1,721,085 research outputs found
Recommended from our members
Behavioral measures of persistent pain in mice
Full text linkThe use of animal models in the understanding of the neurobiology of pain perception is essential for the development of new pharmacotherapies. Yet, in modeling human clinical experience, there is a lack of meaningful and appropriate dependent variables of pain-related behaviors in the mouse. In this thesis, we address the problem of finding behavioral measures of pain in mice that fully encompass the range of experience inherent to human pain conditions. Therefore, in this work complex behaviors were assessed as potential measures of persistent pain in miceWe investigated a wide range of quality of life behaviors in three classic pain models: spared nerve injury, chronic constriction injury and injection of complete Freund's adjuvant. Mechanical hypersensitivity is prominent in each of these conditions and persists for many weeks. To assess more complex behavioral outcomes, home cage behavior was continuously monitored after injury and a battery of motor disability and affective behavior tests were performed on these mice. No model of chronic pain produced long-lasting changes to behaviors of daily life, either in the home cage or in tests of affect and disability.Next, we observed behaviors in three other models of persistent pain: osteoarthritis, disc-degeneration, and dental pulp exposure. In a pilot study of the former two models, mice with joint degeneration were tested for locomotor ability and motivation, but showed no signs of disability. Lastly, we measured behavior in the setting of dental pulp inflammation, for which there is no standard method of measuring pain levels. As with other models, pulpal injury also did not impact behavior in the home cage. Instead, we used an operant assay of sucrose consumption as a measure of dental pain in mice. Data from this task suggest that pain can, in fact, influence some elements of complex behavior. However, as alteration in daily life activities is the feature that is so disrupted in patients with chronic pain, our results suggest that many murine pain models do not fully reflect the human conditions and raise questions regarding the limitations of these models in pain research
Recommended from our members
The cellular logic of pain modality discrimination
Full text linkNoxious stimuli are detected by primary afferent neurons of the dorsal root ganglia (DRG). Such neurons, known as nociceptors, can be divided into several distinct populations based on the heterogeneous distribution of receptors, ion channels, and neurotransmitters, however, functional correlates of these anatomical differences are yet unidentified. The work in this thesis further examines the neurochemical and functional segregation of nociceptor subtypes through a genetic and pharmacological investigation of neurons that express the heat and capsaicin receptor, TRPV1. TRPV1 is activated by noxious heat stimuli (>43 °C), and is robustly expressed by primary afferent nociceptors. In addition, some have argued that TRPV1 is widely distributed in cells outside of the DRG, although there is considerable disagreement as to the extent and localization of this expression. To address this question, we generated a line of mice in which TRPV1 + cells co-express two reporter genes: placental alkaline phosphatase and nuclear lacZ. These enzymes allow for the sensitive and accurate identification of TRPV1+ cells and processes. Using this approach, we observed that, in contrast to numerous previous reports, TRPV1 expression in the nervous system is largely limited to peptidergic, primary afferent neurons. We additionally found evidence for TRPV1 in arteriolar smooth muscle cells, highlighting an important substrate for the actions of heat, protons, and other TRPV1 agonists on vascular tone. We then investigated the relative contribution of TRPV1+ and TRPV1- nociceptors to the behavioral responses to stimuli of different pain modalities. Surprisingly, despite the fact that most nociceptors show polymodal response properties in electrophysiological assays, we found that pharmacological ablation of the central branches of TRPV1+ nociceptors selectively abolished heat pain sensitivity without altering behavioral responses to mechanical or cold stimuli. Conversely, we found that genetic ablation of nociceptors expressing the G protein-coupled receptor, MrgprD, which marks a large subset of TRPV1- DRG neurons, selectively reduced behavioral sensitivity to noxious mechanical stimuli. This double-dissociation suggests that the brain can distinguish different noxious stimulus modalities from the earliest stages of sensory processing as a result of distinct contributions from molecularly-defined nociceptor subtypes
Methionine-enkephalin-and Dynorphin A-release from immune cells and control of inflammatory pain
