@article{nattkemper_kim_yap_hoon_mishra_yosipovitch_2024, title={Increased Systemic Levels of Centrally Acting B-Type Natriuretic Peptide Are Associated with Chronic Itch of Different Types}, volume={144}, ISSN={["1523-1747"]}, DOI={10.1016/j.jid.2024.02.026}, abstractNote={B-type natriuretic peptide (BNP) is an itch-selective neuropeptide that was shown to play a role in both histaminergic and nonhistaminergic itch in mice. It was also shown that elevated serum BNP is linked to increased pruritus in nondiabetic hemodialysis patients. This study examined plasma BNP levels of 77 patients and N-terminal pro-BNP levels of 33 patients with differing types of chronic itch to see whether BNP and N-terminal pro-BNP levels can correlate with itch severity. Plasma BNP and N-terminal pro-BNP levels of all patients with itch correlated with itch numerical rating scale and in particular for patients with chronic pruritus of unknown origin. On the basis of this clinical observation, this study further showed that increasing pathophysiological levels of BNP in mice by intravenous or osmotic pump induced significant scratching. In addition, pharmacological and ablation strategies determined that BNP acts centrally by activating the natriuretic peptide receptor A in the dorsal horn of the spinal cord. These data support that BNP and N-terminal pro-BNP levels are associated with chronic itch and may be used in clinical setting.}, number={10}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, author={Nattkemper, Leigh A. and Kim, Brian S. and Yap, Qai Ven and Hoon, Mark A. and Mishra, Santosh K. and Yosipovitch, Gil}, year={2024}, month={Oct}, pages={2267–2272} }
 @article{mishra_gaddameedhi_2023, title={A new role of TRPM8 in circadian rhythm and molecular clock}, volume={1}, ISSN={["1748-1716"]}, url={https://doi.org/10.1111/apha.13934}, DOI={10.1111/apha.13934}, abstractNote={Over the past decades, studies of the TRPM8 channel, a nonselective cation channel, have provided much insight into the fundamental mechanisms of sensory neuron function that lead to the detection of cold sensors. In the current issue of Acta Physiologica, Reimundez et al1 provide evidence of a novel role of TRPM8 in circadian function in mice. The TRPM (transient receptor potential ion channels, where “m” stands for melastatin) is a family of eight different channels, TRPM1TRPM8.2 The TRPM8 is a cold sensor and is also activated by chemical ligands such as menthol and icilin, but recently, their role in maintaining core body temperature has also been recognized.3,4 TRPM8 is expressed in sensory neurons whose axonal afferents innervate peripheral tissues such as skin and oral cavity. Still, it has not been detected in the brain and spinal cord. Besides nerve tissues, TRPM8 is expressed in tissues such as the prostate, bladder, lungs, and urogenital tract. However, other than the sensory nervous system, the functional role of TRPM8 channels is not well understood. In this issue of Acta Physiologica, Reimundez et al1 provide solid experimental evidence for such a novel mechanism— where they demonstrate that TRPM8 might regulate Period 2 (Per2) mRNA levels in central clock (SCN) and peripheral clock (liver and white adipose tissue) and the circadian regulation of core body temperature. Their publication is among the most significant advances in the field of circadian regulation using cold sensors— it will probably set up the stage for several future research activities in which Reimundez and colleagues' ideas will be rigorously dissected and probed in circadian biology research. Previously, Ordás et al5 demonstrated the presence of TRPM8 fibers in the suprachiasmatic nucleus of the hypothalamus (SCN) of the brain, which is the principal circadian pacemaker in mammals and host a range of other physiological processes such as circadian oscillation, autonomic/peripheral and central nervous system function, regulating core body temperature and sleep– wake cycle. Since SCN receives axonal projections mainly from intrinsically photosensitive retinal ganglion cells (ipRGCs) that are responsible for resetting the circadian clock through SCN neuron activity with light as a primary zeitgeber.6 Here, authors used conventional PCR and mouse reporter lines to show the expression of TRPM8 in the inner retina, specifically in the ganglion cell layer (GC) and in the inner nuclear layer (INL). Next, they used the colocalization technique to demonstrate that melanopsin, a marker of ipRGCs7 and using mouse reporter lines, that TRPM8 expressing cells are indeed expressed in a subset of ipRGCs cells. Furthermore, they showed that TRPM8 is also expressed in cholinergic amacrine cells, characterized by releasing two neurotransmitters, GABA and acetylcholine. Injection of the fluorescent anterograde tracer cholera toxin subunit B (CTB594) into both eyes in two TRPM8 reporter lines indicates the existence of ipRGCs expressing TRPM8 and projecting to the SCN (Figure 1). The choroid is an essential high blood flow vascular structure in the eye and is known to regulate ocular and retinal temperature8 and is richly innervated by sensory trigeminal nerve fibers; therefore, the authors next examined the role of TRPM8 in regulation of eye temperature (Teye) using infrared (IR) thermography. Interestingly, they discovered mice lacking TRPM8 started to decline at temperatures below 25°C, and Trpm8−/− mice displayed a significantly lower Teye than WT littermates when the temperature plate was around 15°C. This suggests a function of TRPM8 and ambient temperature in regulating choroid and ciliary body blood flow and, therefore, in controlling internal ocular temperature. The ability of mice to regulate homeostatic temperature control and the expression of TRPM8 in the ipRGCs is indicative but does not directly link that to central clock regulation. The authors performed expression and functional studies to investigate a direct link between TRPM8 and circadian clockwork at the SCN. First, they determined the expression of the Per2 gene, which is one of the essential components of core circadian clocks in the SCN.9 Authors found in the TRPM8 deficient mouse SCN a significant}, journal={ACTA PHYSIOLOGICA}, author={Mishra, Santosh K. and Gaddameedhi, Shobhan}, year={2023}, month={Jan} }
