activated by nonthermal stimuli such as capsaicin [transient receptor potential vanilloid 1 (TRPV1)] or hypo-osmolarity (TRPV2 and TRPV4). No nonthermal stimuli have yet been described for TRPV3, a warmth-gated ion channel expressed prominently in skin keratinocytes. Here, we demonstrate that 2-aminoethoxydiphenyl borate (2-APB), a compound used to inhibit store-operated Ca2+ channels and IP3 receptors, produces robust activation of recombinant TRPV3 in human embryonic kidney 293 cells with an EC50 of 28 µM. 2-APB also sensitizes TRPV3 to activation by heat, even at subthreshold concentrations. In inside-out membrane patches from TRPV3-expressing cells, 2-APB increases the open probability of TRPV3. Also, whereas heat alone is capable of activating TRPV3-mediated currents in only a small proportion of primary mouse keratinocytes, 2-APB activates heat-evoked, TRPV3-mediated currents in the majority of these cells. Together, these findings identify 2-APB as the first known chemical activator of TRPV3 and enhance the notion that TRPV3 participates in the detection of heat by keratinocytes. [ABSTRACT FROM AUTHOR]

The article focuses on a study conducted by researcher Matthias Heidenreich and colleagues on tuning of mechanoreceptors by mutations inactivating the potassium channel KCNQ4. In the study, KCNQ4 is found in the peripheral nerve endings of hair follicle from mice and humans and explains touch sensitivity in mice and humans and describes gene mutation which establishes KCNQ4 as a molecular marker and modulates touch sensitivity in humans and mice.

The hair follicle undergoes a lifelong developmental cycle that depends on the integration between activating and inhibitory signals acting to regulate and guide the proliferation and differentiation of pluripotent epithelial stem cells. The effectors and mechanisms responsible for re-entry of quiescent telogen hair follicles into the hair-producing anagen stage in mature skin remain incompletely understood. In the June 1, 2013, issue of Genes & Development, Yucel and colleagues (pp. 1217-1222) reported the unexpected finding that Cav 1.2, the pore-forming subunit in a well-characterized voltage-gated, L-type calcium channel, is expressed in hair follicle stem cells and contributes to anagen re-entry but does so in a calcium flux-independent fashion. [ABSTRACT FROM AUTHOR]

2-Aminoethyl diphenylborinate was recently identified as a chemical activator of TRPV1, TRPV2, and TRPV3, three heat-gated members of the transient receptor potential vanilloid (TRPV) ion channel subfamily. Here we demonstrated that two structurally related compounds, diphenylboronic anhydride (DPBA) and diphenyltetrahydrofuran (DPTHF), can also modulate the activity of these channels. DPBA acted as a TRPV3 agonist, whereas DPTHF exhibited prominent antagonistic activity. However, all three diphenyl-containing compounds promoted some degree of channel activation or potentiation, followed by channel block. Strong TRPV3 activation by DPBA often leads to the appearance of a secondary, enhanced, current phase. A similar biphasic response was observed during TRPV3 heat stimulation; an initial, gradually sensitizing phase (I1) was followed by an abrupt transition to a secondary phase (I2). I2 was characterized by larger current amplitude, loss of outward rectification, and alterations in the following properties: permeability among cations; ruthenium red and DPTHF sensitivity; temperature dependence; and voltage-dependent gating. The I1 to I2 transition depended strongly on TRPV3 current density. Removal of extracellular divalent cations resulted in heat-evoked currents resembling I2, whereas mutation of a putative Ca2+-binding residue in the pore loop domain, aspartate 641, facilitated detection of the I1 to I2 transition, suggesting that the conversion to I2 resulted from the agonist- and time-dependent loss of divalent cationic inhibition. Primary keratinocytes overexpressing exogenous TRPV3 also exhibited biphasic agonist-evoked currents. Thus, strong activation by either chemical or thermal stimuli led to biphasic TRPV3 signaling behavior that may be associated with changes in the channel pore. [ABSTRACT FROM AUTHOR]