No full textWe have previously shown that β-endorphin (END) is contained and released from memory-type T-cells within inflamed tissue and that it is capable to control pain (J Clin Invest 100(1) (1997) 142). Methionine-enkephalin (MET) and Dynorphin-A (DYN) are endogenous opioids with preference for δ- and κ-opioid receptors, respectively. Both MET and DYN are produced and contained within immune cells. The goal of this study was to determine the release characteristics of MET and DYN in a rat model of localized hindpaw inflammation and to examine the antinociceptive role of MET and DYN in a Freund's adjuvant induced model of inflammatory pain. We found that corticotropin-releasing factor (CRF) can stimulate the release of both MET and DYN from lymphocytes. This release is dose-dependent and reversible by the selective CRF antagonist α-helical-CRF. Furthermore, CRF (1.5 ng) produces analgesia when injected into the inflamed paw, which is reversible by direct co-administration of antibodies to MET. Lymphocyte content of MET was 7.0±1.4 ng/million cells, whilst DYN content was ˜30-fold lower. Both END and DYN, but not MET, were released by IL-1. Consistently, IL-1 produced peripheral analgesic effects which were not reversed by antibodies to MET. These results indicate that both MET and DYN play a role in peripheral analgesia but have different characteristics of release. These studies further support a role of the immune system in the control of inflammatory pain. This may be particularly important in patients suffering from compromised immune systems as with cancer and AIDS
Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis
Full text linkBackground Despite 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. Objectives We 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). Methods We 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. Results Systemic 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. Conclusions Although additional research is clearly needed, existing approved GABA agonists should be considered in the management of chronic itch, notably atopic dermatitis. 1 2017 American Academy of Allergy, Asthma & ImmunologyScopu
Recommended from our members
Exploiting animal toxins to probe molecular mechanisms of pain
Full text linkVenoms from spiders, snakes, cone snails and scorpions have evolved to produce avast pharmacopoeia of toxins that modulate receptor or channel function as a means ofproducing shock, hemolysis, paralysis and pain. As such, venoms from these animalsrepresent a rich potential source of potent and selective toxins that can be exploited tostudy and manipulate somatosensory and nociceptive signaling pathways. In this work, Ihave identified and characterized two novel toxins from the Brazilian lancehead pit viper(Bothrops moojeni) and Tanzania blue ringleg centipede (Scolopendra morsitans). TheBrazilian lancehead snake venom contains a novel secreted phospholipase A2(sPLA2)-like protein that can promote ATP release from pannexin hemichannels.Studies on the cellular and behavioral effects of this toxin reveal a role of regulatedendogenous nucleotide release in nociception. The discovered Tanzania blue ringlegcentipede toxin represents a new family of toxins that show evolutionary relationshipwith α-scorpion toxins and could potentially function as potassium channel blockers
Recommended from our members
Neural control of hunger and thirst
Full text linkAnimals must maintain internal state within narrow limits to survive. This process, known as homeostasis, is coordinated by specialized neural circuits that sense deviations in internal state and respond with compensatory physiological and behavioral outputs. Two important examples are hunger and thirst, which are generated in response to energy deficit and dehydration. However, surprisingly little is known about the neural circuits controlling hunger and thirst, in part because the brain contains many intermingled neural cell types with different functions. In this dissertation, we describe two studies that take advantage of the power of mouse genetics to study feeding and drinking behavior, as well as the underlying neural cell types and circuits. We also describe the development of mouse genetic tools to identify gene expression markers for uncharacterized neural cell types.In our first study, we identify forebrain neural populations that are activated by dehydration, including an excitatory population in the median preoptic nucleus (MnPO). We show that activation of these neurons promotes drinking and increases blood pressure. We also demonstrate that reduction of their activity is negatively reinforcing, supporting a theory called drive reduction and resolving decades of debate about the motivational mechanism of thirst. In addition, we examine outputs to three regions downstream of the MnPO and find that they partially dissociate the behavioral and cardiovascular effects.In our second study, we examine dietary amino acid sensing in mice. Prior to our work, it was proposed that animals rejected food lacking a single essential amino acid (EAA) within minutes of feeding. However, we are unable to replicate this result and therefore systematically reinvestigate the effects of dietary EAA deficiency. Our main findings are that dietary amino acid sensing depends on physiological need and that distinct mechanisms are responsible for sensing of different EAAs.Together, the work described in this dissertation sheds light on neural control of feeding and drinking behavior. It will be important in future studies to elucidate the neural circuit downstream of the MnPO that controls thirst and the mechanisms underlying detection of individual dietary amino acids
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
- …