 @article{meneses_gidcumb_marcus_gonzalez_lai_mishra_lascelles_nolan_2023, title={Acute radiotherapy-associated oral pain may promote tumor growth at distant sites}, volume={13}, ISSN={["2234-943X"]}, url={http://dx.doi.org/10.3389/fonc.2023.1029108}, DOI={10.3389/fonc.2023.1029108}, abstractNote={IntroductionPatients developing acute radiotherapy induced dermatitis or oral mucositis commonly experience pain. When severe, this radiotherapy-associated pain (RAP) can necessitate treatment breaks; unfortunately, in a variety of cancers, prolongation of the radiotherapy course has been associated with early cancer relapse and/or death. This is often attributed to accelerated repopulation, but it is unknown whether pain or pain signaling constituents might alter tumor behavior and hasten metastatic disease progression. We studied this by testing the hypothesis that severe acute RAP at one site can hasten tumor growth at a distant site.MethodsMice underwent single fraction tongue irradiation (27 Gy, or 0 Gy “sham” control) to induce severe glossitis. At the time of maximal oral RAP, one of three luciferase-transfected tumor cell lines were injected via tail vein (4T1, B16F10, MOC2; each paired to their syngeneic host: BALB/c or C57BL/6); tumor burden was assessed via in vivo transthoracic bioluminescence imaging and ex vivo pulmonary nodule quantification. Survival was compared using Kaplan-Meier statistics.ResultsTongue irradiation and resultant RAP promoted lung tumor growth of 4T1-Luc2 cells in BALB/c mice. This effect was not a result of off-target radiation, nor an artefact of environmental stress caused by standard (subthermoneutral) housing temperatures. RAP did not affect the growth of B16F10-Luc2 cells, however, C57BL/6 mice undergoing tail vein injection of MOC2-Luc2 cells at the time of maximal RAP experienced early lung tumor-attributable death. Lung tumor growth was normalized when RAP was reduced by treatment with resiniferatoxin (300 µg/kg, subcutaneously, once).DiscussionThis research points towards radiation-induced activation of capsaicin-responsive (TRPV1) neurons as the cause for accelerated growth of tumors at distant (unirradiated) sites.}, journal={FRONTIERS IN ONCOLOGY}, publisher={Frontiers Media SA}, author={Meneses, Constanza S. and Gidcumb, Emily M. and Marcus, Karen L. and Gonzalez, Yarines and Lai, Yen Hao and Mishra, Santosh K. and Lascelles, B. Duncan X. and Nolan, Michael W.}, year={2023}, month={May} }
 @misc{wheeler_williams_yu_mishra_2024, title={Brain Natriuretic Peptide Exerts Inflammation and Peripheral Itch in a Mouse Model of Atopic Dermatitis}, volume={144}, ISSN={["1523-1747"]}, DOI={10.1016/j.jid.2023.09.273}, abstractNote={Atopic dermatitis (AD) is a globally prevalent disease that affects both children and adults, and the incidence of AD is increasing worldwide (Bylund et al, 2020). AD is characterized by dry, inflamed, and itchy skin, but the etiology behind neuroinflammation and itch related to AD skin is only beginning to be understood. The brain natriuretic peptide (BNP), a byproduct of the NPPB gene, is expressed in primary afferent neurons, which are known to be responsible for central itch (Meng et al, 2018; Mishra and Hoon, 2013; Mishra et al, 2020; Pitake et al, 2018; Usoskin et al, 2015).}, number={3}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, author={Wheeler, Joshua J. and Williams, Nidha and Yu, Junho and Mishra, Santosh K.}, year={2024}, month={Mar}, pages={705–707} }
 @article{minnema_gupta_mishra_lascelles_2022, title={Investigating the Role of Artemin and Its Cognate Receptor, GFR alpha 3, in Osteoarthritis Pain}, volume={16}, ISSN={["1662-453X"]}, url={https://europepmc.org/articles/PMC8829392}, DOI={10.3389/fnins.2022.738976}, abstractNote={Osteoarthritis (OA) associated pain (OA-pain) is a significant global problem. OA-pain limits limb use and mobility and is associated with widespread sensitivity. Therapeutic options are limited, and the available options are often associated with adverse effects. The lack of therapeutic options is partly due to a lack of understanding of clinically relevant underlying neural mechanisms of OA-pain. In previous work in naturally occurring OA-pain in dogs, we identified potential signaling molecules (artemin/GFRα3) that were upregulated. Here, we use multiple approaches, including cellular, mouse genetic, immunological suppression in a mouse model of OA, and clinically relevant measures of sensitivity and limb use to explore the functional role of artemin/GFRα3 signaling in OA-pain. We found the monoiodoacetate (MIA)-induced OA-pain in mice is associated with decreased limb use and hypersensitivity. Exogenous artemin induces mechanical, heat, and cold hypersensitivity, and systemic intraperitoneal anti-artemin monoclonal antibody administration reverses this hypersensitivity and restores limb use in mice with MIA-induced OA-pain. An artemin receptor GFRα3 expression is increased in sensory neurons in the MIA model. Our results provide a molecular basis of arthritis pain linked with artemin/GFRα3 signaling and indicate that further work is warranted to investigate the neuronal plasticity and the pathways that drive pain in OA.}, journal={FRONTIERS IN NEUROSCIENCE}, author={Minnema, Laura and Gupta, Ankita and Mishra, Santosh K. and Lascelles, B. Duncan X.}, year={2022}, month={Jan} }
 @article{lai_baumer_meneses_roback_robertson_mishra_lascelles_nolan_2021, title={Irradiation of the Normal Murine Tongue Causes Upregulation and Activation of Transient Receptor Potential (TRP) Ion Channels}, volume={196}, ISSN={["1938-5404"]}, url={http://dx.doi.org/10.1667/rade-21-000103.1}, DOI={10.1667/RADE-21-000103.1}, abstractNote={Signal transduction at sensory neurons occurs via transmembrane flux of cations, which is largely governed by the transient receptor potential (TRP) family of ion channels. It is unknown whether TRP channel activation contributes to the pain that accompanies radiation-induced oral mucositis. This study sought to characterize changes in TRP channel expression and function that occur in the locally irradiated tissues and afferent neurons of mice. Female CD-1 mice received single high-dose (27 Gy) tongue irradiation, or sham irradiation. Animals were euthanized either before overt glossitis developed (days 1 and 5 postirradiation), when glossitis was severe (day 11), or after mice had recovered (days 21 and 45). Tongue irradiation caused upregulation of the Trpv1 gene in trigeminal ganglia (TG) neurons. Other TRP genes (Trpv2, Trpv4, Trpa1, Trpm8) and Gfrα3 (which acts upstream of several TRP channels) were also upregulated in TGs and/or tongue tissue, in response to radiation. Ex vivo calcium imaging experiments demonstrated that the proportions of TG neurons responding to histamine (an activator of TRPV1, TRPV4 and TRPA1), TNF-α (an activator of TRPV1, TRPV2 and TRPV4), and capsaicin (a TRPV1 agonist), were increased as early as one day after tongue irradiation; these changes persisted for at least 21 days. In a subsequent experiment, we found that genetic deletion of TRPV1 mitigated weight loss (a surrogate marker of pain severity) in mice with severe glossitis. The results intimate that various TRP channels, and TRPV1 in particular, should be explored as analgesic targets for patients experiencing pain after oral irradiation.