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Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.

IntroductionMotion sickness has afflicted travelers since ancient times. Neurokinin-1 (NK1) receptor antagonists have therapeutic potential as treatments for the symptoms of motion sickness due to the widespread expression of NK1 receptors throughout important locations in the emetic pathway in the network of brainstem nuclei and the gut. This study evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness symptoms in variable sea conditions.MethodsA total of 365 adult participants with a history of motion sickness embarked on boat trips under variable sea conditions. Study participants were distributed across 34 boat trips that took place between November 2021 and April 2023 in coastal waters of the United States. Participants were randomized 1:1:1 and received 170 mg tradipitant (n = 120), 85 mg tradipitant (n = 123) or placebo (n = 122). The symptoms of vomiting and nausea were evaluated with questionnaires every 30 min during the approximately four-hour trips. The primary efficacy endpoint for the study was the percentage of vomiting during vehicle travel. Statistical hypothesis testing was performed at the two-sided alpha level of 0.05 unless specified otherwise. Tests were declared statistically significant if the calculated p-value was ≤ 0.05.ResultsThe incidence of vomiting in both dosing arms of tradipitant was significantly lower than the placebo group across all boat trips (170 mg tradipitant = 18.3%, 85 mg tradipitant = 19.5%, placebo = 44.3%, p

The rostral ventromedial medulla (RVM) is important in descending modulation of spinal nociceptive transmission, but it is unclear if the RVM also modulates spinal pruriceptive transmission. RVM ON cells are activated by noxious algesic and pruritic stimuli and are pronociceptive. Many RVM-spinal projection neurons express the neurokinin-1 receptor (Tacr1), and ON-cells are excited by local administration of substance P (SP). We hypothesized that Tacr1-expressing RVM ON cells exert an inhibitory effect on itch opposite to their pronociceptive action. Intramedullary microinjection of SP significantly potentiated RVM ON cells and reduced pruritogen-evoked scratching while producing mild mechanical sensitization. Chemogenetic activation of RVM Tacr1-expressing RVM neurons also reduced acute pruritogen-evoked scratching. Optotagging experiments confirmed RVM Tacr1-expressing neurons to be ON cells. We conclude that Tacr1-expressing ON cells in RVM play a significant role in the modulation of pruriceptive transmission.

The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via Gq and Gs proteins. Neurokinin A also activates NK1R, but leads to selective Gq signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryogenic-electron microscopy structures of active NK1R bound to SP or the Gq-biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent Gs signaling but not Gq signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.

A remarkable molecular and functional heterogeneity of the primary sensory neurons and dorsal horn interneurons transmits pain- and or itch-relevant information, but the molecular signature of the projection neurons that convey the messages to the brain is unclear. Here, using retro-TRAP (translating ribosome affinity purification) and RNA sequencing, we reveal extensive molecular diversity of spino- and trigeminoparabrachial projection neurons. Among the many genes identified, we highlight distinct subsets of Cck+ -, Nptx2+ -, Nmb+ -, and Crh+ -expressing projection neurons. By combining in situ hybridization of retrogradely labeled neurons with Fos-based assays, we also demonstrate significant functional heterogeneity, including both convergence and segregation of pain- and itch-provoking inputs into molecularly diverse subsets of NK1R- and non-NK1R-expressing projection neurons.

Behavioral and clinical studies suggest a critical role of substance P (SP)/neurokinin-1 receptor (NK-1R) signaling in alcohol dependence. Here, we examined regulation of GABA transmission in the medial subdivision of the central amygdala (CeM) by the SP/NK-1R system, and its neuroadaptation following chronic alcohol exposure. In naïve rats, SP increased action potential-dependent GABA release, and the selective NK-1R antagonist L822429 decreased it, demonstrating SP regulation of CeM activity under basal conditions. SP induced a larger GABA release in alcohol-dependent rats accompanied by decreased NK-1R expression compared to naïve controls, suggesting NK-1R hypersensitivity which persisted during protracted alcohol withdrawal. The NK-1R antagonist blocked acute alcohol-induced GABA release in alcohol-dependent and withdrawn but not in naïve rats, indicating that dependence engages the SP/NK-1R system to mediate acute effects of alcohol. Collectively, we report long-lasting CeA NK-1R hypersensitivity corroborating that NK-1Rs are promising targets for the treatment of alcohol use disorder.

Reelin (Reln) and Disabled-1 (Dab1) participate in the Reln-signaling pathway and when either is deleted, mutant mice have the same spinally mediated behavioral abnormalities, increased sensitivity to noxious heat and a profound loss in mechanical sensitivity. Both Reln and Dab1 are highly expressed in dorsal horn areas that receive and convey nociceptive information, Laminae I-II, lateral Lamina V, and the lateral spinal nucleus (LSN). Lamina I contains both projection neurons and interneurons that express Neurokinin-1 receptors (NK1Rs) and they transmit information about noxious heat both within the dorsal horn and to the brain. Here, we ask whether the increased heat nociception in Reln and dab1 mutants is due to incorrectly positioned dorsal horn neurons that express NK1Rs. We found more NK1R-expressing neurons in Reln-/- and dab1-/- Laminae I-II than in their respective wild-type mice, and some NK1R neurons co-expressed Dab1 and the transcription factor Lmx1b, confirming their excitatory phenotype. Importantly, heat stimulation in dab1-/- mice induced Fos in incorrectly positioned NK1R neurons in Laminae I-II. Next, we asked whether these ectopically placed and noxious-heat responsive NK1R neurons participated in pain behavior. Ablation of the superficial NK1Rs with an intrathecal injection of a substance P analog conjugated to the toxin saporin (SSP-SAP) eliminated the thermal hypersensitivity of dab1-/- mice, without altering their mechanical insensitivity. These results suggest that ectopically positioned NK1R-expressing neurons underlie the heat hyperalgesia of Reelin-signaling pathway mutants, but do not contribute to their profound mechanical insensitivity.