Mammalian survival requires constant monitoring of environmental and body temperature. Recently, several members of the transient receptor potential vanilloid (TRPV) subfamily of ion channels have been identified that can be gated by increases in temperature into the warm (TRPV3 and TRPV4) or painfully hot (TRPV1 and TRPV2) range. In rodents, TRPV3 and TRPV4 proteins have not been detected in sensory neurons but are highly expressed in skin epidermal keratinocytes. Here, we show that in response to warm temperatures (>32 °C), the mouse 308 keratinocyte cell line exhibits nonselective transmembrane cationic currents and Ca[sup 2+] influx. Both TRPV3 and TRPV4 are expressed in 308 cells. However, the warmth-evoked responses we observe most closely resemble those mediated by recombinant TRPV4 on the basis of their electrophysiological properties and sensitivity to osmolarity and the phorbol ester, 4α-phorbol-12,13-didecanoate. Together, these data support the notion that keratinocytes are capable of detecting modest temperature elevations, strongly suggest that TRPV4 participates in these responses, and define a system for the cell biological analysis of warmth transduction. [ABSTRACT FROM AUTHOR]

The article focuses on astrocytes contribute to pain gating in the spinal cord. Topics include the various pain therapies have been developed on the basis of the gate control theory of pain, and the postulates that nonpainful sensory inputs mediated by large-diameter afferent fibers can attenuate noxious signals relayed to the brain.

Although joint pain in rheumatoid arthritis (RA) is conventionally thought to result from inflammation, arthritis pain and joint inflammation are at least partially uncoupled. This suggests that additional pain mechanisms in RA remain to be explored. Here we show that FcγRI, an immune receptor for IgG immune complex (IgG-IC), is expressed in a subpopulation of joint sensory neurons and that, under naïve conditions, FcγRI crosslinking by IgG-IC directly activates the somata and peripheral terminals of these neurons to evoke acute joint hypernociception without obvious concurrent joint inflammation. These effects were diminished in both global and sensory neuron-specific Fcgr1 knockout mice. In murine models of inflammatory arthritis, FcγRI signaling was upregulated in joint sensory neurons. Acute blockade or global genetic deletion of Fcgr1 significantly attenuated arthritis pain and hyperactivity of joint sensory neurons without measurably altering joint inflammation. Conditional deletion of Fcgr1 in sensory neurons produced similar analgesic effects in these models. We therefore suggest that FcγRI expressed in sensory neurons contributes to arthritis pain independently of its functions in inflammatory cells. These findings expand our understanding of the immunosensory capabilities of sensory neurons and imply that neuronal FcγRI merits consideration as a target for treating RA pain. [ABSTRACT FROM AUTHOR]

The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2 ) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2. [ABSTRACT FROM AUTHOR]

Examines the role of vanilloid receptor expression in urinary bladder epithelial cells. Characterization of dorsal root ganglia and urothelial cultures; Determination of the confocal imaging of the urothelium; Analysis of bladder epithelium.

Competing Interests: Competing interests statement:The authors declare no competing interest.

Kinase translocation reporters (KTRs) are powerful tools for single-cell measurement of time-integrated kinase activity but suffer from restricted dynamic range and limited sensitivity, particularly in neurons. To address these limitations, we developed enhanced KTRs (eKTRs) for protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) that display high sensitivity, rapid response kinetics, broad dynamic range, cell type-specific tuning, and an ability to detect PKA and ERK activity in primary sensory neurons. Moreover, co-expression of optically separable eKTRs for PKA and ERK revealed the kinetics of expected and unexpected crosstalk between PKA, ERK, protein kinase C, and calcium signaling pathways, demonstrating the utility of eKTRs for live cell monitoring of diverse and interacting signaling pathways. These results open the door to improved live-cell and in vivo measurements of key signaling pathways in neurons, while at the same time demonstrating the importance of KTR size and NLS strength to KTR dynamics., Competing Interests: Disclosure and competing interests statement: SJT, MJC, and SJG are co-inventors of proprietary materials described in this paper that are owned by Johns Hopkins University, and as a result they may receive compensation related to their licensing and commercial use.