}, number={4}, journal={RADIATION RESEARCH}, publisher={Radiation Research Society}, author={Lai, Yen and Baumer, Wolfgang and Meneses, Constanza and Roback, Donald M. and Robertson, James B. and Mishra, Santosh K. and Lascelles, B. Duncan X. and Nolan, Michael W.}, year={2021}, month={Oct}, pages={331–344} }
 @misc{hashimoto_mishra_olivry_yosipovitch_2021, title={Periostin, an Emerging Player in Itch Sensation}, volume={141}, ISSN={["1523-1747"]}, url={https://doi.org/10.1016/j.jid.2021.03.009}, DOI={10.1016/j.jid.2021.03.009}, abstractNote={Periostin, an extracellular matrix and matricellular protein, binds to several types of integrins that transduce its signals. Its function in allergic inflammation is the establishment of sustained chronic inflammation through an amplification of T helper type 2‒immune responses. In addition, recent studies have shown a significant role of periostin in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells (e.g., macrophages, eosinophils, basophils, and keratinocytes). The objective of this review is to describe the role of periostin in itch induction in human and animal models and its expression in human pruritic conditions.}, number={10}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, publisher={Elsevier BV}, author={Hashimoto, Takashi and Mishra, Santosh K. and Olivry, Thierry and Yosipovitch, Gil}, year={2021}, month={Oct}, pages={2338–2343} }
 @misc{shirolkar_mishra_2022, title={Role of TRP ion channels in pruritus}, volume={768}, ISSN={["1872-7972"]}, DOI={10.1016/j.neulet.2021.136379}, abstractNote={The transient receptor potential (TRP) channel superfamily responds to various physical, chemical, and environmental stimuli including the detection of sensations both harmful and non-harmful. Among these sensations is pruritus, or itch. There are at least 27 different TRP channels and about six of them are involved in pruriception. The function of these six receptors is primarily seen in the skin and the dorsal root ganglia. Identification and biological insights provided by these receptors in pruriception is important for human health as mutations and activations of many of these channels cause discomfort and disease. This review will focus on involvement of TRP channels in pruriception that may render these channels as the targets of many antagonistic topical medications, which may help patients' better cope with the pruritus that results from various cutaneous and systemic diseases.}, journal={NEUROSCIENCE LETTERS}, author={Shirolkar, Parth and Mishra, Santosh K.}, year={2022}, month={Jan} }
 @article{gupta_chiavaccini_minnema_chiu_knazovicky_hash_mishra_lascelles_2021, title={Serum artemin is not correlated with sensitivity within dogs with naturally occurring osteoarthritis pain}, volume={11}, ISSN={["2045-2322"]}, url={https://europepmc.org/articles/PMC7988108}, DOI={10.1038/s41598-021-85976-y}, abstractNote={AbstractOsteoarthritis (OA) pain is associated with peripheral and central sensitization in humans and results in widespread increased sensitivity across the body. Sensitization contributes to the OA-associated pain (OAP) state. We recently identified increased levels of an endogenous neurotrophic factor, artemin (ARTN), in dogs with OAP compared to healthy pain-free controls. Circulating ARTN released from damaged tissues in OA, may play a central role in widespread sensitivity and pain. However, the relationship between ARTN and somatosensory sensitivity remains unknown. The study aimed to assess the relationship between serum ARTN concentrations and measures of sensitivity in dogs with OAP using quantitative sensory testing. We hypothesized that there would be a positive association between circulating ARTN and increased sensitivity to mechanical and thermal stimuli in dogs with OAP. We used linear and logistic regression models to assess the relationship between ARTN, sensitization, and pain within a cohort of 43 dogs with spontaneous OAP. Serum ARTN was not associated with the degree of sensitization within dogs with OAP. Further, across dogs with varying OAP severity, we did not find any association between ARTN, and clinical measures of joint pain and disability. Although a relationship between ARTN and joint pain was not ruled out.}, number={1}, journal={SCIENTIFIC REPORTS}, author={Gupta, Ankita and Chiavaccini, Ludovica and Minnema, Laura M. and Chiu, King Wa and Knazovicky, David and Hash, Jonathan A. and Mishra, Santosh K. and Lascelles, B. Duncan X.}, year={2021}, month={Mar} }
 @article{wilzopolski_kietzmann_mishra_stark_baeumer_rossbach_2021, title={TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch}, volume={11}, ISSN={["2218-273X"]}, DOI={10.3390/biom11081166}, abstractNote={Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.}, number={8}, journal={BIOMOLECULES}, author={Wilzopolski, Jenny and Kietzmann, Manfred and Mishra, Santosh K. and Stark, Holger and Baeumer, Wolfgang and Rossbach, Kristine}, year={2021}, month={Aug} }
 @article{mishra_2022, title={The Role of CNTNAP2 in Itch Sensation}, volume={142}, ISSN={["1523-1747"]}, DOI={10.1016/j.jid.2021.07.152}, abstractNote={Itch is a hallmark symptom associated with atopic dermatitis (AD), which is an allergic disorder accentuated by both immunological dysregulation and epidermal barrier defect (Wahlgren, 1991). Autism spectrum disorders (ASDs) are complex neurobehavioral and neurodevelopmental conditions that cause a variety of phenotypes, including impaired social communication, stereotyped behaviors, and altered sensory processing (Dawes et al., 2018; Vahia, 2013). A longitudinal study and a systemic review reveal an association between early AD and subsequent ASD (Lee et al., 2016; Tongo et al., 2015), but how itch is regulated in individuals with ASD remains unknown.}, number={1}, journal={JOURNAL OF INVESTIGATIVE DERMATOLOGY}, author={Mishra, Santosh K.}, year={2022}, month={Jan}, pages={251–253} }