This article discusses the implications of µ-opioid receptor expression in the brainstem for respiratory control. The rise in opioid use has led to a significant increase in fatal opioid overdoses, which has become a public health crisis. Opioid-induced respiratory depression (OIRD) is a global issue that requires coordinated efforts in public health policy, medical education, and patient safety initiatives. The article explores the expression of µ-opioid receptors in specific brainstem areas involved in respiratory control and related behaviors. Understanding the neural control of breathing and the impact of opioids at various levels is crucial for developing interventions and improving patient outcomes. [Extracted from the article]

BackgroundDespite recent insights into the pathophysiology of acute and chronic itch, chronic itch remains an often intractable condition. Among major contributors to chronic itch is dysfunction of spinal cord gamma aminobutyric acidergic (GABAergic) inhibitory controls.ObjectivesWe sought to test the hypothesis that selective GABA agonists as well as cell transplant-derived GABA are antipruritic against acute itch and in a transgenic mouse model of atopic dermatitis produced by overexpression of the TH2 cell-associated cytokine, IL-31 (IL-31Tg mice).MethodsWe injected wild-type and IL-31Tg mice with combinations of GABA-A (muscimol) or GABA-B (baclofen) receptor agonists 15 to 20 minutes prior to injection of various pruritogens (histamine, chloroquine, or endothelin-1) and recorded spontaneous scratching before and after drug administration. We also tested the antipruritic properties of intraspinal transplantation of precursors of GABAergic interneurons in the IL-31Tg mice.ResultsSystemic muscimol or baclofen are antipruritic against both histamine-dependent and -independent pruritogens, but the therapeutic window using either ligand alone was very small. In contrast, combined subthreshold doses of baclofen and muscimol produced a significant synergistic antipruritic effect, with no sedation. Finally, transplant-mediated long-term enhancement of GABAergic signaling not only reduced spontaneous scratching in the IL-31Tg mice but also dramatically resolved the associated skin lesions.ConclusionsAlthough additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis.

Anorexia nervosa (AN) is a complex and multifactorial disorder occurring predominantly in women. Despite having the highest mortality among psychiatric conditions, it still lacks robust and effective treatment. Disorders such as AN are most likely syndromes with multiple genetic contributions, however, genome-wide studies have been underpowered to reveal associations with this uncommon illness. Here, we generated induced pluripotent stem cells (iPSCs) from adolescent females with AN and unaffected controls. These iPSCs were differentiated into neural cultures and subjected to extensive transcriptome analysis. Within a small cohort of patients who presented for treatment, we identified a novel gene that appears to contribute to AN pathophysiology, TACR1 (tachykinin 1 receptor). The participation of tachykinins in a variety of biological processes and their interactions with other neurotransmitters suggest novel mechanisms for how a disrupted tachykinin system might contribute to AN symptoms. Although TACR1 has been associated with psychiatric conditions, especially anxiety disorders, we believe this report is its first association with AN. Moreover, our human iPSC approach is a proof-of-concept that AN can be modeled in vitro with a full human genetic complement, and represents a new tool for understanding the elusive molecular and cellular mechanisms underlying the disease.

UnlabelledThe neuropeptide substance P (SP) exhibits cytokine-like properties and exerts different effects in autoimmune inflammation. Various immune cells express SP and its neurokinin-1 receptor (NK1R) isoforms. A role for SP has been demonstrated in a number of autoimmune conditions, including multiple sclerosis (MS). In this work, we studied the role of SP and NK1R in human immune cells with a focus on their relationship with IL-12/IL-23 family cytokines and the associated IFN-γ/IL-17.Aims(1) To determine the role of SP mediated effects on induction of various inflammatory cytokines in peripheral blood mononuclear cells (PBMC); (2) to investigate the expression of SP and its receptor in T cells and the effects of stimulation with IL-12 and IL-23. Quantitative real-time PCR, flow cytometry, ELISA, promoter studies on PBMC and primary T cells from healthy volunteers, and Jurkat cell line. Treatment with SP significantly increased the expression of IL-12/IL-23 subunit p40, IL-23 p19 and IL-12 p35 mRNA in human PBMC. Expression of NK1R and SP in T cells was upregulated by IL-23 but a trend was observed with IL-12. The IL-23 effect likely involves IL-17 production that additionally mediates IL-23 effects. Mutual interactions exist with SP enhancing the cytokines IL-23 and IL-12, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. These findings suggest a proinflammatory role for SP in autoimmune inflammation. We propose a model whereby immunocyte derived SP stimulates Th1 and Th17 autoreactive cells migrating to the central nervous system (CNS), enhances their crossing the blood brain barrier and perpetuates inflammation in the CNS by being released from damaged nerves and activating both resident glia and infiltrating immune cells. SP may be a therapeutic target in MS.

We investigated roles for spinal neurons expressing the neurokinin-1 receptor (NK1R) and/or gastrin-releasing peptide receptor (GRPR) in a mouse model of ovalbumin (OVA)-induced chronic atopic dermatitis. Mice receiving repeated topical application of OVA exhibited atopic-like skin lesions and behavioral signs of chronic itch including spontaneous scratching, touch-evoked scratching (alloknesis), and enhancement of chloroquine-evoked scratching (hyperknesis). Substance P-saporin (SP-SAP) and bombesin-saporin (BB-SAP) were intrathecally injected into OVA-sensitized mice to neurotoxically ablate NK1R- or GRPR-expressing spinal neurons, respectively. SP-SAP diminished the expression of NK1R in the superficial spinal dorsal horn and significantly attenuated all behavioral signs of chronic itch. BB-SAP reduced the spinal dorsal horn expression of GRPR and significantly attenuated hyperknesis, with no effect on spontaneous scratching or alloknesis. To investigate whether NK1R-expressing spinal neurons project in ascending somatosensory pathways, we performed a double-label study. The retrograde tracer, Fluorogold (FG), was injected into either the somatosensory thalamus or lateral parabrachial nucleus. In the upper cervical (C1-2) spinal cord, most neurons retrogradely labeled with FG were located in the dorsomedial aspect of the superficial dorsal horn. Of FG-labeled spinal neurons, 89% to 94% were double labeled for NK1R. These results indicate that NK1R-expressing spinal neurons play a major role in the expression of symptoms of chronic itch and give rise to ascending somatosensory projections. Gastrin-releasing peptide receptor-expressing spinal neurons contribute to hyperknesis but not to alloknesis or ongoing itch. NK1R-expressing spinal neurons represent a potential target to treat chronic itch.

Migraine secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the trigeminal nucleus caudalis (TNC). Reported efficacy of extracranial botulinum toxin (BoNT) in treating migraine is surprising since a local extracranial effect of BoNT cannot account for its effect upon meningeal input. We hypothesize that intradermal BoNT acts through central transport in somatic afferents. Anesthetized C57Bl/6 mice (male) received unilateral supraorbital (SO) injections of BoNT-B (1.5 U/40 μl) or saline. 3 days later, mice received ipsilateral (ipsi)-SO capsaicin (20 μl of 0.5mM solution) or meningeal capsaicin (4 μl of 0.35 μM). Pre-treatment with ipsi-SO BoNT-B i) decreased nocicsponsive ipsilateral wiping behavior following ipsi-SO capsaicin; ii) produced cleavage of VAMP in the V1 region of ipsi-TG and in TG neurons showing WGA after SO injection; iii) reduced expression of c-fos in ipsi-TNC following ipsi-SO capsaicin; iv) reduced c-fos activation and NK-1 internalization in ipsi-TNC secondary to ipsi-meningeal capsaicin; and vi) SO WGA did not label dural afferents. We conclude that BoNT-B is taken up by peripheral afferents and transported to central terminals where it inhibits transmitter release resulting in decreased activation of second order neurons. Further, this study supports the hypothesis that SO BoNT exerts a trans-synaptic action on either the second order neuron (which receives convergent input from the meningeal afferent) or the terminal/TG of the converging meningeal afferent.

