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Neuron Mar 2022It is well known that affective and pleasant touch promotes individual well-being and facilitates affiliative social communication, although the neural circuit that...
It is well known that affective and pleasant touch promotes individual well-being and facilitates affiliative social communication, although the neural circuit that mediates this process is largely unknown. Here, we show that social-touch-like tactile stimulation (ST) enhances firing of oxytocin neurons in the mouse paraventricular hypothalamus (PVH) and promotes social interactions and positively reinforcing place preference. These results link pleasant somatosensory stimulation to increased social interactions and positive affective valence. We further show that tachykinin 1 (Tac1) neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) send monosynaptic excitatory projections to PVH oxytocin neurons. Functionally, activation of PVH-projecting Tac1 neurons increases firing of oxytocin neurons, promotes social interactions, and increases preference for the social touch context, whereas reducing activity of Tac1 neurons abolishes ST-induced oxytocin neuronal firing. Together, these results identify a dipeptidergic pathway from l/vlPAG Tac1 neurons to PVH oxytocin neurons, through which pleasant sensory experience promotes social behavior.
Topics: Animals; Mice; Oxytocin; Social Interaction; Tachykinins; Touch; Touch Perception
PubMed: 35045339
DOI: 10.1016/j.neuron.2021.12.022 -
The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress.Cell May 2018Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation...
Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function and suggest potential new therapeutic applications for Nk3R antagonists.
Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brain; Female; Genetic Vectors; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neurokinin B; Neurons; Protein Isoforms; Protein Precursors; RNA Interference; RNA, Small Interfering; Receptors, Tachykinin; Social Isolation; Stress, Psychological; Tachykinins; Up-Regulation
PubMed: 29775595
DOI: 10.1016/j.cell.2018.03.037 -
Gastroenterology Apr 2023Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs).
METHODS
We searched the literature to September 7, 2022. We judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to P-score.
RESULTS
We identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR, 0.30; 95% CI, 0.16-0.57; P-score = .99) followed by domperidone (RR, 0.68; 95% CI, 0.48-0.98; P-score = .76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR, 0.58; 95% CI, 0.44-0.77; P-score = .96) and tachykinin-1 antagonists (RR, 0.69; 95% CI, 0.52-0.93; P-score = .83). For individual symptoms, oral metoclopramide ranked first for nausea (RR 0.46; 95% CI, 0.21-1.00; P-score = .95), fullness (RR 0.67; 95% CI, 0.35-1.28; P-score = .86), and bloating (RR 0.53; 95% CI, 0.30-0.93; P-score = .97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo.
CONCLUSIONS
In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.
Topics: Humans; Gastroparesis; Network Meta-Analysis; Nausea; Dopamine Antagonists; Tachykinins
PubMed: 36581089
DOI: 10.1053/j.gastro.2022.12.014 -
Nature Jan 2019Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example...
Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1 and LBX1 drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.
Topics: Adaptation, Psychological; Animals; Avoidance Learning; Chronic Pain; Conditioning, Classical; Female; Humans; Male; Mediodorsal Thalamic Nucleus; Mice; Neural Pathways; Neurons, Afferent; Parabrachial Nucleus; Protein Precursors; Receptors, G-Protein-Coupled; TRPV Cation Channels; Tachykinins
PubMed: 30532001
DOI: 10.1038/s41586-018-0793-8 -
International Journal of Molecular... Dec 2021Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma.... (Review)
Review
Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma. Some of them exacerbate asthma symptoms, such as neuropeptide Y and tachykinins, while others have ameliorating properties, such as nociception, neurotensin or β-defensin 2. Interacting with peptide receptors located in the lungs or on immune cells opens up new therapeutic possibilities for the treatment of asthma, especially when it is resistant to available therapies. This article provides a concise review of the most important and current findings regarding the involvement of regulatory peptides in asthma pathology.
Topics: Animals; Asthma; Gene Expression Regulation; Humans; Neuropeptide Y; Neurotensin; Peptides; Receptors, Peptide; Tachykinins; beta-Defensins
PubMed: 34948451
DOI: 10.3390/ijms222413656 -
Biomolecular Concepts Jun 2014Over 80 years has passed since the discovery of substance P (SP), and a variety of peptides of the tachykinin (TK) family have been found and investigated. SP,... (Review)
Review
Over 80 years has passed since the discovery of substance P (SP), and a variety of peptides of the tachykinin (TK) family have been found and investigated. SP, neurokinin A (NKA), and neurokinin B (NKB) are representative peptides in mammalian species. SP and NKA are major excitatory neurotransmitters in the peripheral nervous system, while NKB is primarily involved in the central nervous system (CNS). Moreover, TK peptides play roles not only as neurotransmitters but also as local factors and are involved in almost all aspects of the regulation of physiological functions and pathophysiological processes. The role of SP as a mediator of pain processing and inflammation in peripheral tissues in coordination with transient receptor potential channels is well established, while novel aspects of TKs in relation to hematopoiesis, venous thromboembolism, tendinopathy, and taste perception have been clarified. In the CNS, the NKB signaling system in the hypothalamus has been shown to play a crucial role in the regulation of gonadotropin hormone secretion and the onset of puberty, and molecular biological studies have elucidated novel prophylaxic activities of TKs against neurogenic movement disorders based on their molecular structure. This review provides an overview of the novel aspects of TKs reported around the world in the last 5 years, with particular focus on nociception, inflammation, hemopoiesis, gonadotropin secretion, and CNS diseases.