 @misc{fan_mishra_2022, title={The emerging role of neuroimmune interactions in atopic dermatitis and itch}, volume={289}, ISSN={["1742-4658"]}, DOI={10.1111/febs.15860}, abstractNote={Millions of people globally suffer from allergic diseases, and the cases have been rising in the past decades. One of the major manifestations of allergic diseases is itch, which is an unpleasant symptom that triggers the urge to scratch and greatly affects the quality of life. Thus, research on how sensation of itch is detected/transmitted from the contact of the allergen to the nervous system is crucial in mitigating itch. Recent studies have attempted to elucidate the mechanisms of itch in allergic diseases. Here, we aim to review the endogenous mediators released from immune/nonimmune skin cells (that are indirectly involved in the propagation of itch) and the sensory neurons that express receptors for these itch mediators that are associated with direct transmission of itch in cutaneous allergic diseases. As the mechanisms for allergic itch become clearer, new therapeutic approaches to relieve itch are likely to be developed. Recent clinical trials are testing numerous compounds that target the endogenous mediators and their receptors. These studies provide the possibility of more effective itch treatment for allergic diseases.}, number={10}, journal={FEBS JOURNAL}, author={Fan, Jennifer and Mishra, Santosh K.}, year={2022}, month={May}, pages={2723–2735} }
 @article{hoffman_kyriazis_dimitriou_mishra_koch_drosatos_2020, title={B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes to septic hypotension}, volume={5}, ISSN={["2379-3708"]}, DOI={10.1172/jci.insight.133675}, abstractNote={B-type natriuretic peptide (BNP) is secreted by ventricular cardiomyocytes in response to various types of cardiac stress and has been used as a heart failure marker. In septic patients, increased BNP suggests poor prognosis; however, no causal link has been established. Among various effects, BNP decreases systemic vascular resistance and increases natriuresis that leads to lower blood pressure. We previously observed that JNK inhibition corrects cardiac dysfunction and suppresses cardiac BNP mRNA in endotoxemia. In this study, we investigated the transcriptional mechanism that regulates BNP expression and the involvement of plasma BNP in causing septic hypotension. Our in vitro and in vivo findings confirmed that activation of JNK signaling increases BNP expression in sepsis via direct binding of c-Jun in activating protein–1 (AP-1) regulatory elements of the Nppb promoter. Accordingly, genetic ablation of BNP, as well as treatment with a potentially novel neutralizing anti-BNP monoclonal antibody (19B3) or suppression of its expression via administration of JNK inhibitor SP600125 improved cardiac output, stabilized blood pressure, and improved survival in mice with polymicrobial sepsis. Therefore, inhibition of JNK signaling or BNP in sepsis appears to stabilize blood pressure and improve survival.}, number={8}, journal={JCI INSIGHT}, author={Hoffman, Matthew and Kyriazis, Ioannis D. and Dimitriou, Alexandra and Mishra, Santosh K. and Koch, Walter J. and Drosatos, Konstantinos}, year={2020}, month={Apr} }
 @article{kittaka_debrecht_mishra_2020, title={Differential contribution of sensory transient receptor potential channels in response to the bioactive lipid sphingosine-1-phosphate}, volume={16}, ISSN={["1744-8069"]}, DOI={10.1177/1744806920903515}, abstractNote={Somatosensation encompasses a wide range of sensations including pain, itch, touch, and temperature and is essential for the detection of environmental stimuli, ultimately allowing an organism to escape, communicate, and adapt to its environment. Such sensations are detected by primary sensory neurons whose nerve endings are located in the skin. Compared to external stimuli, mechanisms underlying endogenous stimulation of primary sensory neurons, such as by lipids, are still largely unknown. Here, we focus on one of the endogenous bioactive lipids, sphingosine-1-phosphate (S1P), to investigate the physiological roles of S1P in pain and itch. We showed that S1P-induced calcium responses in sensory neurons through S1P receptors. Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are nonselective calcium-permeable ion channels that are known to be involved in pain and itch. Neurons that respond to S1P show reduced responsiveness when treated with antagonists that block either TRPA1 or TRPV1 alone or in combination. In addition, using single and double knockout mice (TRPA1; TRPV1; TRPA1/TRPV1) with loss of function of these channels, we demonstrated that both TRP channels are involved in S1P-induced neuronal responses in vitro. Next, we examined the effects of S1P on pain and itch responsiveness in freely behaving mice post-S1P injection into the cheek, neck, and hind paw. Our findings reveal that S1P induces both pain and itch in vivo and that these responses are partially dependent upon the TRPV1, but not TRPA1 channels.}, journal={MOLECULAR PAIN}, author={Kittaka, Hiroki and DeBrecht, Jennifer and Mishra, Santosh K.}, year={2020}, month={Feb} }
 @article{mishra_wheeler_pitake_ding_jiang_fukuyama_paps_ralph_coyne_parkington_et al._2020, title={Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch}, volume={31}, ISSN={["2211-1247"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85082772179&partnerID=MN8TOARS}, DOI={10.1016/j.celrep.2020.03.036}, abstractNote={Chronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin αVβ3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and genetic approaches, we inhibited the function of neuronal integrin αVβ3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD-causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch.}, number={1}, journal={CELL REPORTS}, author={Mishra, Santosh K. and Wheeler, Joshua J. and Pitake, Saumitra and Ding, Huiping and Jiang, Changyu and Fukuyama, Tomoki and Paps, Judy S. and Ralph, Patrick and Coyne, Jacob and Parkington, Michelle and et al.}, year={2020}, month={Apr} }
