ABSTRACT
Evolution has yielded multiple complex and complementary mechanisms to detect environmental danger and protect tissues from damage. The nervous system rapidly processes information and coordinates complex defense behaviors, and the immune system eliminates diverse threats by virtue of mobile, specialized cell populations. The two systems are tightly integrated, cooperating in local and systemic reflexes that restore homeostasis in response to tissue injury and infection. They further share a broad common language of cytokines, growth factors, and neuropeptides that enables bidirectional communication. However, this reciprocal cross talk permits amplification of maladaptive feedforward inflammatory loops that contribute to the development of allergy, autoimmunity, itch, and pain. Appreciating the immune and nervous systems as a holistic, coordinated defense system provides both new insights into inflammation and exciting opportunities for managing acute and chronic inflammatory diseases.
Subject(s)
Hypersensitivity/physiopathology , Inflammation , Neuroimmunomodulation , Pain/physiopathology , Animals , Autoimmunity , Cell Communication , Cytokines/metabolism , Homeostasis , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Neuropeptides/metabolismABSTRACT
Neuro-immune interactions link physiological and immune responses in host defense. Hanc et al.1 report that nociceptors attract dendritic cells (DCs) via the chemokine (C-C motif) ligand 2 (CCL2), initiate a "sentinel" DC program via the neuropeptide calcitonin gene-related peptide (CGRP), and enhance DC inflammatory responses through direct connections. These neuroimmune units integrate nociceptors' rapid responsiveness with DCs' immune coordination, functioning as an advanced warning system.
Subject(s)
Calcitonin Gene-Related Peptide , Nociceptors , Nociceptors/physiology , Dendritic CellsABSTRACT
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.
Subject(s)
CD8-Positive T-Lymphocytes , Melanoma , Nociceptors , Animals , Mice , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/pharmacology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Melanoma/immunology , Melanoma/pathology , Nociceptors/physiology , Sensory Receptor Cells/metabolism , Neurites/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Survival Rate , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Genes, RAG-1/genetics , Humans , Biopsy , PrognosisABSTRACT
The immune and sensory nervous systems communicate to maintain homeostasis. Wu et al. recently demonstrated that sensory neurons innervate the mouse spleen. These neurons promote calcitonin gene-related peptide (CGRP)-dependent responses in splenic B cell germinal centers (GCs) and antigen-specific antibody production. Dietary capsaicin activates these neurons to enhance humoral immunity against influenza virus infection.
Subject(s)
B-Lymphocytes , Germinal Center , Immunity, Humoral , Spleen , Animals , Spleen/immunology , Spleen/innervation , Humans , Germinal Center/immunology , Mice , B-Lymphocytes/immunology , Sensory Receptor Cells/immunology , Sensory Receptor Cells/physiology , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/immunology , Capsaicin/pharmacologyABSTRACT
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Various immune cells in the skin contribute to its function as a first line of defense against infection and disease, and the skin's dense innervation by pain-sensing sensory neurons protects the host against injury or damage signals. Dendritic cells (DCs) are a heterogeneous population of cells that link the innate immune response to the adaptive response by capturing, processing, and presenting antigens to promote T-cell differentiation and activation. DCs are abundant across peripheral tissues, including the skin, where they are found in the dermis and epidermis. Langerhans cells (LCs) are a DC subset located only in the epidermis; both populations of cells can migrate to lymph nodes to contribute to broad immune responses. Dermal DCs and LCs are found in close apposition with sensory nerve fibers in the skin and express neurotransmitter receptors, allowing them to communicate directly with the peripheral nervous system. Thus, neuroimmune signaling between DCs and/or LCs and sensory neurons can modulate physiologic and pathophysiologic pathways, including immune cell regulation, host defense, allergic response, homeostasis, and wound repair. Here, we summarize the latest discoveries on DC- and LC-neuron interaction with neurons while providing an overview of gaps and areas not previously explored. Understanding the interactions between these 2 defence systems may provide key insight into developing therapeutic targets for treating diseases such as psoriasis, neuropathic pain, and lupus.