TRPM8 is the molecular sensor for cold; however, the physiological role of TRPM8+ neurons at mucosal surfaces is unclear. Here we evaluated the distribution and peptidergic properties of TRPM8+ fibers in naive and inflamed colons, as well as their role in mucosal inflammation. We found that Trpm8(-/-) mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis, and that Trpm8(-/-) CD11c+ DCs (dendritic cells) showed hyperinflammatory responses to toll-like receptor (TLR) stimulation. This was phenocopied in calcitonin gene-related peptide (CGRP) receptor-deficient mice, but not in substance P receptor-deficient mice, suggesting a functional link between TRPM8 and CGRP. The DSS phenotype of CGRP receptor-deficient mice could be adoptively transferred to wild-type (WT) mice, suggesting that CGRP suppresses the colitogenic activity of bone marrow-derived cells. TRPM8+ mucosal fibers expressed CGRP in human and mouse colon. Furthermore, neuronal CGRP contents were increased in colons from naive and DSS-treated Trpm8(-/-) mice, suggesting deficient CGRP release in the absence of TRPM8 triggering. Finally, treatment of Trpm8(-/-) mice with CGRP reversed their hyperinflammatory phenotype. These results suggest that TRPM8 signaling in mucosal sensory neurons is indispensable for the regulation of innate inflammatory responses via the neuropeptide CGRP.

Although the intracellular trafficking of G protein-coupled receptors controls specific signaling events, it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation. By using bioluminescence resonance energy transfer and superresolution microscopy, we found that substance P (SP) induces the association of the neurokinin 1 receptor (NK1R) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes: the scaffolding proteins β-arrestin (βARRs) 1 and 2 and the transmembrane metallopeptidases ECE-1c and ECE-1d. In HEK293 cells and non-transformed human colonocytes, we observed that G protein-coupled receptor kinase 2 and βARR1/2 terminate plasma membrane Ca(2+) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus. βARRs deliver the SP-NK1R endosomes, where ECE-1 associates with the complex, degrades SP, and allows the NK1R, freed from βARRs, to recycle. Thus, both ECE-1 and βARRs mediate the resensitization of NK1R Ca(2+) signaling at the plasma membrane. Sustained exposure of colonocytes to SP activates NF-κB and stimulates IL-8 secretion. This proinflammatory signaling is unaffected by inhibition of the endosomal ERK pathway but is suppressed by ECE-1 inhibition or βARR2 knockdown. Inhibition of protein phosphatase 2A, which also contributes to sustained NK1R signaling at the plasma membrane, similarly attenuates IL-8 secretion. Thus, the primary function of βARRs and ECE-1 in SP-dependent inflammatory signaling is to promote resensitization, which allows the sustained NK1R signaling from the plasma membrane that drives inflammation.

NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H(+)-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS). Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus) neurons from control and chronic hypoxia-adapted (CHx) adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats.

Introduction: Novel therapies are needed for the treatment of motion sickness given the inadequate relief and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions.Methods: A total of 126 adults participated in the Motion Sifnos study. Groups of participants were assigned to one of seven boat trips lasting ~4 h on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 min, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS.Results: Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant = 17.5%, placebo = 39.7%, p = 0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant = 15.79%, placebo = 72.22%, p = 0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant = 3.19, placebo = 4.57, p = 0.0235).Discussion: Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness.

Introduction: Novel therapies are needed for the treatment of motion sickness given the inadequate relief and bothersome and dangerous adverse effects of currently approved therapies. Neurokinin-1 (NK1) receptor antagonists have the potential to be effective in improving the symptoms of motion sickness, given the involvement of Substance P in nauseogenic and emetic pathways and the expression of NK1 receptors in the gastrointestinal system. Here we evaluated the efficacy of tradipitant, a novel NK1 receptor antagonist, in preventing motion sickness in variable sea conditions. Methods: A total of 126 adults participated in the Motion Sifnos study. Groups of participants were assigned to one of seven boat trips lasting ~4 h on the Pacific Ocean. Participants were randomized 1:1 to tradipitant 170 mg or placebo and completed the Motion Sickness Severity Scale (MSSS) every 30 min, in addition to other assessments. Severity of motion sickness was assessed with the incidence of vomiting and the MSSS. Results: Participants on tradipitant had a significantly lower incidence of vomiting as compared to those on placebo across all boat trips (tradipitant = 17.5%, placebo = 39.7%, p = 0.0039). For trips exposed to rough sea conditions, the difference in the incidence of vomiting between the groups was more dramatic (tradipitant = 15.79%, placebo = 72.22%, p = 0.0009). Across these trips, motion sickness symptoms were significantly lower in the tradipitant group compared to the placebo group (tradipitant = 3.19, placebo = 4.57, p = 0.0235). Discussion: Tradipitant has the potential to be an effective therapy for the prevention of vomiting and treatment of nausea in people with motion sickness. [ABSTRACT FROM AUTHOR]

The neurokinin‐1 (NK‐1) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood in horses, and clinical use of NK‐1 receptor antagonists has not been reported. This study aimed to determine the pharmacokinetics and safety of maropitant after administration of multiple doses. We hypothesized that maropitant concentrations would be similar at steady state to those reported in dogs, with minimal adverse effects. Maropitant was administered at 4 mg/kg orally, once daily for 5 days in seven adult horses. Serial plasma maropitant concentrations were measured by liquid chromatography‐mass spectrometry. Noncompartmental pharmacokinetic parameters were determined. The maximum, minimum, and average concentrations of maropitant achieved at steady state were 375.5 ± 200, 16.8 ± 7.7, and 73.5 ± 45.1 ng/ml, respectively. The terminal elimination half‐life was 11.6 ± 1.4 hr, and the accumulation index was 1.3 ± 0.07. Heart rate decreased between Day 1 and Day 5 (p =.005), with three horses having heart rates of 20 beats per minute and atrioventricular block on Day 5. Pharmacokinetics of repeated maropitant administration suggests the drug could be considered for use in healthy horses. Further investigation on the clinical relevancy of its cardiac effects is warranted. [ABSTRACT FROM AUTHOR]