 @article{panigrahi_praharaj_kittaka_mridha_black_singh_mercer_bokhoven_torkko_agarwal_et al._2019, title={Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients}, volume={8}, ISSN={["2045-7634"]}, DOI={10.1002/cam4.1885}, abstractNote={AbstractAfrican American men face a stark prostate cancer (PCa)‐related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome‐based “protein signature” for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2‐fold (P ˂ 0.05) in the sera of African American men with PCa. Mass spectrometry‐based proteomic analysis of serum exosomes identified seven unique and fifty‐five overlapping proteins (up‐ or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute‐phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA‐hT cells secreted exosomes strongly induced a proinflammatory M2‐phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6‐fold) in exosomes from African Americans with PCa, but a lesser loading (0.6‐fold) was observed in exosomes from Caucasian men with PCa compared to race‐matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men.}, number={3}, journal={CANCER MEDICINE}, author={Panigrahi, Gati K. and Praharaj, Prakash P. and Kittaka, Hiroki and Mridha, Asit R. and Black, Olen M. and Singh, Rakesh and Mercer, Roger and Bokhoven, Adrie and Torkko, Kathleen C. and Agarwal, Chapla and et al.}, year={2019}, month={Mar}, pages={1110–1123} }
 @article{pitake_middleton_abdus-saboor_mishra_2019, title={Inflammation Induced Sensory Nerve Growth and Pain Hypersensitivity Requires the N-Type Calcium Channel Cav2.2}, volume={13}, ISSN={["1662-453X"]}, DOI={10.3389/fnins.2019.01009}, abstractNote={Voltage-gated calcium channels (VGCCs) are important mediators of pain hypersensitivity during inflammatory states, but their role in sensory nerve growth remains underexplored. Here, we assess the role of the N-type calcium channel Cav2.2 in the complete Freund’s adjuvant (CFA) model of inflammatory pain. We demonstrate with in situ hybridization and immunoblotting, an increase in Cav2.2 expression after hind paw CFA injection in sensory neurons that respond to thermal stimuli, but not in two different mechanosensitive neuronal populations. Further, Cav2.2 upregulation post-CFA correlates with thermal but not mechanical hyperalgesia in behaving mice, and this hypersensitivity is blocked with a specific Cav2.2 inhibitor. Voltage clamp recordings reveal a significant increase in Cav2.2 currents post-CFA, while current clamp analyses demonstrate a significant increase in action potential frequency. Moreover, CFA-induced sensory nerve growth, which involves the extracellular signal-related kinase (ERK1/2) signaling pathway and likely contributes to inflammation-induced hyperalgesia, was blocked with the Cav2.2 inhibitor. Together, this work uncovers a role for Cav2.2 during inflammation, demonstrating that VGCC activity can promote thermal hyperalgesia through both changes in firing rates of sensory neurons as well as promotion of new neurite outgrowth.}, journal={FRONTIERS IN NEUROSCIENCE}, author={Pitake, Saumitra and Middleton, Leah J. and Abdus-Saboor, Ishmail and Mishra, Santosh K.}, year={2019}, month={Sep} }
 @article{wheeler_lascelles_olivry_mishra_2019, title={Itch-associated Neuropeptides and Their Receptor Expression in Dog Dorsal Root Ganglia and Spinal Cord}, volume={99}, ISSN={["1651-2057"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85074372654&partnerID=MN8TOARS}, DOI={10.2340/00015555-3297}, abstractNote={Most canine visits to veterinarians are related to skin diseases with itch being the chief complaint. Historically, several itch-inducing molecules and pathways have been identified in mice, but whether or not these are similar in dogs is not yet known. Herein, we set out to study the expression of pruritogenic neuropeptides, their cognate receptors with a limited functional validation thereof using a multidisciplinary approach. We demonstrated the expression of somatostatin and other major neuropeptides and receptors in canine dorsal root ganglia neurons. Next, we showed that interleukin-31, serotonin, and histamine activate such neurons. Furthermore, we demonstrated the physiological release of somatostatin from dog dorsal root ganglia neurons in response to several endogenous itch mediators. In summary, our results provide the first evidence that dogs use similar pruritogenic pathways to those characterized in mice and we thus identify multiple targets for the future treatment of itch in dogs.}, number={12}, journal={ACTA DERMATO-VENEREOLOGICA}, author={Wheeler, Joshua J. and Lascelles, B. Duncan X. and Olivry, Thierry and Mishra, Santosh K.}, year={2019}, month={Nov}, pages={1131–1135} }
 @article{huang_polgár_solinski_mishra_tseng_iwagaki_boyle_dickie_kriegbaum_wildner_et al._2018, title={Author Correction: Circuit dissection of the role of somatostatin in itch and pain}, volume={21}, ISSN={1097-6256 1546-1726}, url={http://dx.doi.org/10.1038/S41593-018-0149-6}, DOI={10.1038/S41593-018-0149-6}, abstractNote={In the version of this article initially published online, the labels were switched for the right-hand pair of bars in Fig. 4e. The left one of the two should be Chloroquine + veh, the right one Chloroquine + CNO. The error has been corrected in the print, HTML and PDF versions of the article.}, number={6}, journal={Nature Neuroscience}, publisher={Springer Science and Business Media LLC}, author={Huang, Jing and Polgár, Erika and Solinski, Hans Jürgen and Mishra, Santosh K. and Tseng, Pang-Yen and Iwagaki, Noboru and Boyle, Kieran A. and Dickie, Allen C. and Kriegbaum, Mette C. and Wildner, Hendrik and et al.}, year={2018}, month={Apr}, pages={894–894} }
 @article{huang_polgar_solinski_mishra_tseng_iwagaki_boyle_dickie_kriegbaum_wildner_et al._2018, title={Circuit dissection of the role of somatostatin in itch and pain}, volume={21}, ISSN={["1546-1726"]}, DOI={10.1038/s41593-018-0119-z}, abstractNote={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. Huang et al. demonstrate that somatostatin (Sst)-expressing primary afferents are pruriceptors. In spinal cord, they show that Sst potentiates itch by disinhibition involving dynorphin-expressing spinal neurons and that Sst also suppresses pain.}, number={5}, journal={NATURE NEUROSCIENCE}, author={Huang, Jing and Polgar, Erika and Solinski, Hans Jurgen and Mishra, Santosh K. and Tseng, Pang-Yen and Iwagaki, Noboru and Boyle, Kieran A. and Dickie, Allen C. and Kriegbaum, Mette C. and Wildner, Hendrik and et al.}, year={2018}, month={May}, pages={707-+} }
 @article{wilzopolski_rossbach_mishra_baumer_kietzmann_2018, title={Histamine H4 receptor mediates itch through TRPV1 and TRPA1 ion channels}, volume={41}, journal={Journal of Veterinary Pharmacology and Therapeutics}, author={Wilzopolski, J. and Rossbach, K. and Mishra, S. K. and Baumer, W. and Kietzmann, M.}, year={2018}, pages={48–48} }