Subject(s)
Dendritic Cells , Langerhans Cells , Skin , Humans , Langerhans Cells/immunology , Animals , Skin/immunology , Skin/innervation , Dendritic Cells/immunology , Sensory Receptor Cells/physiology , Sensory Receptor Cells/immunology , Cell Communication/immunology , NeuroimmunomodulationABSTRACT
Evolution has created complex mechanisms to sense environmental danger and protect tissues, with the nervous and immune systems playing pivotal roles. These systems work together, coordinating local and systemic reflexes to restore homeostasis in response to tissue injury and infection. By sharing receptors and ligands, they influence the pathogenesis of various diseases. Recently, a less-explored aspect of neuroimmune communication has emerged: the release of neuropeptides from immune cells and cytokines/chemokines from sensory neurons. This article reviews evidence of this unique neuroimmune interplay and its impact on the development of allergy, inflammation, itch, and pain. We highlight the effects of this neuroimmune signaling on vital processes such as host defense, tissue repair, and inflammation resolution, providing avenues for exploration of the underlying mechanisms and therapeutic potential of this signaling.
Subject(s)
Cytokines , Sensory Receptor Cells , Humans , Signal Transduction , Inflammation , Neuroimmunomodulation/physiologyABSTRACT
Worldwide prevalence of cervical cancer decreased significantly with the use of human papilloma virus (HPV)-targeted prophylactic vaccines. However, these multivalent antiviral vaccines are inert against established tumors, which leave patients with surgical ablative options possibly resulting in long-term reproductive complications and morbidity. In an attempt to bypass this unmet medical need, we designed a new E7 protein-based vaccine formulation using Accum™, a technology platform designed to promote endosome-to-cytosol escape as a means to enhance protein accumulation in target cells. Prophylactic vaccination of immunocompetent mice using the Accum-E7 vaccine (aE7) leads to complete protection from cervical cancer despite multiple challenges conducted with ascending C3.43 cellular doses (0.5-, 1.0-, and 2.0 × 106 cells). Moreover, the humoral response induced by aE7 was higher in magnitude compared with naked E7 protein vaccination and displayed potent inhibitory effects on C3.43 proliferation in vitro. When administered therapeutically to animals with pre-established C3.43 or Tal3 tumors, the vaccine-induced response synergized with multiple immune checkpoint blockers (anti-PD-1, anti-CTLA4, and anti-CD47) to effectively control tumor growth. Mechanistically, the observed therapeutic effect requires cross-presenting dendritic cells as well as CD8 T cells predominantly, with a non-negligible role played by both CD4+ and CD19+ lymphocytes. good laboratory practice (GLP) studies revealed that aE7 is immunogenic and well tolerated by immunocompetent mice with no observed adverse effects despite the use of a fourfold exceeding dose. In a nutshell, aE7 represents an ideal vaccine candidate for further clinical development as it uses a single engineered protein capable of exhibiting both prophylactic and therapeutic activity.
Subject(s)
Cancer Vaccines , Oncogene Proteins, Viral , Papillomavirus Infections , Papillomavirus Vaccines , Uterine Cervical Neoplasms , Female , Humans , Animals , Mice , Uterine Cervical Neoplasms/pathology , Papillomavirus E7 Proteins/metabolism , CD8-Positive T-Lymphocytes , Vaccination , Mice, Inbred C57BL , Papillomavirus Infections/prevention & control , Oncogene Proteins, Viral/geneticsABSTRACT
BACKGROUND: The Accum® platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum® was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum®-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum® variants, which led to the identification of the AccuTOX® molecule. METHODS: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX® along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX® treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX® was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). RESULTS: In total, 7 Accum® variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX®) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum®), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX® enhances H2-Kb cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. CONCLUSIONS: AccuTOX® exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum® molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications.
