scholarly journals Genetic mapping in Diversity Outbred mice identifies aTrpa1variant influencing late phase formalin response

2018 ◽  
Author(s):  
Jill M. Recla ◽  
Jason A. Bubier ◽  
Daniel M. Gatti ◽  
Jennifer L. Ryan ◽  
Katie H. Long ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Genetic Mapping ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Cation Channel ◽  
Chromosome 1 ◽  
Formalin Injection ◽  
Late Response ◽  
Diversity Outbred ◽  
Isoform Expression

ABSTRACTIdentification of genetic variants that influence susceptibility to chronic pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with chronic pain, we measured late phase response to formalin injection in 275 male and female Diversity Outbred (DO) mice genotyped for over 70 thousand SNPs. One quantitative trait locus (QTL) reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus,Nociq4(nociceptive sensitivity inflammatory QTL 4; MGI:5661503), harbors the well-known pain geneTrpa1(transient receptor potential cation channel, subfamily A, member 1).Trpa1is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of DO founder strain allele effects revealed a significant effect of the CAST/EiJ allele atTrpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the seven other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants inTrpa1by assessing channel conductance,Trpa1/Trpv1interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained byTrpa1isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.

scholarly journals Genetic mapping in Diversity Outbred mice identifies a Trpa1 variant influencing late-phase formalin response

Pain ◽  
2019 ◽  
Vol 160 (8) ◽  
pp. 1740-1753 ◽  
Author(s):  
Jill M. Recla ◽  
Jason A. Bubier ◽  
Daniel M. Gatti ◽  
Jennifer L. Ryan ◽  
Katie H. Long ◽  
...  
Keyword(s):  
Genetic Mapping ◽  
Late Phase ◽  
Diversity Outbred ◽  
Outbred Mice

scholarly journals A Critical Temporal Window for Selectin-dependent CD4+ Lymphocyte Homing and Initiation of Late-Phase Inflammation in Contact Sensitivity

2004 ◽  
Vol 199 (9) ◽  
pp. 1223-1234 ◽  
Author(s):  
John M. Hwang ◽  
Jun Yamanouchi ◽  
Pere Santamaria ◽  
Paul Kubes
Keyword(s):  
Early Phase ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Leukocyte Recruitment ◽  
Late Response ◽  
Inflammatory Disorder ◽  
Contact Sensitivity ◽  
Microscopy Technique ◽  
Cd4 Lymphocyte ◽  
Cd4 Lymphocytes

Contact sensitivity (CS) is an inflammatory disorder characterized by early and late phases of leukocyte recruitment. We used a noninvasive intravital microscopy technique allowing for the direct visualization of leukocyte rolling and adhesion on blood vessel endothelium. By blocking specific adhesion molecules, we elucidated the molecular mechanisms mediating early leukocyte recruitment to be E- and P-selectin and demonstrated that leukocyte recruitment in the late phase had a different adhesive profile (mainly α4-integrin). Complete blockade of E- and P-selectin within the first 2 h of leukocyte–endothelial cell interactions (but not later) eliminated selectin-independent leukocyte recruitment at 24 h. Despite the predominance of neutrophils in the early phase, specific elimination of CD4+ lymphocytes in the early phase eliminated the late response. CD4+ lymphocytes homed to skin via E- and P-selectin within the early phase and induced the late phase response. Addition of these same CD4+ lymphocytes 2 h after antigen challenge was too late for these cells to home to the skin and induce late phase responses. Our data clearly demonstrate that the antigen-challenged microenvironment is only accessible to CD4+ lymphocytes for the first 2 h, and that this process is essential for the subsequent recruitment of other leukocyte populations in late phase responses.

scholarly journals Immune Actions on the Peripheral Nervous System in Pain

2021 ◽  
Vol 22 (3) ◽  
pp. 1448
Author(s):  
Jessica Aijia Liu ◽  
Jing Yu ◽  
Chi Wai Cheung
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Process Integration ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Lipid Mediators ◽  
Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Piroxicam reduces acute and chronic pain response in type 1 diabetic rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Abbas Alimoradian ◽  
Fatemeh Samimi ◽  
Hadise Aslfalah ◽  
Seied Amirhossein Latifi ◽  
Mehdi Salehi ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Normal Saline ◽  
Life Quality ◽  
Chronic Phase ◽  
Diabetic Rats ◽  
Effective Control ◽  
Diabetic Patients ◽  
Formalin Injection ◽  
Analgesic Effects

Abstract Objectives Pain associated with various underlying pathologies is a major cause of morbidity and diminished life quality in diabetic patients. Effective control of pain requires the use of analgesics with the best efficacy and with minimal side effects. Therefore, our aim in this study was to investigate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on pain in diabetic rats. Methods In this study, we investigated the analgesic effects of drugs belonging to three different classes of NSAIDs in a rat model of diabetes. Four diabetic groups received normal saline, diclofenac, piroxicam and ketorolac, respectively, and four non-diabetic groups received normal saline, diclofenac, piroxicam and ketorolac. Type 1 diabetes was induced in rats by a single injection of streptozotocin (60 mg/kg bw). Formalin (50 µL of 2.5%) nociception assay was used to examine the effect of treatment with diclofenac, piroxicam and ketorolac on acute and chronic pain in healthy and diabetic rats. Results Piroxicam showed significant analgesic effects both in the acute phase of pain (5–10 min after injection of formalin into the left hind paw), and in the chronic phase (20–60 min after formalin injection) in healthy as well as diabetic rats. Diclofenac and ketorolac also reduced pain scores in healthy rats. However, these two drugs failed to diminish pain in diabetic rats. Conclusion Our data point for better efficacy of piroxicam in controlling pain in diabetes.

scholarly journals Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

2015 ◽  
Vol 212 (13) ◽  
pp. 2289-2304 ◽  
Author(s):  
Binh L. Phong ◽  
Lyndsay Avery ◽  
Tina L. Sumpter ◽  
Jacob V. Gorman ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cell ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Cell Types ◽  
Mast Cell Activation ◽  
Positive Role ◽  
Ample Evidence

T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.