 @article{pandey_zhang_mishra_adikaram_harris_kahler_loshakov_sholevar_genis_kittock_et al._2017, title={A central role for R7bp in the regulation of itch sensation}, volume={158}, ISSN={["1872-6623"]}, DOI={10.1097/j.pain.0000000000000860}, abstractNote={Abstract
          Itch is a protective sensation producing a desire to scratch. Pathologic itch can be a chronic symptom of illnesses such as uremia, cholestatic liver disease, neuropathies and dermatitis, however current therapeutic options are limited. Many types of cell surface receptors, including those present on cells in the skin, on sensory neurons and on neurons in the spinal cord, have been implicated in itch signaling. The role of G protein signaling in the regulation of pruriception is poorly understood. We identify here 2 G protein signaling components whose mutation impairs itch sensation. R7bp (a.k.a. Rgs7bp) is a palmitoylated membrane anchoring protein expressed in neurons that facilitates Gαi/o -directed GTPase activating protein activity mediated by the Gβ5/R7-RGS complex. Knockout of R7bp diminishes scratching responses to multiple cutaneously applied and intrathecally-administered pruritogens in mice. Knock-in to mice of a GTPase activating protein-insensitive mutant of Gαo (Gnao1 G184S/+) produces a similar pruriceptive phenotype. The pruriceptive defect in R7bp knockout mice was rescued in double knockout mice also lacking Oprk1, encoding the G protein-coupled kappa-opioid receptor whose activation is known to inhibit itch sensation. In a model of atopic dermatitis (eczema), R7bp knockout mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists. Taken together, our results indicate that R7bp is a key regulator of itch sensation and suggest the potential targeting of R7bp-dependent GTPase activating protein activity as a novel therapeutic strategy for pathological itch.}, number={5}, journal={PAIN}, author={Pandey, Mritunjay and Zhang, Jian-Hua and Mishra, Santosh K. and Adikaram, Poorni R. and Harris, Benjamin and Kahler, John F. and Loshakov, Anna and Sholevar, Roxanne and Genis, Allison and Kittock, Claire and et al.}, year={2017}, month={May}, pages={931–944} }
 @misc{fukuyama_ganchingco_mishra_olivry_rzagalinski_volmer_baeumer_2017, title={Janus kinase inhibitors display broad anti-itch properties: A possible link through the TRPV1 receptor}, volume={140}, ISSN={["1097-6825"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85013487374&partnerID=MN8TOARS}, DOI={10.1016/j.jaci.2016.12.960}, abstractNote={Janus kinase (JAK) inhibitors are being proposed for the treatment of cancer and inflammatory diseases, such as atopic dermatitis. Their mechanism of action, especially that to reduce itch, remains speculative. The JAK inhibitor oclacitinib is currently approved for the treatment of lesions and pruritus in dogs with atopic dermatitis,1,2 whereas tofacitinib is under clinical development for the treatment of the homologous human disease (https://www.clinicaltrials.gov/ct2/show/NCT02001181). In rodent and canine models of allergic dermatitis and in human patients with psoriasis and atopic dermatitis, the antipruritic effect of JAK inhibitors is rapidly visible.}, number={1}, journal={JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY}, author={Fukuyama, Tomoki and Ganchingco, Joy Rachel and Mishra, Santosh K. and Olivry, Thierry and Rzagalinski, Ignacy and Volmer, Dietrich A. and Baeumer, Wolfgang}, year={2017}, month={Jul}, pages={306-+} }
 @article{goswami_mishra_maric_kaszas_gonnella_clokie_kominsky_gross_keller_mannes_et al._2014, title={Molecular Signatures of Mouse TRPV1-Lineage Neurons Revealed by RNA-Seq Transcriptome Analysis}, volume={15}, ISSN={1526-5900}, url={http://dx.doi.org/10.1016/j.jpain.2014.09.010}, DOI={10.1016/j.jpain.2014.09.010}, abstractNote={Disorders of pain neural systems are frequently chronic and, when recalcitrant to treatment, can severely degrade the quality of life. The pain pathway begins with sensory neurons in dorsal root or trigeminal ganglia, and the neuronal subpopulations that express the transient receptor potential cation channel, subfamily V, member 1 (TRPV1) ion channel transduce sensations of painful heat and inflammation and play a fundamental role in clinical pain arising from cancer and arthritis. In the present study, we elucidate the complete transcriptomes of neurons from the TRPV1 lineage and a non-TRPV1 neuroglial population in sensory ganglia through the combined application of next-gen deep RNA-Seq, genetic neuronal labeling with fluorescence-activated cell sorting, or neuron-selective chemoablation. RNA-Seq accurately quantitates gene expression, a difficult parameter to determine with most other methods, especially for very low and very high expressed genes. Differentially expressed genes are present at every level of cellular function from the nucleus to the plasma membrane. We identified many ligand receptor pairs in the TRPV1 population, suggesting that autonomous presynaptic regulation may be a major regulatory mechanism in nociceptive neurons. The data define, in a quantitative, cell population–specific fashion, the molecular signature of a distinct and clinically important group of pain-sensing neurons and provide an overall framework for understanding the transcriptome of TRPV1 nociceptive neurons. Perspective Next-gen RNA-Seq, combined with molecular genetics, provides a comprehensive and quantitative measurement of transcripts in TRPV1 lineage neurons and a contrasting transcriptome from non-TRPV1 neurons and cells. The transcriptome highlights previously unrecognized protein families, identifies multiple molecular circuits for excitatory or inhibitory autocrine and paracrine signaling, and suggests new combinatorial approaches to pain control.}, number={12}, journal={The Journal of Pain}, publisher={Elsevier BV}, author={Goswami, Samridhi C. and Mishra, Santosh K. and Maric, Dragan and Kaszas, Krisztian and Gonnella, Gian Luigi and Clokie, Samuel J. and Kominsky, Hal D. and Gross, Jacklyn R. and Keller, Jason M. and Mannes, Andrew J. and et al.}, year={2014}, month={Dec}, pages={1338–1359} }
 @article{mishra_hoon_2013, title={The Cells and Circuitry for Itch Responses in Mice}, volume={340}, ISSN={0036-8075 1095-9203}, url={http://dx.doi.org/10.1126/science.1233765}, DOI={10.1126/science.1233765}, abstractNote={The Master Switch for Itch?