Topics: Animals; Central Nervous System Diseases; Gene Expression Regulation; Gonadotropins; Hematopoiesis; Humans; Inflammation; Neurotransmitter Agents; Nociception; Tachykinins
PubMed: 25372755
DOI: 10.1515/bmc-2014-0008 -
The Lancet. Microbe Aug 2023The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in... (Review)
Review
The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in concentrating, sexual dysfunction, and digestive disturbances. Hence, neurological dysfunction and autonomic impairments predominate in post-COVID-19 condition. Tachykinins including the most studied substance P are neuropeptides expressed throughout the nervous and immune systems, and contribute to many physiopathological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems and participate in inflammation, nociception, and cell proliferation. Substance P is a key molecule in neuroimmune crosstalk; immune cells near the peripheral nerve endings can send signals to the brain with cytokines, which highlights the important role of tachykinins in neuroimmune communication. We reviewed the evidence that relates the symptoms of post-COVID-19 condition to the functions of tachykinins and propose a putative pathogenic mechanism. The antagonism of tachykinins receptors can be a potential treatment target.
Topics: Humans; Substance P; COVID-19; Tachykinins; Neuropeptides; Receptors, Tachykinin
PubMed: 37327802
DOI: 10.1016/S2666-5247(23)00111-8 -
The Journal of Biological Chemistry Dec 2023The tachykinin receptors neurokinin 1 (NK1R) and neurokinin 2 (NK2R) are G protein-coupled receptors that bind preferentially to the natural peptide ligands substance P...
The tachykinin receptors neurokinin 1 (NK1R) and neurokinin 2 (NK2R) are G protein-coupled receptors that bind preferentially to the natural peptide ligands substance P and neurokinin A, respectively, and have been targets for drug development. Despite sharing a common C-terminal sequence of Phe-X-Gly-Leu-Met-NH2 that helps direct biological function, the peptide ligands exhibit some degree of cross-reactivity toward each other's non-natural receptor. Here, we investigate the detailed structure-activity relationships of the ligand-bound receptor complexes that underlie both potent activation by the natural ligand and cross-reactivity. We find that the specificity and cross-reactivity of the peptide ligands can be explained by the interactions between the amino acids preceding the FxGLM consensus motif of the bound peptide ligand and two regions of the receptor: the β-hairpin of the extracellular loop 2 (ECL2) and a N-terminal segment leading into transmembrane helix 1. Positively charged sidechains of the ECL2 (R177 of NK1R and K180 of NK2R) are seen to play a vital role in the interaction. The N-terminal positions 1 to 3 of the peptide ligand are entirely dispensable. Mutated and chimeric receptor and ligand constructs neatly swap around ligand specificity as expected, validating the structure-activity hypotheses presented. These findings will help in developing improved agonists or antagonists for NK1R and NK2R.
Topics: Animals; Humans; Cell Line; Chlorocebus aethiops; Ligands; Neurokinin A; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Substance P; Tachykinins; Receptors, Neurokinin-2
PubMed: 37944618
DOI: 10.1016/j.jbc.2023.105438 -
BioMed Research International 2015The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest... (Review)
Review
The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.
Topics: Animals; Humans; Models, Biological; Molecular Targeted Therapy; Receptors, Neurokinin-1; Tachykinins
PubMed: 26421291
DOI: 10.1155/2015/495704 -
Journal of Internal Medicine Jan 2001A brief overview of recent developments in the substance P field is provided, in addition to a historical introduction. It is emphasized that there are multiple... (Review)
Review
A brief overview of recent developments in the substance P field is provided, in addition to a historical introduction. It is emphasized that there are multiple tachykinins and tachykinin receptors and that there are examples of coexistence of several tachykinin peptides and of several tachykinin receptors in single cells, and there is evidence for tachykininergic cotransmission. The distribution and functional significance of tachykinins in the gastrointestinal tract and in sensory neurones, and interactions with other peptides and transmitters, are reviewed. The recent production of knock-out mice for either substance P or the NK1 receptor is discussed, as well as the exciting concept of substance P receptor internalization. Finally, the development of specific substance P antagonists is summarized, and possible clinical implications discussed, and, in particular, a recent study which reports that a substance P antagonist shows clinical efficacy in depression.
Topics: Animals; Antidepressive Agents; Glutamic Acid; Guinea Pigs; History, 20th Century; Humans; Intestinal Mucosa; Mice; Mice, Knockout; Neurokinin-1 Receptor Antagonists; Neurons; Neuropeptides; Receptors, Neurokinin-1; Receptors, Tachykinin; Substance P; Tachykinins
PubMed: 11168782
DOI: 10.1046/j.0954-6820.2000.00773.x