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3 + and Cysltr2 + . NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca 2+ signaling induced by KCl depolarization, αβ-meATP, or the pruritogen histamine. Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Following peripheral nerve injury, denervated tissues can be reinnervated via regeneration of injured neurons or collateral sprouting of neighboring uninjured afferents into denervated territory. While there has been substantial focus on mechanisms underlying regeneration, collateral sprouting has received less attention. Here, we used immunohistochemistry and genetic neuronal labeling to define the subtype specificity of sprouting-mediated reinnervation of plantar hindpaw skin in the mouse spared nerve injury (SNI) model, in which productive regeneration cannot occur. Following initial loss of cutaneous afferents in the tibial nerve territory, we observed progressive centripetal reinnervation by multiple subtypes of neighboring uninjured fibers into denervated glabrous and hairy plantar skin of male mice. In addition to dermal reinnervation, CGRP-expressing peptidergic fibers slowly but continuously repopulated denervated epidermis, Interestingly, GFRα2-expressing nonpeptidergic fibers exhibited a transient burst of epidermal reinnervation, followed by a trend towards regression. Presumptive sympathetic nerve fibers also sprouted into denervated territory, as did a population of myelinated TrkC lineage fibers, though the latter did so inefficiently. Conversely, rapidly adapting Aβ fiber and C fiber low threshold mechanoreceptor (LTMR) subtypes failed to exhibit convincing sprouting up to 8 weeks after nerve injury in males or females. Optogenetics and behavioral assays in male mice further demonstrated the functionality of collaterally sprouted fibers in hairy plantar skin with restoration of punctate mechanosensation without hypersensitivity. Our findings advance understanding of differential collateral sprouting among sensory neuron subpopulations and may guide strategies to promote the progression of sensory recovery or limit maladaptive sensory phenomena after peripheral nerve injury., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Jeon et al.)

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Pain that accompanies deafferentation is one of the most mysterious and misunderstood medical conditions. Prevalence rates for the assorted conditions vary considerably but the most reliable estimates are greater than 50% for strokes involving the somatosensory system, brachial plexus avulsions, spinal cord injury, and limb amputation, with controversy surrounding the mechanistic contributions of deafferentation to ensuing neuropathic pain syndromes. Deafferentation pain has also been described for loss of other body parts (e.g., eyes and breasts) and may contribute to between 10% and upwards of 30% of neuropathic symptoms in peripheral neuropathies. There is no pathognomonic test or sign to identify deafferentation pain, and part of the controversy surrounding it stems from the prodigious challenges in differentiating cause and effect. For example, it is unknown whether cortical reorganization causes pain or is a byproduct of pathoanatomical changes accompanying injury, including pain. Similarly, ascertaining whether deafferentation contributes to neuropathic pain, or whether concomitant injury to nerve fibers transmitting pain and touch sensation leads to a deafferentation-like phenotype can be clinically difficult, although a detailed neurologic examination, functional imaging, and psychophysical tests may provide clues. Due in part to the concurrent morbidities, the physical, psychologic, and by extension socioeconomic costs of disorders associated with deafferentation are higher than for other chronic pain conditions. Treatment is symptom-based, with evidence supporting first-line antineuropathic medications such as gabapentinoids and antidepressants. Studies examining noninvasive neuromodulation and virtual reality have yielded mixed results., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Neuropathic pain is a chronic condition arising from damage to somatosensory pathways that results in pathological hypersensitivity. Persistent pain can be viewed as a consequence of maladaptive plasticity which, like most enduring forms of cellular plasticity, requires altered expression of specific gene programs. Control of gene expression at the level of protein synthesis is broadly utilized to directly modulate changes in activity and responsiveness in nociceptive pathways and provides an effective mechanism for compartmentalized regulation of the proteome in peripheral nerves through local translation. Levels of noncoding RNAs (ncRNAs) are commonly impacted by peripheral nerve injury leading to persistent pain. NcRNAs exert spatiotemporal regulation of local proteomes and affect signaling cascades supporting altered sensory responses that contribute to hyperalgesia. This review discusses ncRNAs found in the peripheral nervous system (PNS) that are dysregulated following nerve injury and the current understanding of their roles in pathophysiological pain-related responses including neuroimmune interactions, neuronal survival and axon regeneration, Schwann cell dedifferentiation and proliferation, intercellular communication, and the generation of ectopic action potentials in primary afferents. We review progress in the field beyond cataloging, with a focus on the relevant target transcripts and mechanisms underlying pain modulation by ncRNAs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