          
            Recently, gastrin-releasing peptide (GRP) has been implicated as the primary neurotransmitter between itch-sensitive nerve fibers and downstream neurons in the spinal cord. However,
            Mishra and Hoon
            (p.
            968
            ) challenge this view, provide evidence that natriuretic polypeptide b (Nppb) is the central itch neurotransmitter, and suggest that GRP is released by second-order neurons in the spinal dorsal horn that express the Nppb receptor and are excited by Nppb.
          }, number={6135}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Mishra, S. K. and Hoon, M. A.}, year={2013}, month={May}, pages={968–971} }
 @article{pogorzala_mishra_hoon_2013, title={The Cellular Code for Mammalian Thermosensation}, volume={33}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.5788-12.2013}, DOI={10.1523/jneurosci.5788-12.2013}, abstractNote={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.}, number={13}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Pogorzala, L. A. and Mishra, S. K. and Hoon, M. A.}, year={2013}, month={Mar}, pages={5533–5541} }
 @article{mishra_holzman_hoon_2012, title={A Nociceptive Signaling Role for Neuromedin B}, volume={32}, ISSN={0270-6474 1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.1533-12.2012}, DOI={10.1523/jneurosci.1533-12.2012}, abstractNote={Here we used an array-based differential screen to uncover the expression of the neuropeptide neuromedin B (NMB) in the trigeminal ganglia of mice. Double-labeling experiments reveal NMB is expressed in a subset of sensory neurons that colabel with calcitonin gene-related peptide and TRPV1 suggestive of a role for NMB in nociception. Indeed, administration of NMB antagonist greatly attenuates edema and nerve sensitization following stimulation of peripheral nerves with mustard oil, demonstrating that NMB contributes to neurogenic inflammation. Moreover, direct injection of NMB causes local swelling and nociceptive sensitization. Interestingly, we also find that the receptor for NMB is expressed in interneurons in the superficial layers of the dorsal horn. We used NMB-saporin to specifically eliminate NMBR-expressing neurons and determined they are required in responses to noxious heat, but not for reaction to mechanical and pruritic stimuli. Thus, NMB may be a neurotransmitter that is selectively involved in the perception of thermal stimuli.}, number={25}, journal={Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Mishra, S. K. and Holzman, S. and Hoon, M. A.}, year={2012}, month={Jun}, pages={8686–8695} }
 @article{shukla_zheng_mishra_amin_steiner_grant_kesavapany_pant_2013, title={A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice}, volume={27}, ISSN={0892-6638 1530-6860}, url={http://dx.doi.org/10.1096/fj.12-217497}, DOI={10.1096/fj.12-217497}, abstractNote={Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin‐dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24‐aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood‐brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70–80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity‐free candidate for AD.—Shukla, V., Zheng, Y.‐L., Mishra, S. K., Amin, N. D., Steiner, J., Grant, P., Kesavapany, S., Pant, H. C. A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice. FASEB J. 27, 174–186 (2013). www.fasebj.org}, number={1}, journal={The FASEB Journal}, publisher={FASEB}, author={Shukla, Varsha and Zheng, Ya-Li and Mishra, Santosh K. and Amin, Niranjana D. and Steiner, Joseph and Grant, Philip and Kesavapany, Sashi and Pant, Harish C.}, year={2013}, month={Jan}, pages={174–186} }
 @article{shukla_mishra_pant_2011, title={Oxidative stress in neurodegeneration}, volume={2011}, DOI={10.1155/2011/572634}, abstractNote={It has been demonstrated that oxidative stress has a ubiquitous role in neurodegenerative diseases. Major source of oxidative stress due to reactive oxygen species (ROS) is related to mitochondria as an endogenous source. Although there is ample evidence from tissues of patients with neurodegenerative disorders of morphological, biochemical, and molecular abnormalities in mitochondria, it is still not very clear whether the oxidative stress itself contributes to the onset of neurodegeneration or it is part of the neurodegenerative process as secondary manifestation. This paper begins with an overview of how oxidative stress occurs, discussing various oxidants and antioxidants, and role of oxidative stress in diseases in general. It highlights the role of oxidative stress in neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. The last part of the paper describes the role of oxidative stress causing deregulation of cyclin-dependent kinase 5 (Cdk5) hyperactivity associated with neurodegeneration.}, journal={Advances in Pharmacological Sciences}, author={Shukla, V. and Mishra, S.K. and Pant, H.C.}, year={2011}, pages={1–13} }
 @article{kaszas_keller_coddou_mishra_hoon_stojilkovic_jacobson_iadarola_2011, title={Small Molecule Positive Allosteric Modulation of TRPV1 Activation by Vanilloids and Acidic pH}, volume={340}, ISSN={1521-0103}, url={http://dx.doi.org/10.1124/jpet.111.183053}, DOI={10.1124/jpet.111.183053}, abstractNote={Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a high-conductance, nonselective cation channel strongly expressed in nociceptive primary afferent neurons of the peripheral nervous system and functions as a multimodal nociceptor gated by temperatures greater than 43°C, protons, and small-molecule vanilloid ligands such as capsaicin. The ability to respond to heat, low pH, vanilloids, and endovanilloids and altered sensitivity and expression in experimental inflammatory and neuropathic pain models made TRPV1 a major target for the development of novel, nonopioid analgesics and resulted in the discovery of potent antagonists. In human clinical trials, observations of hyperthermia and the potential for thermal damage by suppressing the ability to sense noxious heat suggested that full-scale blockade of TRPV1 function can be counterproductive and subtler pharmacological approaches are necessary. Here we show that the dihydropyridine derivative 4,5-diethyl-3-(2-methoxyethylthio)-2-methyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1477) behaves as a positive allosteric modulator of both proton and vanilloid activation of TRPV1. Under inflammatory-mimetic conditions of low pH (6.0) and protein kinase C phosphorylation, addition of MRS1477 further increased sensitivity of already sensitized TPRV1 toward capsaicin. MRS1477 does not affect inhibition by capsazepine or ruthenium red and remains effective in potentiating activation by pH in the presence of an orthosteric vanilloid antagonist. These results indicate a distinct site on TRPV1 for positive allosteric modulation that may bind endogenous compounds or novel pharmacological agents. Positive modulation of TRPV1 sensitivity suggests that it may be possible to produce a selective analgesia through calcium overload restricted to highly active nociceptive nerve endings at sites of tissue damage and inflammation.