Intestinal inflammation is a painful syndrome with multiple symptoms, including chronic pain. This study examined the possible role of sensory neurons and substance P in symptoms of an animal model of acute intestinal inflammation. The model was induced by injecting ethanol and zymosan into the colon of anesthetized male rats. Three hours later, sections of the colon were stained with hematoxylin and eosin. To determine the role of substance P, 5 mg/kg of the neurokinin-1 receptor (NK-1r) antagonist, CP-96,345, or 300 microg/kg of an antisense oligonucleotide targeted at NK-1r mRNA was administered. Spinal cord sections were examined for internalization of NK-1r, as an indicator of substance P release. Sections of colon revealed infiltration of inflammatory cells following ethanol and zymosan treatment. Plasma extravasation in rats given ethanol and zymosan was significantly greater than in controls given saline only (P

Intra-articularly injected complete Freund's adjuvant creates in rats a chronic monoarthritis suitable for studying neuronal plasticity and chronic pain. Using such a model, we report electrophysiological and morphological evidence of alterations in somatosensory synaptic function. In arthritic rats, the baseline activity of dorsal spinal cord wide dynamic range or nociceptive-specific neurons was greater than in control animals. Moreover, neuronal responses elicited by an innocuous stimulation with von Frey filaments applied to the arthritic joint were greater in amplitude and produced the afterdischarge that normally characterizes a nociceptive response. In contrast to the response in control animals, passive movement of the arthritic joint produced an increase in the amplitude of the response of these neurons to iontophoretic application of glutamate receptor agonists over a time frame of 10-30 min. This potentiation was blocked by pretreatment with a neurokinin-1 (NK-1) receptor antagonist, suggesting the involvement of substance P. Ultrastructural analysis of the dorsal horn revealed that movement of the arthritic joint also induced NK-1 receptor internalization, indicative of nociception. Morphological examination revealed significantly increased expression of substance P and its receptor within the superficial dorsal horn of monoarthritic animals. These unique functional and chemical changes reflect alterations in both presynaptic and postsynaptic mechanisms in nociceptive transmission at the spinal level. Thus, although treatment of arthritis should obviously target its peripheral aetiology, targeting its central components is a logical therapeutic complementary objective.

Intra-articularly injected complete Freund's adjuvant creates in rats a chronic monoarthritis suitable for studying neuronal plasticity and chronic pain. Using such a model, we report electrophysiological and morphological evidence of alterations in somatosensory synaptic function. In arthritic rats, the baseline activity of dorsal spinal cord wide dynamic range or nociceptive-specific neurons was greater than in control animals. Moreover, neuronal responses elicited by an innocuous stimulation with von Frey filaments applied to the arthritic joint were greater in amplitude and produced the afterdischarge that normally characterizes a nociceptive response. In contrast to the response in control animals, passive movement of the arthritic joint produced an increase in the amplitude of the response of these neurons to iontophoretic application of glutamate receptor agonists over a time frame of 10-30 min. This potentiation was blocked by pretreatment with a neurokinin-1 (NK-1) receptor antagonist, suggesting the involvement of substance P. Ultrastructural analysis of the dorsal horn revealed that movement of the arthritic joint also induced NK-1 receptor internalization, indicative of nociception. Morphological examination revealed significantly increased expression of substance P and its receptor within the superficial dorsal horn of monoarthritic animals. These unique functional and chemical changes reflect alterations in both presynaptic and postsynaptic mechanisms in nociceptive transmission at the spinal level. Thus, although treatment of arthritis should obviously target its peripheral aetiology, targeting its central components is a logical therapeutic complementary objective.

Prurigo nodularis (PN) is a subtype of chronic prurigo presenting single to multiple symmetrically distributed, hyperkeratotic and intensively itching papules and nodules. PN evolves along with chronic pruritus in the context of diverse dermatological, systemic, neurological or psychiatric conditions. Permanent scratching is possibly a major trigger of PN, although its exact pathophysiology remains unclear. Current state-of-the-art therapy for PN consists of topical steroids, capsaicin, calcineurin inhibitors, ultraviolet (UV) therapy, systemic administration of gabapentinoids, μ-opioid receptor antagonists, antidepressants or immunosuppressants. Novel treatment concepts, such as inhibitors of neurokinin-1, opioid and interleukin-31 receptors, have been developed and are currently being clinically tested.

1. Nicotine can activate primary afferent nociceptors, one result of which is to increase neurogenic plasma extravasation. In this study we have demonstrated a novel proinflammatory effect of sub-nanomolar nicotine, mediated by peripheral action at sensory neurons. This action is normally masked by adrenal medulla-derived delta-opioid receptor agonists. 2. While neurogenic plasma extravasation in the knee joint of the rat was not increased by intra-articular perfusion of nicotine (10(-8) M), perfusion of nicotine, at concentrations as low as 10(-10) M, combined with naloxone to block opioid receptors (or naltrindole to block delta-opioid receptors) was able to enhance bradykinin-induced plasma extravasation. This pro-inflammatory effect of intra-articular nicotine was mimicked by subcutaneous nicotine which was abolished by intra-articularly-administered hexamethonium, a nicotinic receptor antagonist. 3. Following denervation of the adrenal medulla, intra-articular nicotine, alone at 10(-8) M, enhanced plasma extravasation, which was no longer enhanced by naloxone. 4. Destruction of primary afferents by neonatal treatment with capsaicin or blockade of sensory neurotransmitter by neurokinin-1 receptor antagonist RP-87,580 abolished the pro-inflammatory effect of nicotine. 5. The effect of nicotine we describe in promoting inflammation is exerted at extremely low concentrations and therefore could have relevance to smokers, patients receiving medicinal nicotine as therapy and even second-hand smokers. Since receptor mechanisms on peripheral terminals of nociceptors may also be present on central terminals, actions of the endogenous nicotinic agonist acetylcholine, at central terminals of primary afferents or at other sites in the central nervous system, may be similarly modulated by opioids.