Subject(s)
Drug Synergism , Immune Checkpoint Inhibitors , Reactive Oxygen Species , Animals , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Cell Line, Tumor , Humans , Reactive Oxygen Species/metabolism , Cell Proliferation/drug effects , Mice , Neoplasms/drug therapy , Neoplasms/pathology , Neoplasms/immunology , Mice, Inbred C57BL , Female , Cell Death/drug effectsABSTRACT
Central nervous system trauma induces marked inflammation that has beneficial and deleterious consequences. In a recent issue of Neuron, Gadani et al. (2015) show that injured spinal cord releases the alarmin IL-33 to drive chemokines that recruit monocytes and promote recovery.
Subject(s)
Central Nervous System Diseases , Gene Expression Regulation/physiology , Interleukins/metabolism , Neuroglia/metabolism , Recovery of Function/physiology , Animals , Female , MaleABSTRACT
Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain1,2. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine-a tryptophan metabolite that blocks antitumour immunity-inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity.
Subject(s)
Autoimmune Diseases/immunology , Biopterins/analogs & derivatives , Neoplasms/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Administration, Oral , Alcohol Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases/metabolism , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/pathology , Biopterins/biosynthesis , Biopterins/metabolism , Biopterins/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Coenzymes/metabolism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , GTP Cyclohydrolase/genetics , GTP Cyclohydrolase/metabolism , Humans , Hypersensitivity/immunology , Iron/metabolism , Kynurenine/metabolism , Kynurenine/pharmacology , Male , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Neoplasms/drug therapy , Neoplasms/pathology , T-Lymphocytes/drug effects , T-Lymphocytes/metabolismABSTRACT
The mammalian airways and lungs are exposed to a myriad of inhaled particulate matter, allergens, and pathogens. The immune system plays an essential role in protecting the host from respiratory pathogens, but a dysregulated immune response during respiratory infection can impair pathogen clearance and lead to immunopathology. Furthermore, inappropriate immunity to inhaled antigens can lead to pulmonary diseases. A complex network of epithelial, neural, stromal, and immune cells has evolved to sense and respond to inhaled antigens, including the decision to promote tolerance versus a rapid, robust, and targeted immune response. Although there has been great progress in understanding the mechanisms governing immunity to respiratory pathogens and aeroantigens, we are only beginning to develop an integrated understanding of the cellular networks governing tissue immunity within the lungs and how it changes after inflammation and over the human life course. An integrated model of airway and lung immunity will be necessary to improve mucosal vaccine design as well as prevent and treat acute and chronic inflammatory pulmonary diseases. Given the importance of immunology in pulmonary research, the American Thoracic Society convened a working group to highlight central areas of investigation to advance the science of lung immunology and improve human health.
Subject(s)
Lung Diseases , Respiratory Tract Infections , Animals , Humans , Lung , Mammals , Particulate Matter , ThoraxABSTRACT
The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptor-induced CD8+ T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.
Subject(s)
Metal Nanoparticles , Nociceptors , CD8-Positive T-Lymphocytes , Ganglia, Spinal , Gold , Neurons , Nociceptors/physiology , TRPV Cation ChannelsABSTRACT
BACKGROUND: Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. OBJECTIVE: We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. METHODS: We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific FcεR1γ knockdown (TRPV1Cre::FcεR1γfl/fl) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. RESULTS: Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor FcεR1, the levels of which increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies TH2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre::FcεR1γfl/fl mice and in FcεR1α-/- mice into which bone marrow has been transplanted. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell-derived nociceptors. CONCLUSIONS: Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1-expressing vagal sensory neurons, and TH2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, FcεR1γ expressed by nociceptors.
