2007 — 2009 |
Davidson, Steve |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Central Nerual Mechanisms Involved in the Control of Itch @ University of Minnesota Twin Cities
[unreadable] DESCRIPTION (provided by applicant): Itch is a major clinical problem from which relief is sought by patients suffering from a variety of diseases and infections. Scratching and other noxious counter-stimuli block the perception of itch; however, neither the neural circuits nor the neurotransmitters involved in suppressing itch are known. Many spinothalamic tract (STT) neurons in the dorsal horn respond to pruritogens (itch producing agents) and are thought to link activity in primary afferent pruriceptors to perceptual experience. Preliminary findings in the monkey indicate that noxious counter-stimuli can inhibit the discharge of STT neurons during a response to a pruritic agent. Therefore, the major goal of this proposed study is to determine the mechanisms responsible for the inhibition of pruritogen evoked responses in primate STT neurons. Extracellular recordings will be performed from single, antidromically identified STT neurons determined to be responsive to the itch producing agent histamine or cowhage (a non-histaminergic and therefore clinically relevant pruritogen). The specific aims of this project are to determine: 1) whether a descending pathway from supraspinal sites is involved in inhibiting pruritogen evoked responses of STT neurons; and 2) whether the inhibition of a pruritogen evoked STT response requires the inhibitory neurotransmitters GABA and/or glycine. These studies will contribute to an overall understanding of itch and begin to address the neural mechanisms of its control. For most everyday itches, a quick scratch will abolish the aversive sensation; however, itch caused by disease or infection is one of the leading symptoms driving individuals to seek professional medical treatment. The aim of this research proposal is to determine how the nervous system controls itch. Knowledge about the brain and spinal cord mechanisms involved in the control of itch may lead to more effective treatments for itch and improve public health. [unreadable] [unreadable] [unreadable]
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0.943 |
2011 — 2014 |
Davidson, Steve |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Reversal of Pain by Group Ii Metabotropic Glutamate Receptors
DESCRIPTION (provided by applicant): Inflammation or injury can sensitize nociceptive neurons and the resulting hyperexcitability is thought to mediate increased pain sensation. Although pain typically resolves with time, the mechanisms that promote the return to Dr. g are poorly understood. Dysfunction of such a mechanism could contribute to the persistence of chronic pain, while activation could provide relief from pain. The central hypothesis of this proposal is that peripheral group II metabotropic glutamate receptors (mGluRs) regulate the reversal of nociceptor sensitization and hyperalgesia. This hypothesis will be tested with a combination of anatomical, neurophysiological, and behavioral methods. Two subtypes of group II mGluRs exist, mGluR2 and mGluR3. The specific expression of each subtype within dorsal root ganglia (DRG) will be characterized. We will then determine whether mGluR2 or mGluR3 is necessary for the normal recovery from inflammatory and neuropathic pain using mGluR2 and mGluR3 knockout mice. We propose that group II mGluRs can reverse nociceptor sensitization. To test this, patch-clamp techniques will be used to measure neuronal excitability in sensitized DRG neurons. After pharmacological manipulation of group II mGluRs excitability will be reassessed. Membrane excitability is determined by current flux through ion channels, but it is not clear whether group II mGluRs regulate currents involved in sensitization. Two candidate currents, the tetrodotoxin- resistant Na+ and T-type Ca2+ current will be tested for their ability to be modulated by group II mGluRs in sensitized DRG neurons. We hypothesize that group II mGluRs are involved in the endogenous recovery from hyperalgesia. To test this, we will determine whether positive allosteric modulators of group II mGluRs accelerate the recovery from inflammatory hyperalgesia. Finally, we will determine whether group II mGluRs are capable of relieving ongoing neuropathic pain using an operant conditioning paradigm.