Background: Chemotherapy-induced neuropathic pain is a disabling condition following cancer treatment. Vincristine has more neurotoxicity than other vinca alkaloid agents. This study evaluated the correlation of different doses of nefopam with antiallodynic effects in a mouse vincristine neuropathy model. Methods: A peripheral neuropathic mouse model was made by intraperitoneal injection of vincristine (0.1 mg/kg/day; 5-day-on, 2-day-off schedule over 12 days). After the development of allodynia, mice were injected intraperitoneally with 0.9% normal saline (NS group) or various doses (10, 30, 60 mg/kg) of nefopam (Nefopam group). We examined allodynia using von Frey hairs pre-administration and at 30, 60, 90, 120, 180, 240 mins, and 24 hrs after drug administration. We also measured the neurokinin-1 receptor concentrations in the spinal cord to confirm the antiallodynic effect of nefopam after drug administration. Results: The peripheral neuropathic mouse model showed prominent mechanical allodynia. Intraperitoneal nefopam produced a clear dose-dependent increase in paw withdrawal threshold compared with pre-administration values and versus the NS group. The concentration of neurokinin-1 receptor was significantly decreased in the Nefopam group (P< 0.05). Conclusion: Intraperitoneally administered nefopam yielded a dose-dependent attenuation of mechanical allodynia and decreased neurokinin-1 receptor concentration, suggesting that the neurokinin-1 receptor is involved in the antiallodynic effects of nefopam in vincristine neuropathy. [ABSTRACT FROM AUTHOR]

Background: Substance P and the neurokinin-1 (NK-1) receptor are implicated in chronic refractory cough pathophysiology. We assessed the efficacy and safety of orvepitant, a brain-penetrant NK-1 antagonist, in an open-label study in CRC patients with chronic refractory cough.Methods: Thirteen patients with daytime cough frequency >3 to <250 coughs/h took orvepitant 30 mg once daily for 4 weeks. Objective cough frequency was measured over 24 h at baseline and weeks 1, 4, and 8. The primary end point was change from Baseline in daytime cough frequency at week 4. Secondary end points included cough severity visual analog scale (VAS) score, global ratings of change for cough frequency and severity, and Cough-specific Quality of Life Questionnaire score.Results: All patients completed the study. Mean baseline cough frequency was 71.4/h. A statistically and clinically significant improvement in objective daytime cough frequency was observed at week 4: reduction from baseline of 18.9 (26%) coughs/h (95% CI, 9.6-28.3; P < .001). This effect was apparent at week 1 (reduction from baseline of 27.0 [38%] coughs/h [95% CI, 11.4-42.7; P = .001]) and sustained after drug discontinuation at week 8 (reduction from baseline of 20.4 [29%] coughs/h [95% CI, 3.2-37.5; P = .020]). Statistically significant improvements were seen for severity VAS and quality of life. Orvepitant was safe and well-tolerated.Conclusions: Orvepitant resulted in a significant and sustained improvement in objective cough frequency, severity VAS, and quality of life; appeared safe; and merits further clinical investigation.Trial Registry: EU Clinical Trials Register; No.: 2014-003947-36; URL: www.clinicaltrialsregister.eu. [ABSTRACT FROM AUTHOR]

Patients with chronic pruritus are in desperate need of novel treatment options, as current therapeutic possibilities are often not effective, have a poor level of evidence and are mostly off‐label. In recent years, much effort has been put into the identification of potential targets for the treatment of chronic pruritus. More importantly, a number of promising new drugs that are aimed at treating pruritus in different conditions are currently in advanced stages of clinical trials. Here, current pharmacological developments leading to potential new drugs for the treatment of chronic pruritus within various conditions are summarized. Hopefully, these new approaches will result in effective and safe therapies for our patients with chronic pruritus associated with dermatological or non‐dermatological diseases in the near future. [ABSTRACT FROM AUTHOR]

The neurokinin‐1 (NK) receptor antagonist, maropitant citrate, mitigates nausea and vomiting in dogs and cats. Nausea is poorly understood and likely under‐recognized in horses. Use of NK‐1 receptor antagonists in horses has not been reported. The purpose of this study was to determine the pharmacokinetic profile of maropitant in seven adult horses after single intravenous (IV; 1 mg/kg) and intragastric (IG; 2 mg/kg) doses. A randomized, crossover design was performed. Serial blood samples were collected after dosing; maropitant concentrations were measured using LC‐MS/MS. Pharmacokinetic parameters were determined using noncompartmental analysis. The mean plasma maropitant concentration 3 min after IV administration was 800 ± 140 ng/ml, elimination half‐life was 10.37 ± 2.07 h, and volume of distribution was 6.54 ± 1.84 L/kg. The maximum concentration following IG administration was 80 ± 40 ng/ml, and elimination half‐life was 9.64 ± 1.27 hr. Oral bioavailability was variable at 13.3 ± 5.3%. Maropitant concentrations achieved after IG administration were comparable to those in small animals. Concentrations after IV administration were lower than in dogs and cats. Elimination half‐life was longer than in dogs and shorter than in cats. This study is the basis for further investigations into using maropitant in horses. [ABSTRACT FROM AUTHOR]

Herb-partitioned moxibustion can effectively mitigate visceral pain, a major symptom in inflammatory bowel disease, but the analgesic mechanism is still unclear. Moreover, extracellular signal-regulated kinase, substance P, and neurokinin-1 are involved in formation of central hyperalgesia. Thus, we postulated that the analgesic effect of herb-partitioned moxibustion may be associated with these factors. Accordingly, in this study, we established an inflammatory bowel disease visceral pain model in rat by enema with a mixed solution of 5% trinitrobenzenesulfonic acid and 50% ethanol. Bilateral Tianshu (ST25) and Qihai (CV6) points were selected for herb-partitioned moxibustion. Our results showed that herb-partitioned moxibustion improved visceral pain and down-regulated extracellular signal-regulated kinase, substance P, and neurokinin-1 protein and mRNA expression in dorsal root ganglia. These results indicate that down-regulation of extracellular signal-regulated kinase, substance P, and neurokinin-1 protein and mRNA may be a central mechanism for the analgesic effect of herb-partitioned moxibustion.