Late pulmonary responses induced by Ascaris allergen in conscious squirrel monkeys

1986 ◽  
Vol 61 (6) ◽  
pp. 2081-2087 ◽  
Author(s):  
R. Hamel ◽  
C. S. McFarlane ◽  
A. W. Ford-Hutchinson
Keyword(s):  
Time Course ◽  
Late Phase ◽  
Dynamic Compliance ◽  
Negative Control ◽  
Squirrel Monkeys ◽  
Antigen Challenge ◽  
Late Response ◽  
Primate Model ◽  
Positive Skin ◽  
Pulmonary Response

This study presents an antigen-dependent model of biphasic pulmonary changes to Ascaris suum in conscious squirrel monkeys. Animals with strong positive skin reactivity towards A. suum were trained to sit quietly in chairs and to breathe through face masks. Dynamic compliance (Cdyn) and pulmonary resistance (RL) were measured in these conscious animals before and for a period of 11 h after administration of an aerosol of Ascaris or ragweed antigen. The aerosol of Ascaris antigen induced reproducible increases (42%) in RL (P less than 0.001) and decreases (17%) in Cdyn (P less than 0.01) that peaked respectively 5 and 35 min after antigen challenge and lasted 60–90 min. After recovery, a second bronchoconstriction began between 2 and 8 h and peaked between 4 and 10 h after antigen challenge. Decreases in Cdyn (41%) were significantly greater (P less than 0.003) whereas mean increases in RL (44%) were similar during the late phase as compared with the first phase. The mean Cdyn decreases lasted a minimum of 2 h, whereas RL increases lasted less than 60 min. The time course of the responses varied from animal to animal but changes in individual animals were reproducible over a period of 6 mo. No significant correlation was observed between the cutaneous and the pulmonary responses to Ascaris and the late response was not reversed by aerosol administration of salbutamol (1.0 mg/ml). As a negative control animals were exposed to an aerosol of ragweed extract after which no immediate or late pulmonary response were observed. The results suggest that this primate model may be useful to study the pathophysiology of asthma in humans.

Dorsal Root Ganglion Neuron Types and Their Functional Specialization

2018 ◽  
pp. 127-155 ◽  
Author(s):  
Edward C. Emery ◽  
Patrik Ernfors
Keyword(s):  
Chronic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drg Neurons ◽  
Low Threshold

Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. This article reviews the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.

scholarly journals Molecular Cloning, Characterization, and Chromosome Mapping of Reptilian Estrogen Receptors

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5710-5720 ◽  
Author(s):  
Yoshinao Katsu ◽  
Kazumi Matsubara ◽  
Satomi Kohno ◽  
Yoichi Matsuda ◽  
Michihisa Toriba ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Hormone Receptor ◽  
Molecular Mechanisms ◽  
Steroid Hormone ◽  
Chromosome 1 ◽  
Sex Steroid ◽  
Steroid Hormone Receptor ◽  
Sex Steroid Hormone ◽  
Ligand Interactions ◽  
Rat Snake

In many vertebrates, steroid hormones are essential for ovarian differentiation during a critical developmental stage as well as promoting the growth and differentiation of the adult female reproductive system. Although studies have been extensively conducted in mammals and a few fish, amphibians, and bird species, the molecular mechanisms of sex steroid hormone (estrogens) action have been poorly examined in reptiles. Here, we evaluate hormone receptor and ligand interactions in two species of snake, the Okinawa habu (Protobothrops flavoviridis, Viperidae) and the Japanese four-striped rat snake (Elaphe quadrivirgata, Colubridae) after the isolation of cDNAs encoding estrogen receptor α (ESR1) and estrogen receptor β (ESR2). Using a transient transfection assay with mammalian cells, the transcriptional activity of reptilian (Okinawa habu, Japanese four-striped rat snake, American alligator, and Florida red-belly freshwater turtle) ESR1 and ESR2 was examined. All ESR proteins displayed estrogen-dependent activation of transcription via an estrogen-response element-containing promoter; however, the responsiveness to various estrogens was different. Further, we determined the chromosomal locations of the snake steroid hormone receptor genes. ESR1 and ESR2 genes were localized to the short and long arms of chromosome 1, respectively, whereas androgen receptor was localized to a pair of microchromosomes in the two snake species examined. These data provide basic tools that allow future studies examining receptor-ligand interactions and steroid endocrinology in snakes and also expands our knowledge of sex steroid hormone receptor evolution.

scholarly journals Precise genetic mapping and integrative bioinformatics in Diversity Outbred mice reveals Hydin as a novel pain gene

2014 ◽  
Vol 25 (5-6) ◽  
pp. 211-222 ◽  
Author(s):  
Jill M. Recla ◽  
Raymond F. Robledo ◽  
Daniel M. Gatti ◽  
Carol J. Bult ◽  
Gary A. Churchill ◽  
...  
Keyword(s):  
Genetic Mapping ◽  
Diversity Outbred ◽  
Outbred Mice
Sign in / Sign up

Export Citation Format

Share Document