The Cells and Circuitry for Itch Responses in Mice Mishra, Santosh K.; Hoon, Mark A.
Science (American Association for the Advancement of Science),
05/2013, Letnik:
340, Številka:
6135
Journal Article
Recenzirano
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Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response ...remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb -/- mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb -/- mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.
Chronic itch is a major symptom of many inflammatory skin diseases. This type of pruritus is thought to be facilitated by cytokines that activate cutaneous nerve fibers; however, the molecular ...components and mechanisms involved are poorly understood. We found that the cytokine oncostatin M (OSM) is highly up-regulated in psoriasis, atopic dermatitis, and cutaneous T cell lymphoma, diseases associated with chronic itch. OSM receptor (OSMR) is expressed by itch-selective natriuretic polypeptide B (Nppb) neurons, and single-cell sequencing showed that OSM is mainly produced by dermal T cells and monocytes. Unlike canonical pruritogens, OSM does not activate sensory neurons. Instead, it sensitizes neurons by potentiating neural responses to pruritogens and by enhancing neural excitability. Knockout of OSMR in sensory neurons attenuated OSM-sensitized itch and inflammatory itch in mice, and pharmacological antagonism of the OSMR complex effectively alleviated pruritus in experimental inflammatory dermatitis in a rodent model. Together, our results uncover OSM as an itch neuromodulator and reveal OSM signal transduction as a potential target for antipruritic therapy.
The spinal cord is the initial stage that integrates temperature information from peripheral inputs. Here we used molecular genetics and in vivo calcium imaging to investigate the coding of cutaneous ...temperature in the spinal cord in mice. We found that heating or cooling the skin evoked robust calcium responses in spinal neurons, and their activation threshold temperatures distributed smoothly over the entire range of stimulation temperatures. Once activated, heat-responding neurons encoded the absolute skin temperature without adaptation and received major inputs from transient receptor potential (TRP) channel V1 (TRPV1)-positive dorsal root ganglion (DRG) neurons. By contrast, cold-responding neurons rapidly adapted to ambient temperature and selectively encoded temperature changes. These neurons received TRP channel M8 (TRPM8)-positive DRG inputs as well as novel TRPV1(+) DRG inputs that were selectively activated by intense cooling. Our results provide a comprehensive examination of the temperature representation in the spinal cord and reveal fundamental differences in the coding of heat and cold.
Asthma is a common debilitating inflammatory lung disease affecting over 200 million people worldwide. Here, we investigated neurogenic components involved in asthmatic-like attacks using the ...ovalbumin-sensitized murine model of the disease, and identified a specific population of neurons that are required for airway hyperreactivity. We show that ablating or genetically silencing these neurons abolished the hyperreactive broncho-constrictions, even in the presence of a fully developed lung inflammatory immune response. These neurons are found in the vagal ganglia and are characterized by the expression of the transient receptor potential vanilloid 1 (TRPV1) ion channel. However, the TRPV1 channel itself is not required for the asthmatic-like hyperreactive airway response. We also demonstrate that optogenetic stimulation of this population of TRP-expressing cells with channelrhodopsin dramatically exacerbates airway hyperreactivity of inflamed airways. Notably, these cells express the sphingosine-1-phosphate receptor 3 (S1PR3), and stimulation with a S1PR3 agonist efficiently induced broncho-constrictions, even in the absence of ovalbumin sensitization and inflammation. Our results show that the airway hyperreactivity phenotype can be physiologically dissociated from the immune component, and provide a platform for devising therapeutic approaches to asthma that target these pathways separately.
The cellular code for mammalian thermosensation Pogorzala, Leah A; Mishra, Santosh K; Hoon, Mark A
The Journal of neuroscience,
2013-Mar-27, 2013-03-27, 20130327, Letnik:
33, Številka:
13
Journal Article
Recenzirano
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Mammalian somatosenory neurons respond to thermal stimuli and allow animals to reliably discriminate hot from cold and to select their preferred environments. Previously, we generated mice that are ...completely insensitive to temperatures from noxious cold to painful heat (-5 to 55°C) by ablating several different classes of nociceptor early in development. In the present study, we have adopted a selective ablation strategy in adult mice to study this phenotype and have demonstrated that separate populations of molecularly defined neurons respond to hot and cold. TRPV1-expressing neurons are responsible for all behavioral responses to temperatures between 40 and 50°C, whereas TRPM8 neurons are required for cold aversion. We also show that more extreme cold and heat activate additional populations of nociceptors, including cells expressing Mrgprd. Therefore, although eliminating Mrgprd neurons alone does not affect behavioral responses to temperature, when combined with ablation of TRPV1 or TRPM8 cells, it significantly decreases responses to extreme heat and cold, respectively. Ablation of TRPM8 neurons distorts responses to preferred temperatures, suggesting that the pleasant thermal sensation of warmth may in fact just reflect reduced aversive input from TRPM8 and TRPV1 neurons. As predicted by this hypothesis, mice lacking both classes of thermosensor exhibited neither aversive nor attractive responses to temperatures between 10 and 50°C. Our results provide a simple cellular basis for mammalian thermosensation whereby two molecularly defined classes of sensory neurons detect and encode both attractive and aversive cues.
Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. ...Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb
neurons, and we demonstrate that Nppb
somatostatin
cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR
neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.
Highlights • New itch receptors identified that detect pruritogens released from the skin. • Molecular studies demonstrate itch sensory neurons are selectively tuned. • Novel itch sensory neurons ...neurotransmitter, Nppb, is required for itch. • Itch is encoded by a dedicated spinal cord circuit. • Dynophin, released by inhibitory spinal cord neurons, can reduce itch.
Perception of the thermal environment begins with the activation of peripheral thermosensory neurons innervating the body surface. To understand how temperature is represented in vivo, we used ...genetically encoded calcium indicators to measure temperature-evoked responses in hundreds of neurons across the trigeminal ganglion. Our results show how warm, hot, and cold stimuli are represented by distinct population responses, uncover unique functional classes of thermosensory neurons mediating heat and cold sensing, and reveal the molecular logic for peripheral warmth sensing. Next, we examined how the peripheral somatosensory system is functionally reorganized to produce altered perception of the thermal environment after injury. We identify fundamental transformations in sensory coding, including the silencing and recruitment of large ensembles of neurons, providing a cellular basis for perceptual changes in temperature sensing, including heat hypersensitivity, persistence of heat perception, cold hyperalgesia, and cold analgesia.
•In vivo calcium imaging reveals the peripheral code for mammalian thermosensation•The TRPV1 channel is essential for innocuous warmth detection•Cold sensory neurons include functionally diverse TRPM8-expressing populations•Injury re-organizes thermal coding and recruits a novel population of thermosensors
Yarmolinsky et al. apply in vivo calcium imaging to demonstrate how temperature is represented in the activity of populations of primary sensory neurons and how this representation is transformed by injury to produce altered thermal perception.
The 2022 World Health Organization classification contains new renal tumour entities. Some of them are based on a molecular driver event. The classification of penile squamous cell carcinomas is ...simplified and based on the presence of human papillomavirus. A new chapter with tumours of the scrotum has been introduced. Nomenclature changes of testicular tumours include replacement of the term “primitive neuroectodermal tumour” by “embryonic neuroectodermal tumour”. The term “carcinoid” has been changed to “neuroendocrine tumour”.
The fifth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO “Blue Book”), published in 2022, contains significant revisions. This review summarises the most relevant changes for renal, penile, and testicular tumours. In keeping with other volumes in the fifth edition series, the WHO classification of urogenital tumours follows a hierarchical classification and lists tumours by site, category, family, and type. The section “essential and desirable diagnostic criteria” included in the WHO fifth edition represents morphologic diagnostic criteria, combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has been introduced, taking recent discoveries in renal tumour genomics into account. Such novel molecularly defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The diverse morphologic patterns of penile squamous cell carcinomas are grouped as human papillomavirus (HPV) associated and HPV independent, and there is an attempt to simplify the morphologic classification. A new chapter with tumours of the scrotum has been introduced. The main nomenclature of testicular tumours is retained, including the use of the term “germ cell neoplasia in situ” (GCNIS) for the preneoplastic lesion of most germ cell tumours and division from those not derived from GCNIS. Nomenclature changes include replacement of the term “primitive neuroectodermal tumour” by “embryonic neuroectodermal tumour” to separate these tumours clearly from Ewing sarcoma. The term “carcinoid” has been changed to “neuroendocrine tumour”, with most examples in the testis now classified as “prepubertal type testicular neuroendocrine tumour”.
Pruritus is a common symptom of dermatological disorders and has a major negative impact on QOL. Previously, it was suggested that human β-defensin peptides elicit itch through the activation of mast ...cells. In this study, we investigated in more detail the mechanisms by which β-defensins induce itch by defining the receptors activated by these peptides in humans and mice, by establishing their action in vivo, and by examining their expression in inflammatory dermal diseases. We found that elevated expression of DEFB103 is highly correlated with skin lesions in psoriasis and atopic dermatitis. We showed that the peptide encoded by this gene and related genes activate Mas-related G protein-coupled receptors with different potencies that are related to their charge density. Furthermore, we establish that although these peptides can activate mast cells, they also activate sensory neurons, with the former cells being dispensable for itch reactions in mice. Together, our studies highlight that specific β-defensins are likely endogenous pruritogens that can directly stimulate sensory neurons.
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