Rolapitant is a selective and long‐acting neurokinin‐1 receptor antagonist approved in an oral formulation in combination with dexamethasone and a 5‐hydroxytryptamine type 3 receptor antagonist for the prevention of delayed chemotherapy‐induced nausea and vomiting in adults. The pharmacokinetic and safety profiles of intravenous (IV) rolapitant were evaluated in two open‐label, phase 1 trials in healthy subjects. Single ascending dose (SAD) and multiple ascending dose studies were conducted in one trial (PR‐11‐5012‐C), and a supratherapeutic SAD study was conducted in a separate trial (PR‐11‐5022‐C). In the SAD and supratherapeutic studies, rolapitant maximum plasma concentration, area under the plasma drug concentration‐time curve (AUC) from time zero to time of last measured concentration, and AUC from time zero to infinity increased dose‐proportionally following single IV infusions of 18 to 270 mg. In the multiple ascending dose study, following 10 daily IV infusions of rolapitant 18, 36, or 54 mg, the mean day 10:day 1 maximum concentration ratio was 1.97, 1.52, and 2.07, respectively, and the mean day 10:day 1 ratio of AUC from 0 to 24 hours was 4.30, 4.59, and 5.38, respectively, indicating drug accumulation over time. Across all studies, rolapitant was gradually eliminated from plasma, with a half‐life of 135‐231 hours. Rolapitant was safe and well tolerated across all studies, with no serious or severe rolapitant‐related treatment‐emergent adverse events. The most common rolapitant‐related treatment‐emergent adverse events were headache, dry mouth, and dizziness, which were predominantly mild in severity. Overall, the pharmacokinetic and safety profiles of IV rolapitant were consistent with those of the oral formulation. [ABSTRACT FROM AUTHOR]

Highlights • Surgery induces neurokinin-1 receptor (NK-1R) activation in the hippocampus. • NK-1R antagonist improves cognitive decline after surgery. • NK-1R antagonist reduces surgery-induced neuroinflammation. • NK-1R antagonist attenuates blood-brain barrier disruption after surgery. Abstract Postoperative neurocognitive disorder (PND) is a major complication in surgical patients, especially the elderly, leading to mild memory impairment after surgery. The underlying pathophysiology remains unknown, although neuroinflammation and blood-brain barrier (BBB) disruption have been increasingly implicated in PND. Emerging evidence suggests that neurokinin-1 receptor (NK-1R), the principal target of proinflammatory neuropeptide substance P (SP), plays a pivotal role in modulating neuroinflammation and BBB integrity. In this study, we used an established mouse model for PND to investigate the effects of a selective NK-1R antagonist L-733,060 on PND-like features after peripheral surgery. Hippocampal SP started to increase at 6 h, peaked at 1 day, and returned to baseline at 3 days after surgery. At 1 day after surgery, NK-1R expression was increased in the hippocampus. At this time point, NK-1R antagonist pretreatment attenuated microgliosis and prevented neutrophil infiltration after surgery. Similarly, proinflammatory cytokines interleukin-1 beta and interleukin-6 were reduced in the hippocampus in NK-1R antagonist-treated mice at 6 h after surgery. Furthermore, surgery-induced BBB disruption, assessed by albumin deposition and expression of tight junction protein claudin-5, was attenuated by NK-1R antagonism at postoperative day 1. Finally, trace fear conditioning test revealed NK-1R antagonism reversed surgery-induced cognitive impairment at 3 days after surgery. Our findings suggest that inhibition of NK-1R signaling protects hippocampus-dependent memory from surgical insult, probably through modulations of neuroinflammation and BBB integrity. [ABSTRACT FROM AUTHOR]

Aim: We compare neurokinin-1 receptor antagonist (NK-1RA)-based triple regimen and conventional duplex regimen for antiemetic efficacy for patients with moderately emetogenic chemotherapy (MEC). Patients & methods: Pooled risk ratios (RRs) were used to evaluate the complete response and no significant nausea. The results were separately analyzed for pure MEC regimens, carboplatin-based regimens and oxaliplatin-based regimens.Results: Ten trials focused on MEC involving 2928 cancer patients using NK-1RA triple regimens or conventional duplex regimen were included. NK-1RA-based triple regimen showed significant better complete responses in overall (RR: 1.14; 95% CI: 1.05-1.24), acute (RR: 1.02; 95% CI: 1.00-1.04) and delayed (RR: 1.13; 95% CI: 1.04-1.23) phase compared with duplex regimen in patients with MEC. Similar results were found for no significant nausea. Subgroup analyses showed that triple regimen showed superior antiemetic efficacy significantly in patients with carboplatin-based chemotherapy, instead of oxaliplatin-based chemotherapy.Conclusion: NK-1RA is recommended to use in carboplatin-based chemotherapy, not oxaliplatin-based chemotherapy. [ABSTRACT FROM AUTHOR]

Prurigo nodularis (PN) is a subtype of chronic prurigo presenting single to multiple symmetrically distributed, hyperkeratotic and intensively itching papules and nodules. PN evolves along with chronic pruritus in the context of diverse dermatological, systemic, neurological or psychiatric conditions. Permanent scratching is possibly a major trigger of PN, although its exact pathophysiology remains unclear. Current state-of-the-art therapy for PN consists of topical steroids, capsaicin, calcineurin inhibitors, ultraviolet (UV) therapy, systemic administration of gabapentinoids, µ-opioid receptor antagonists, antidepressants or immunosuppressants. Novel treatment concepts, such as inhibitors of neurokinin-1, opioid and interleukin-31 receptors, have been developed and are currently being clinically tested. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic form of persistent inflammation. Meanwhile, Substance P is the most associated neuropeptide in neurogenic inflammation and hyperalgesia commonly found in chronic pain. Substance P act by binding to neurokinin-1 receptor. The present study was conducted to evaluate the effect of neurokinin-1 receptor antagonist (CP-96,345) on Adjuvant Induced Arthritis rat model, induced by Complete Freund's Adjuvant (CFA). The objective is to attenuate neurogenic inflammation which in turn will increase the latency time of hyperalgesia response, decreases neurokinin-1 receptor expression, and inhibits the development of RA in AIA rat model. Rats were intra-articularly injected with CFA 1 hour after the administration of CP-96,345 either by 0.63 µg/gr; 1.25 µg/gr; or 2.5 µg/gr also intra-articularly. Caliper measurements and hot-plate test were performed on day 0, 3, 5, 7, 9, 11, and day 13. Expression of neurokinin-1 receptor in joint tissue were evaluated by immunohistochemistry, and RA progress in joint tissue were observed hystopathologically. CP-96,345 at 2.5 µg/gr significantly increases the latency of hyperalgesia response time on CFA induced rats (p=0.044) and decreased the neurokinin-1 receptor expression in joint tissue (p=0.029) compared to CFA induced rats. There was no significant difference for caliper measurements and RA progress between CFA incduced rats and treated group. Conclusively, CP-96,345 increases the latency of hyperalgesia response time and decreases the NK-1 receptor expression in rat joint but could not inhibit RA progression. [ABSTRACT FROM AUTHOR]

Important progress has been achieved in the last few years in the prevention of chemotherapy-induced nausea and vomiting thanks to the introduction in clinical practice first of the 5-HT3 antagonists and of the NK1 antagonists more recently. To prevent acute emesis induced by cisplatin/moderately emetogenic chemotherapy, a combination of aprepitant plus a 5-HT3 antagonist and dexamethasone/a 5-HT3 antagonist plus dexamethasone, is now the most efficacious regimen. For the prevention of delayed emesis induced by cisplatin/moderately emetogenic chemotherapy, a combination of dexamethasone plus aprepitant or metoclopramide or a 5-HT3 antagonist/dexamethasone or a 5-HT3 antagonist are the preferred antiemetic regimens. For the prevention of acute emesis induced by low emetogenic chemotherapy a prophylaxis with a single antiemetic drug such as dexamethasone is suggested while no antiemetic prophylaxis should be administered to prevent acute emesis induced by minimal emetogenic chemotherapy or to prevent delayed emesis induced by low or minimal emetogenic chemotherapy. In this last case a rescue therapy should be administered in patients presenting acute or delayed emesis.