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1 |
2016 — 2017 |
Davidson, Steve |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Functional Characterization and Sensitization of Human Pruriceptors @ University of Cincinnati
? DESCRIPTION (provided by applicant) The relief of chronic itch (pruritus) would improve the quality of life of tens of millions of people in the US. Pruritus is poorly controlled by antihistamines but histamine-independent receptors have only recently been identified as potential targets for anti-pruritics. These newly identified pruritic receptors include the Mas-related G protein receptors, Toll-like receptors, and the thymic stromal lymphopoietin receptor, and have been found in different subsets of rodent sensory neurons. Presently, the localization and signaling mechanisms of homologous itch receptors in human sensory neurons are unknown, creating potential obstacles for translation. For this proposal we have developed a novel strategy to establish target validity at a preclinical stage by performing physiological studies in viable human sensory neurons in vitro. The major objectives of this proposal are to 1) understand the transduction of histaminergic and non-histaminergic itch stimuli in characterized human sensory neurons, and 2) to determine whether keratinocytes obtained from donors with atopic dermatitis control sensitization of pruriceptive neurons. Human sensory neurons will be characterized based on functional responses to pruritogens and on gene expression profile. Pruritic receptors have been shown to couple functionally and selectively to Transient Receptor Potential (TRP) channels in rodents. We will test whether human TRP channels are likewise gated by pruritic receptor activation in human sensory neurons and will examine whether other classes of ion channels couple to human pruritic receptors. In Aim 2 our goal is to understand sensitization of pruriceptive sensory neurons, a phenomenon that can explain the ongoing and heightened itch experienced by individuals with chronic pruritic conditions including atopic dermatitis. We hypothesize that atopic human keratinocytes will control pruritic receptor function and excitability of human sensory neurons. For this aim we develop novel human sensory neurons and human keratinocytes co-culture techniques. Our proposal represents the first steps toward a broader implementation of in vitro human sensory physiology. This strategy will provide valuable preclinical assessment on the feasibility of targeting novel receptors in human for itch and pain, and reduce the risks involved in clinical trials.
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0.94 |
2018 — 2021 |
Davidson, Steve |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Thalamo-Limbic Circuits in Pain @ University of Cincinnati
Pain tolerance varies widely among peoples and, depending on external and internal circumstances, varies within an individual from moment to moment. Although the concept of pain tolerance is familiar, the neurobiological substrates that regulate pain tolerance are unknown. Pain tolerance requires motivational, emotional, and cognitive processing in addition to the sensory dimension of the pain experience. Achieving an understanding the specific neurons and circuits in the brain that regulate pain tolerance may to lead to breakthroughs that will enhance the capacity of patients to cope with intractable pain. This project utilizes innovative techniques to both assess pain tolerance behavior in animals, and to dissect the neural circuits thought to regulate pain tolerance. We have discovered that a subtype of pyramidal neuron in limbic cortical areas including the anterior cingulate cortex and insula becomes hyperexcitable during periods of lowered pain tolerance produced by injury. These neurons express GRM2, the gene encoding group II metabotropic glutamate receptors, which is a potential molecular target to control pain tolerance in clinical settings. The goals of this project are: 1) To identify the thalamo-limbic pathways that regulate pain tolerance; 2) To determine the role of GRM2 limbic cortical neurons in pain tolerance and nociceptive-withdrawal behaviors, and, 3) to determine whether pain tolerance can be modulated by pharmacological manipulation of group II metabotropic glutamate receptors. Optogenetic and pharmacological experiments will be performed in vivo in mouse to learn whether pain tolerance can be modulated independently of standard nociceptive-withdrawal thresholds. Modulation of neural activity in models of inflammatory and neuropathic pain will be tested to determine whether injury-induced changes to pain tolerance can be reversed. Neuro-anatomical and neurophysiological approaches in vitro will be used to generate new information on the plasticity of the thalamo-cortical circuits hypothesized to regulate pain tolerance and the membrane biophysics of GRM2 neurons. These experiments will be performed using animal models of persistent pain to determine whether function and anatomy of thalamo-cortical synapses and GRM2 neurons are altered by pain to provide mechanistic understanding for behavioral changes in pain tolerance. Pharmacological modulation of group II mGluR signaling will be tested in vitro to determine the potential for these receptors to be used in future clinical interventions. Completion of this project will generate new knowledge on the neural systems involved in the supraspinal processing of pain, including pain tolerance, and potentially catalyze an innovative shift in strategy for pain relief to enhance coping ability in chronic pain patients through neuromodulation.
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0.94 |