Subject(s)
Gene Expression , Hypersensitivity/immunology , Hypersensitivity/metabolism , Receptors, IgE/genetics , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Allergens/immunology , Animals , Calcium/metabolism , Disease Models, Animal , Disease Susceptibility/immunology , Genetic Predisposition to Disease , Hypersensitivity/genetics , Hypersensitivity/pathology , Mice , Mice, Knockout , Neurons/immunology , Neurons/metabolism , Nociceptors/metabolism , Ovalbumin/adverse effects , Ovalbumin/immunology , Receptors, IgE/metabolism , Respiratory Mucosa/pathology , Substance P/metabolism , Vagus NerveABSTRACT
Dendritic cells (DCs) are critical players in skin homeostasis. A subset of mannose receptor (CD206)-expressing monocyte-derived DCs was found in skin, and their migratory counterpart is present in skin-draining lymph nodes (sdLNs). Skin CD206+ DCs were shown to upregulate MHC class II (MHCII) progressively, raising the question of whether this feature affects their biology. In this study, we assessed the role of MHCII regulation in the development and migration of these cells in mouse models expressing differential MHCII levels. Using CD206 as a surrogate marker, we found that skin CD206+ DCs develop in an MHCII-independent manner. However, their migration to sdLNs was affected by overexpression rather than absence or lower expression of MHCII. Accordingly, B16 tumor growth was exacerbated in mice overexpressing MHCII in the absence of ubiquitination. Mechanistically, CD206+ DCs from these mice showed decreased IRF4 and CCR7 expression. LPS, which is known to promote monocyte-derived DC recruitment to sdLNs, partially improved these defects. However, GM-CSF delivery restored CD206+ DC migration by promoting IRF4 expression. Collectively, these data show that MHCII downregulation is crucial for IRF4-dependent migration of CD206+ DCs to sdLNs in health and disease.
Subject(s)
Cell Movement , Dendritic Cells/metabolism , Down-Regulation , Histocompatibility Antigens Class II/metabolism , Lectins, C-Type/metabolism , Lymph Nodes/metabolism , Mannose-Binding Lectins/metabolism , Receptors, Cell Surface/metabolism , Skin/metabolism , Ubiquitination , Animals , Mannose Receptor , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
BACKGROUND: Substance P (SP) is linked to itch and inflammation through activation of receptors on mast cells and sensory neurons. There is increasing evidence that SP functions through Mas-related G protein-coupled receptors (Mrgprs) in addition to its conventional receptor, neurokinin-1. OBJECTIVE: Because Mrgprs mediate some aspects of inflammation that had been considered mediated by neurokinin-1 receptor (NK-1R), we sought to determine whether itch induced by SP can also be mediated by Mrgprs. METHODS: Genetic and pharmacologic approaches were used to evaluate the contribution of Mrgprs to SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons from mice. RESULTS: SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons was dependent on Mrgprs rather than NK-1R. CONCLUSION: We deduce that SP activates MrgprA1 on sensory neurons rather than NK-1R to induce itch.
Subject(s)
Ganglia, Spinal/cytology , Pruritus/genetics , Receptors, G-Protein-Coupled/genetics , Adolescent , Adult , Aged , Animals , Capsaicin/pharmacology , Cells, Cultured , Female , Humans , Male , Mice, Transgenic , Middle Aged , Pruritus/chemically induced , Receptors, Neurokinin-1/genetics , Sensory Receptor Cells/drug effects , Substance P , Young AdultABSTRACT
The gastrin-releasing peptide (GRP) and its receptor (GRPR) are important components of itch transmission. Upstream, but not downstream, aspects of GRPR signaling have been investigated extensively. We hypothesize that GRPR signals in part through the PI3Kγ/Akt pathway. We used pharmacological, electrophysiological, and behavioral approaches to further evaluate GRPR downstream signaling pathways. Our data show that GRP directly activates small-size capsaicin-sensitive DRG neurons, an effect that translates into transient calcium flux and membrane depolarization (⼠20 mV). GRPR activation also induces Akt phosphorylation, a proxy for PI3Kγ activity, in ex vivo naive mouse spinal cords and in GRPR transiently expressing HEK293 cells. The intrathecal injection of GRP led to intense scratching, an effect largely reduced by either GRPR antagonists or PI3Kγ inhibitor. Scratching behavior was also induced by the intrathecal injection of an Akt activator. In a dry skin model of itch, we show that GRPR blockade or PI3Kγ inhibition reversed the scratching behavior. Altogether, these findings are highly suggestive that GRPR is expressed by the central terminals of DRG nociceptive afferents, which transmit itch via the PI3Kγ/Akt pathway. SIGNIFICANCE STATEMENT: Itch is the most common symptom of the skin and is related to noncutaneous diseases. It severely impairs patients' quality of life when it becomes chronic and there is no specific or effective available therapy, mainly because itch pathophysiology is not completely elucidated. Our findings indicate that the enzyme PI3Kγ is a key central mediator of itch transmission. Therefore, we suggest PI3Kγ as an attractive target for the development of new anti-pruritic drugs. With this study, we take a step forward in our understanding of the mechanisms underlying the central transmission of itch sensation.