Substance P (SP) and its cognate neurokinin-1 receptor (NK1R) are involved in alcohol-related behaviors. We have previously reported that NK1R antagonism attenuates stress-induced reinstatement of alcohol seeking and suppresses escalated alcohol self-administration, but does not affect primary reinforcement or cue-induced reinstatement. Here, we administered an NK1R antagonist or vehicle prior to footshock-induced reinstatement of alcohol seeking, and mapped the resulting neuronal activation using Fos immunohistochemistry. As expected, vehicle treated animals exposed to footshock showed induction of Fos immunoreactivity in several regions of the brain stress circuitry, including the amygdala (AMG), nucleus accumbens (NAC), dorsal raphe nucleus (DR), prefrontal cortex (PFC), and bed nucleus of the stria terminalis (BNST). NK1R antagonism selectively suppressed the stress-induced increase in Fos in the DR and NAC shell. In the DR, Fos-induction by stress largely overlapped with tryptophan hydroxylase (TrpH), indicating activation of serotonergic neurons. Of NAC shell neurons activated during stress-induced reinstatement of alcohol seeking, about 30% co-expressed dynorphin (DYN), while 70% co-expressed enkephalin (ENK). Few (<1%) activated NAC shell neurons coexpressed choline acetyltransferase (ChAT), which labels the cholinergic interneurons of this region. Infusion of the NK1R antagonist L822429 into the NAC shell blocked stress-induced reinstatement of alcohol seeking. In contrast, L822429 infusion into the DR had no effect, suggesting that the influence of NK1R signaling on neuronal activity in the DR is indirect. Taken together, our results outline a potential pathway through which endogenous NK1R activation mediates stress-induced alcohol seeking. [ABSTRACT FROM AUTHOR]

Breast cancers bear overexpression of neurokinin-1 (NK-1). The aim of this study was to investigate the relationship between NK-1 and EGFR in triple negative breast cancers (TNBCs). Immunohistochemistry was performed to investigate NK-1 and EGFR expressions in TNBCs. [Sar 9 , \Met(O 2 ) 11 ] substance P (SMSP) was used to activate NK-1 in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. L-733060 and siRNA against NK-1 were used to inhibit NK-1. The in vitro regulatory effect of NK-1 was determined using CCK-8 proliferation assay. The effects of NK-1 activation and inhibition on EGFR and its downstreaming pathway were analyzed using western blot and real-time quantitative PCR. We found that the proportion of EGFR positive cases was increased with the increasement of NK-1 levels. SMSP could promote the proliferation of TNBC cells, while L-733060 and siRNA could inhibit cell proliferation and induce apoptosis. Moreover, SMSP could enhance expressions of phosphorylation (p)-EGFR and EGFR, and activate p-Akt and p-Erk. NK1-siRNA could decrease p-EGFR, p-Akt and p-Erk. In the presence of cetuximab (0.2 mg/mL), SMSP still could stimulate cell proliferation, and activate p-EGFR. However, in the presence of erlotinib (10 μM), SMSP could not stimulate cell proliferation and could not activate p-EGFR. Our study showed the interaction between NK-1 and EGFR in TNBCs. These results suggested that NK-1 may regulate TNBC proliferation through EGFR phosphorylation, and the curative effect of EGFR monoclonal antibodies may be affected by NK-1 activation. [ABSTRACT FROM AUTHOR]

The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, which are involved in their viability. This overexpression suggests the possibility of specific treatment against tumour cells using NK-1 receptor antagonists, thus promoting a considerable decrease in the side effects of the treatment. This strategy opens up new approaches for cancer treatment, since these antagonists, after binding to their molecular target, induce the death of tumour cells by apoptosis, exert an antiangiogenic action and inhibit the migration of tumour cells. The use of NK-1 receptor antagonists such as aprepitant (used in clinical practice) as antitumour agents could be a promising innovation. The value of aprepitant as an antitumour agent could be determined faster than for less well-known compounds because many studies addressing its safety and characterization have already been completed. The NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific drugs against tumour cells; and these antagonists could be new candidate anti-cancer drugs. [ABSTRACT FROM AUTHOR]

Abstract: Neurokinin 1 (NK1) encodes full-length (NK1-FL) and truncated (NK1-Tr) receptors, with distinct 3′ UTR. NK1-Tr exerts oncogenic functions and is increased in breast cancer (BC). Enhanced transcription of NK1 resulted in higher level of NK1-Tr. The 3′ UTR of these two transcripts are distinct with NK1-Tr terminating at a premature stop codon. NK1-Tr mRNA gained an advantage over NK1-FL with regards to translation. This is due to the ability of miR519B to interact with sequences within the 3′ UTR of NK1-FL, but not NK1-Tr since the corresponding region is omitted. MiR519b suppressed the translation of NK1-FL in T47D and MDA-MB-231 resulting in increased NK1-Tr protein. Cytokines can induce the transcription of NK1. However, our studies indicated that translation appeared to be independent of cytokine production by the BC cells (BCCs). This suggested that transcription and translation of NK1 might be independent. The findings were validated in vivo. MiR-519b suppressed the growth of MDA-MB-231 in 7/10 nude BALB/c. In total, increased NK1-Tr in BCCs is due to enhanced transcription and suppressed translation of NK1-FL by miR-519b to reduced tumor growth. In summary, we report on miRNA as a method to further regulate the expression of a spiced variant to promote oncogenesis. In addition, the findings have implications for therapy with NK1 antagonists. The oncogenic effect of NK1-Tr must be considered to improve the efficacy of current drugs to NK1. [Copyright &y& Elsevier]