The simple tripartite classification of sensory neurons as A-beta, A-delta, and C fibers fails to convey the complexity of the neurons that encode stimuli as diverse as the texture of a surface, the location of a pinprick, or the direction of hair movement as a breeze moves across the skin. It has also proven to be inadequate when investigating the molecular mechanisms underlying pain, which can encompass any combination of chemical, tactile, and thermal modalities. Beginning with a brief overview of visceral and sensory neuroanatomy, this review expands upon sensory innervation of the skin as a prime example of the heterogeneity and complexity of the somatosensory nervous system. Neuroscientists have characterized defining features of over 15 subtypes of sensory neurons that innervate the skin of the mouse. This has enabled the study of cell-specific mechanisms of pain, which suggests that diverse sensory neuron subtypes may have distinct susceptibilities to toxic injury and different roles in pathologic mechanisms underlying altered sensation. Leveraging this growing body of knowledge for preclinical trials and models of neurotoxicity can vastly improve our understanding of peripheral nervous system dysfunction, advancing the fields of toxicologic pathology and neuropathology alike.

Although joint pain in rheumatoid arthritis (RA) is conventionally thought to result from inflammation, arthritis pain and joint inflammation are at least partially uncoupled. This suggests that additional pain mechanisms in RA remain to be explored. Here we show that FcγRI, an immune receptor for IgG immune complex (IgG-IC), is expressed in a subpopulation of joint sensory neurons and that, under naïve conditions, FcγRI crosslinking by IgG-IC directly activates the somata and peripheral terminals of these neurons to evoke acute joint hypernociception without obvious concurrent joint inflammation. These effects were diminished in both global and sensory neuron-specific Fcgr1 knockout mice. In murine models of inflammatory arthritis, FcγRI signaling was upregulated in joint sensory neurons. Acute blockade or global genetic deletion of Fcgr1 significantly attenuated arthritis pain and hyperactivity of joint sensory neurons without measurably altering joint inflammation. Conditional deletion of Fcgr1 in sensory neurons produced similar analgesic effects in these models. We therefore suggest that FcγRI expressed in sensory neurons contributes to arthritis pain independently of its functions in inflammatory cells. These findings expand our understanding of the immunosensory capabilities of sensory neurons and imply that neuronal FcγRI merits consideration as a target for treating RA pain.

Resolution of inflammation is a critical process that is facilitated by specialized proresolving mediators (SPMs). In this issue, Bang et al. show that the G protein-coupled receptor GPR37 is a receptor for one such SPM, neuroprotectin D1. They also show that GPR37 activation in macrophages enhances phagocytosis, shifts cytokine release toward an antiinflammatory profile, and thereby helps to reverse inflammatory pain.

The perception of innocuous warmth is a sensory capability that facilitates thermoregulatory, social, hedonic, and even predatory functions. It has long been recognized that innocuous warmth perception is triggered by activation of a subpopulation of specially tuned peripheral thermosensory neurons. In addition, there is growing evidence that thermotransduction by nonneuronal cells, such as skin keratinocytes, might contribute to or modulate our thermosensory experience. Yet, the precise molecular mechanisms underlying warmth transduction are only now being uncovered. Recent molecular genetics approaches have led to the identification of multiple candidate warmth-transducing molecules that appear to confer thermosensitivity upon innocuous warmth afferents and/or neighboring cell types. Most, but not all, of these candidate transducers are members of the transient receptor potential (TRP) ion channel family. Among the latter, evidence supporting a function in innocuous warmth sensation is strongest for TRPV1 and TRPM2 in mammals and for TRPA1 in nonmammalian species., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The hair follicle undergoes a lifelong developmental cycle that depends on the integration between activating and inhibitory signals acting to regulate and guide the proliferation and differentiation of pluripotent epithelial stem cells. The effectors and mechanisms responsible for re-entry of quiescent telogen hair follicles into the hair-producing anagen stage in mature skin remain incompletely understood. In the June 1, 2013, issue of Genes & Development, Yucel and colleagues (pp. 1217-1222) reported the unexpected finding that CaV1.2, the pore-forming subunit in a well-characterized voltage-gated, L-type calcium channel, is expressed in hair follicle stem cells and contributes to anagen re-entry but does so in a calcium flux-independent fashion.