Subject(s)
Central Nervous System/metabolism , Gastrin-Releasing Peptide/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Pruritus/pathology , Receptors, Bombesin/metabolism , Synaptic Transmission/physiology , Action Potentials/drug effects , Animals , Anticarcinogenic Agents/therapeutic use , Bombesin/analogs & derivatives , Bombesin/therapeutic use , Capsaicin/toxicity , Central Nervous System/drug effects , Disease Models, Animal , Enzyme Inhibitors/pharmacology , Ganglia, Spinal/cytology , Indoles/pharmacology , Male , Mice , Neurons/drug effects , Neurons/physiology , Pain Threshold/drug effects , Peptide Fragments/therapeutic use , Pruritus/chemically induced , Pruritus/complications , Pruritus/drug therapy , Quinoxalines/pharmacology , Reaction Time/physiology , Synaptic Transmission/drug effects , Thiazolidinediones/pharmacology , p-Methoxy-N-methylphenethylamine/toxicityABSTRACT
Kinins are the endogenous ligands of the constitutive B2 receptor (B2R) and the inducible B1 receptor (B1R). Whereas B2R prevents insulin resistance, B1R is involved in insulin resistance and metabolic syndrome. However, the contribution of B1R in type 2 diabetes associated with obesity remains uncertain. The aim of the present study was to examine the impact of 1-week treatment with a selective B1R antagonist (SSR240612, 10 mg/kg per day, by gavage) on hyperglycemia, hyperinsulinemia, leptinemia, body mass gain, and abnormal plasma fatty acids in obese Zucker diabetic fatty (ZDF) rats. Treatment with SSR240612 abolished the body mass gain and reduced polyphagia, polydipsia, and plasma fatty acid alterations in ZDF rats without affecting hyperglycemia, hyperinsulinemia, and hyperleptinemia. The present study suggests that the upregulated B1R plays a role in body mass gain and circulating fatty acid alterations in ZDF rats. However, mechanisms other than B1R induction would be implicated in glucose metabolism disorder in ZDF rats, based on the finding that SSR240612 did not reverse hyperglycemia and hyperinsulinemia.
Subject(s)
Bradykinin B1 Receptor Antagonists/therapeutic use , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Fatty Acids/blood , Obesity/blood , Obesity/drug therapy , Animals , Bradykinin B1 Receptor Antagonists/pharmacology , Dioxoles/pharmacology , Dioxoles/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Male , Rats , Rats, Zucker , Receptor, Bradykinin B1/metabolism , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Treatment OutcomeABSTRACT
Health professionals are regularly confronted with patients suffering from a fear of movement-related pain (unknown as kinesiophobia). The fear-avoidance attitudes and beliefs of healthcare professionals are likely to play a key role in their patients' therapeutic approach. However, kinesiophobia among health professionals is a relatively young topic. This scoping review aims to explore and catalogue the extent of scientific research that identifies the causes and consequences of kinesiophobia among health professionals while they perform their interventions. The review was based on the Joanna Briggs Institute manual and the PRISMA method for a scoping review. The research was conducted in May 2024 using CINHAL, Medline and Sportdiscus databases with the search terms "fear-avoidance", "kinesiophobia", "pain-related" and "physical therapist". Out of 2,162 potential studies, thirteen articles were included. No study directly mentioned kinesiophobia among health professionals, but it was studied through fear-avoidance beliefs. Two-thirds of the articles indicate that professionals with fear-avoidance beliefs tend to refer their patients to other specialists less frequently and limit their patients' activity, despite treatment guidelines. Most of the studies found were physiotherapists' interventions for chronic back pain patients. The current review emphasizes the need for additional studies involving more healthcare professionals and diverse health conditions.