Background: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters; some seem to play an inhibitory role, whereas others seem to play a facilitory role in the modulation of aggression. Laboratory animal studies of substance P suggest a facilitory role for this undecapeptide in the modulation of aggression, but no studies of substance P have yet been reported with regard to human aggression. Methods: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with personality disorder (PD) and substance P-like immunoreactivity was measured and correlated with measures of aggression and impulsivity. Results: The cerebrospinal fluid substance P-like immunoreactivity levels were directly correlated with a composite measure of aggression and, more specifically, with Buss-Durkee Aggression. No correlation was seen with any measure of impulsivity or of general dimensions of personality. Conclusions: These data suggest a direct relationship between central nervous system substance P containing neural circuits and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of impulsive aggression in human subjects. [Copyright &y& Elsevier]

Many patients with epilepsy are refractory to anticonvulsant drugs or do not tolerate side effects associated with the high doses required to fully prevent seizures. Antagonists of neurokinin-1 (NK1) receptors have the potential to reduce seizure severity, although this potential has not been fully explored in animals or humans. The present study was designed to evaluate the efficacy of the NK1-receptor antagonist, vofopitant, alone and in combination with different anticonvulsant drugs. Studies were conducted in rats using a model of generalized seizure induced by electroshock. Drug concentrations in blood and brain were determined in parallel to distinguish pharmacodynamic from pharmacokinetic interactions. The NK1-receptor antagonist, (vofopitant) had no anticonvulsant efficacy by itself, but could potentiate the anticonvulsant efficacy of lamotrigine and other sodium channel blockers. However, had no effect on the anticonvulsant potency of either valproate or gabapentin. did not produce central nervous system (CNS) side effects at the doses tested, and it did not potentiate side effects induced by high doses of lamotrigine. The NK1-receptor inactive enantiomer of , did not potentiate the efficacy of lamotrigine, suggesting that effects observed with were mediated by NK1 receptors. Analysis of the dose–effect relationship for indicated that a high (>99%) occupancy of NK1 receptors is required for effect, consistent with previous behavioral and human clinical studies with this pharmacologic class. These results suggest that there may be benefit in adding treatment with a suitable NK1-receptor antagonist to treatment with a sodium channel blocker in patients with refractory epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Neurokinin-1 receptor dependent mechanisms may regulate urinary frequency and urgency. We conducted this study to assess the efficacy and tolerability of the neurokinin-1 receptor antagonist serlopitant vs placebo or tolterodine in patients with overactive bladder. Materials and Methods: This randomized, double-blind, 69-center trial enrolled adults with overactive bladder (8 or more average daily micturitions and 1 or more daily urge incontinence episodes). After a 1-week placebo run-in the patients were randomized to 8 weeks of daily 0.25, 1 or 4 mg serlopitant, 4 mg tolterodine extended release or placebo. Patients kept 7-day voiding diaries. The primary end point was change from baseline in micturitions per day. Secondary end points included urgency, total incontinence, urge incontinence episodes and incidence of dry mouth. Results: Of 557 patients randomized 476 completed the trial and had valid efficacy data for analysis. Mean change from baseline in daily micturitions was significantly greater for 0.25 (–1.1) and 4 mg (–1.1) serlopitant, and for tolterodine (–1.5) than for placebo (–0.5), but not for 1 mg serlopitant (–0.8). No serlopitant dose response was demonstrated. Tolterodine was numerically superior to all doses of serlopitant in mean micturitions per day and secondary end points. The incidence of dry mouth on serlopitant (3.3%) was comparable to placebo (4.6%) and lower than tolterodine (8.8%). Serlopitant was generally well tolerated. Conclusions: Serlopitant (0.25 and 4 mg) significantly decreased the primary end point of daily micturitions but not the secondary end points compared with placebo. Serlopitant was generally well tolerated. Thus, NK-1 receptor antagonists may have a role in the treatment of overactive bladder but this compound does not offer advantages in efficacy compared to tolterodine. [Copyright &y& Elsevier]

Background: Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response. [ABSTRACT FROM PUBLISHER]

Slow excitatory postsynaptic potentials (EPSPs) in enteric neurons arise from diverse sources, but which neurotransmitters mediate specific types of slow EPSPs is unclear. We investigated transmitters and receptors mediating slow EPSPs in myenteric neurons evoked by electrical stimulation of the mucosa in guinea pig small intestine. Segments of ileum or jejunum were dissected to allow access to the myenteric plexus adjacent to intact mucosa, in vitro. AH and S neurons were impaled with conventional intracellular electrodes. Trains of stimuli delivered to the mucosa evoked slow EPSPs in AH neurons that were blocked or depressed by the neurokinin-1 (NK1) tachykinin antagonist SR 140333 (100 nM) in 10 of 11 neurons; the NK3 tachykinin receptor antagonist SR142801 (100 nM) had no effect on slow EPSPs in seven of nine AH neurons. Single pulses to the mucosa evoked fast EPSPs and slow depolarizations in S neurons. The depolarizations were divided into intermediate (durations 300-900 ms) or slow (durations 1.3-9 s) EPSPs. The slow EPSPs were blocked by pyridoxal phosphate-6-axophenyl-2-4-disulfonic acid (30 μM, N = 3) or the specific P2Y1 antagonist MRS 2179 (10 μM, N = 6) and were predominantly in anally projecting S neurons that were immunoreactive for nitric oxide synthase (NOS). In contrast, intermediate EPSPs were predominantly evoked in NOS-negative neurons; these were abolished by MRS 2179 (N = 8). Thus activation of pathways running from the mucosa excites three different types of slow EPSP in myenteric neurons, which are mediated by either a tachykinin (NK1, AH neurons) or a purine nucleotide (P2Y1, S neurons). [ABSTRACT FROM AUTHOR]

Abstract: Neurogenic inflammation describes the local release of neuropeptides, notably substance P (SP), from afferent neurons and might play a role in the pathogenesis of pulpal disease. The fibroblast is the most numerous cell type in the dental pulp, and recent work has suggested that it is involved in the inflammatory response. Primary pulp fibroblast cell populations were isolated by enzymatic digestion. Whole pulp tissue was obtained from freshly extracted sound (n = 35) and carious (n = 39) teeth. Expression of SP and neurokinin-1 receptor (NK-1) mRNA by pulp fibroblasts was determined by reverse transcriptase polymerase chain reaction (RT-PCR). SP was expressed by pulpal fibroblasts at both mRNA and protein levels. In addition, NK-1 mRNA and protein expression was detected in fibroblast cultures by RT-PCR and Western blotting, respectively. SP levels, determined by radioimmunoassay, were significantly greater (P < .05) in carious compared with sound teeth. These findings suggest that pulp fibroblasts play a role in neurogenic inflammation in pulpal disease. [Copyright &y& Elsevier]