The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared with wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E(2) (PGE(2)) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naive mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-17203212 [corrected], however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE(2).

Six of the mammalian transient receptor potential (TRP) ion channel subtypes are nonselective cation channels that can be activated by increases or decreases in ambient temperature. Five of them can alternatively be activated by nonthermal stimuli such as capsaicin [transient receptor potential vanilloid 1 (TRPV1)] or hypo-osmolarity (TRPV2 and TRPV4). No nonthermal stimuli have yet been described for TRPV3, a warmth-gated ion channel expressed prominently in skin keratinocytes. Here, we demonstrate that 2-aminoethoxydiphenyl borate (2-APB), a compound used to inhibit store-operated Ca2+ channels and IP3 receptors, produces robust activation of recombinant TRPV3 in human embryonic kidney 293 cells with an EC50 of 28 microm. 2-APB also sensitizes TRPV3 to activation by heat, even at subthreshold concentrations. In inside-out membrane patches from TRPV3-expressing cells, 2-APB increases the open probability of TRPV3. Also, whereas heat alone is capable of activating TRPV3-mediated currents in only a small proportion of primary mouse keratinocytes, 2-APB activates heat-evoked, TRPV3-mediated currents in the majority of these cells. Together, these findings identify 2-APB as the first known chemical activator of TRPV3 and enhance the notion that TRPV3 participates in the detection of heat by keratinocytes.

We have investigated the intracellular signaling mechanisms underlying the release of nitric oxide (NO) evoked by beta-adrenoceptor (AR) agonists in urinary bladder strips and cultured bladder urothelial cells from adult rats. Reverse transcription-PCR revealed that inducible NO synthase and endothelial NOS but not neuronal NOS genes were expressed in urothelial cells. NO release from both urothelial cells and bladder strips was decreased (37-42%) in the absence of extracellular Ca2+ (100 microm EGTA) and was ablated after incubation with BAPTA-AM (5 microm) or caffeine (10 mm), indicating that the NO production is mediated in part by intracellular calcium stores. NO release was reduced (18-24%) by nifedipine (10 microm) and potentiated (29-32%) by incubation with the Ca2+ channel opener BAYK8644 (1-10 microm). In addition, beta-AR-evoked NO release (isoproterenol; dobutamine; terbutaline; 10(-9) to 10(-5) m) was blocked by the NOS inhibitors N(G)-nitro-L-arginine methyl ester (30 microm) or N(G)-monomethyl-L-arginine (50 microm), by beta-adrenoceptor antagonists (propranol, beta1/beta2; atenolol, beta1; ICI 118551; beta2; 100 microm), or by the calmodulin antagonist trifluoperazine (50 microm). Incubating cells with the nonhydrolyzable GTP analog GTPgammaS (1 microm) or the membrane-permeant cAMP analog dibutyryl-cAMP (10-100 microm) directly evoked NO release. Forskolin (10 microm) or the phosphodiesterase IBMX (50 microm) enhanced (39-42%) agonist-evoked NO release. These results indicate that beta-adrenoceptor stimulation activates the adenylate cyclase pathway in bladder epithelial cells and initiates an increase in intracellular Ca2+ that triggers NO production and release. These findings are considered in light of recent reports that urothelial cells may exhibit a number of "neuron-like" properties, including the expression of receptors/ion channels similar to those found in sensory neurons.