}, number={1}, journal={Journal of Pharmacology and Experimental Therapeutics}, publisher={American Society for Pharmacology & Experimental Therapeutics (ASPET)}, author={Kaszas, K. and Keller, J. M. and Coddou, C. and Mishra, S. K. and Hoon, M. A. and Stojilkovic, S. and Jacobson, K. A. and Iadarola, M. J.}, year={2011}, month={Oct}, pages={152–160} }
 @article{mishra_hoon_2011, title={TRPV1 lineage neurons and their functional role in thermal nociception}, volume={71}, ISSN={0168-0102}, DOI={10.1016/j.neures.2011.07.341}, journal={Neuroscience Research}, publisher={Elsevier BV}, author={Mishra, Santosh and Hoon, Mark}, year={2011}, month={Sep}, pages={e80} }
 @article{mishra_tisel_orestes_bhangoo_hoon_2010, title={TRPV1-lineage neurons are required for thermal sensation}, volume={30}, ISSN={0261-4189}, url={http://dx.doi.org/10.1038/emboj.2010.325}, DOI={10.1038/emboj.2010.325}, abstractNote={The ion-channel TRPV1 is believed to be a major sensor of noxious heat, but surprisingly animals lacking TRPV1 still display marked responses to elevated temperature. In this study, we explored the role of TRPV1-expressing neurons in somatosensation by generating mice wherein this lineage of cells was selectively labelled or ablated. Our data show that TRPV1 is an embryonic marker of many nociceptors including all TRPV1- and TRPM8-neurons as well as many Mrg-expressing neurons. Mutant mice lacking these cells are completely insensitive to hot or cold but in marked contrast retain normal touch and mechanical pain sensation. These animals also exhibit defective body temperature control and lose both itch and pain reactions to potent chemical mediators. Together with previous cell ablation studies, our results define and delimit the roles of TRPV1- and TRPM8-neurons in thermosensation, thermoregulation and nociception, thus significantly extending the concept of labelled lines in somatosensory coding.}, number={3}, journal={The EMBO Journal}, publisher={Wiley}, author={Mishra, Santosh K and Tisel, Sarah M and Orestes, Peihan and Bhangoo, Sonia K and Hoon, Mark A}, year={2010}, month={Dec}, pages={582–593} }
 @article{mishra_hoon_2010, title={Ablation of TrpV1 neurons reveals their selective role in thermal pain sensation}, volume={43}, ISSN={1044-7431}, url={http://dx.doi.org/10.1016/j.mcn.2009.10.006}, DOI={10.1016/j.mcn.2009.10.006}, abstractNote={Here we make use of neural ablation to investigate the properties of the TrpV1-expressing neurons in the trigeminal and dorsal root ganglia of mice. Resiniferotoxin (RTX), a potent TrpV1 agonist, administered either by direct injection in the ganglion or intrathecally killed approximately 70% of TrpV1 cells and resulted in modest thermal analgesia. Interestingly, after carageenan injection in the hind paw, the analgesic effects of RTX were dramatically increased with mice now paradoxically showing far less response to heat applied at sites of inflammation. This additional carageenan and RTX-induced analgesia was transient, lasting less than 2 days, and likely resulted from deafferentation of remaining TrpV1 neurons. Remarkably, although RTX affected sensitivity to heat, mechanical sensitivity (both of normal and inflamed tissue) was completely unaltered by toxin-mediated silencing of the TrpV1 sensory input. Thus, our data demonstrate that TrpV1 neurons are selectively tuned nociceptors that mediate responses to thermal but not mechanical pain and insinuate a labeled line model for somatosensory coding.}, number={1}, journal={Molecular and Cellular Neuroscience}, publisher={Elsevier BV}, author={Mishra, Santosh K. and Hoon, Mark A.}, year={2010}, month={Jan}, pages={157–163} }
 @article{mishra_braun_shukla_füllgrabe_schomerus_korf_gachet_ikehara_sevigny_robson_et al._2006, title={Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation}, volume={133}, ISSN={0950-1991 1477-9129}, url={http://dx.doi.org/10.1242/dev.02233}, DOI={10.1242/dev.02233}, abstractNote={We have previously shown that the extracellular nucleoside triphosphate-hydrolyzing enzyme NTPDase2 is highly expressed in situ by stem/progenitor cells of the two neurogenic regions of the adult murine brain:the subventricular zone (type B cells) and the dentate gyrus of the hippocampus (residual radial glia). We explored the possibility that adult multipotent neural stem cells express nucleotide receptors and investigated their functional properties in vitro. Neurospheres cultured from the adult mouse SVZ in the presence of epidermal growth factor and fibroblast growth factor 2 expressed the ecto-nucleotidases NTPDase2 and the tissue non-specific isoform of alkaline phosphatase, hydrolyzing extracellular ATP to adenosine. ATP, ADP and, to a lesser extent, UTP evoked rapid Ca2+ transients in neurospheres that were exclusively mediated by the metabotropic P2Y1 and P2Y2 nucleotide receptors. In addition,agonists of these receptors and low concentrations of adenosine augmented cell proliferation in the presence of growth factors. Neurosphere cell proliferation was attenuated after application of the P2Y1-receptor antagonist MRS2179 and in neurospheres from P2Y1-receptor knockout mice. In situ hybridization identified P2Y1-receptor mRNA in clusters of SVZ cells. Our results infer nucleotide receptor-mediated synergism that augments growth factor-mediated cell proliferation. Together with the in situ data, this supports the notion that extracellular nucleotides contribute to the control of adult neurogenesis.}, number={4}, journal={Development}, publisher={The Company of Biologists}, author={Mishra, S.K. and Braun, N. and Shukla, V. and Füllgrabe, M. and Schomerus, C. and Korf, H.W. and Gachet, C. and Ikehara, Y. and Sevigny, J. and Robson, S.C. and et al.}, year={2006}, month={Feb}, pages={675–684} }