Anesthesiology & Pain Medicine >> Research >> Focus Areas >> Pain Medicine & Neuroscience >> Molecular Mechanisms of Sleep Responses to Viral Infection
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Research Focus Areas:
Pain Medicine & Neuroscience

Molecular Mechanisms of Sleep Responses to Viral Infection

Principal Investigators

James Krueger, PhD (WSU: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)

Description

Influenza virus-induced brain-regulated acute phase responses (APR) include enhanced duration of non-rapid eye movement sleep (NREMS). The molecular pathways for these responses remain under investigated as do the brain anatomical pathways involved. Although influenza PR8 virus is considered non-neurotropic, recently we showed that upon intranasal challenge the virus localizes to the olfactory bulb (OB) and undergoes at least partial replication, as evidenced by expression of positive sense viral RNA in the OB, and up-regulates OB and hypothalamic (HT) cytokine expression. We investigate the hypothesis that the OB-HT pathway modulates the APR via molecular steps involving pathogen pattern recognition receptors in the OB, their induction of interleukin-1(IL1)-related molecules in the OB and HT and HT IL1/growth hormone releasing hormone (GHRH) mechanisms. Preliminary data; a) characterize a brain-specific IL1 receptor accessory protein (AcPb) that attenuates APRs, b) present a transgenic mouse expressing the IL1 type I receptor (ILRI) only on neurons, and c) show that mice lacking the GHRH receptor sleep less after viral challenge unlike any other mouse; previously we showed that GABAergic HT-neurons are receptive for both IL1 and GHRH. We propose three aims that will clarify the role of the OB-HT pathway in APR sleep responses. Aim 1 tests the hypothesis that AcPb attenuates the APR-IL1 and sleep responses to viral challenge. Aim 2 tests the hypothesis that PR-8- initiation of the APR sleep response is dependent upon OB glial expression of the ILRI. Aim 3 tests the hypothesis that HT-GHRH/GHRH receptor mechanisms are critical to the flu-initiated sleep component of the APR. We develop an animal model that for the first time allows determination of the role of a brain-specific cytokine signaling mechanism, AcPb, in neuro-immune inflammatory processes. We characterize the relative contribution of the ILRI expression on neurons vs. glia in the APR sleep responses induced by virus. We make use of mice with a spontaneous mutation resulting in non-functional GHRH receptors to elaborate the OB-HT cytokine/GHRH mechanisms leading to APR sleep responses. Anticipated results will characterize OB involvement in the initiation of the APR and thereby provide a new readily accessible target for drug therapy and thus for the rapid translation of basic research to the clinic. PUBLIC HEALTH RELEVANCE: These studies determine molecular mechanisms occurring in the olfactory bulb induced by influenza virus that are responsible for the viral-induced acute phase response including sleep. We examine the role of a brain- specific cytokine adaptor protein, called interleukin-1 receptor accessory protein (AcPb), in the brain regulation of sickness behavior. We also examine the specific roles neurons and glia play in this process. Further, we link the molecular events occurring in the olfactory bulb to the hypothalamus by characterizing the role the growth hormone releasing hormone receptor in sleep responses to influenza. Expected results will allow for the rapid translation of basic science to the clinic; e.. nasal application of AcPb to attenuate brain-regulated aspects of the cytokine storm.

Public Health Relevance

These studies determine molecular mechanisms occurring in the olfactory bulb induced by influenza virus that are responsible for the viral-induced acute phase response including sleep. We examine the role of a brain- specific cytokine adaptor protein, called interleukin-1 receptor accessory protein (AcPb), in the brain regulation of sickness behavior. We also examine the specific roles neurons and glia play in this process. Further, we link the molecular events occurring in the olfactory bulb to the hypothalamus by characterizing the role the growth hormone releasing hormone receptor in sleep responses to influenza. Expected results will allow for the rapid translation of basic science to the clinic; e.. nasal application of AcPb to attenuate brain-regulated aspects of the cytokine storm.

Pain Medicine & Neuroscience:
Research Projects

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Controlling Pain After Trauma
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Cytokine and Neurotransmitter Interactions in Sleep Regulation
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Disability from Pediatric Traumatic Brain Injury
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Drug Interactions at the Human Blood-Brain Barrier
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Effectiveness of Oxymorphone for Acute Postoperative Pain Pediatric Subjects
S.Bhananker, M.D.
Identifying Virtual Reality Analgesia Mechanisms by Pharmacologic Manipulation
S. R. Sharar, M. D., D.A. Patterson, Ph.D, H.Hunter, Ph.D., et al.
Influence of Dexmedetomidine on the Evoked Potentials During Spine Surgery
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Innovations In Pediatric Pain Research
T. Palermo, Ph.D.
Ketorolac in Surgical Infants: Pharmacokinetics/Analgesia
A.M. Lynn, M.D.
Mechanism Of Action Of Volatile Anesthetics
P.G. Morgan, M.D.
Memantine for Post-Operative Pain Control in the Opiate-Tolerant Patient
G. Terman, M.D., Ph.D.
Modulation of Pruritus by Spinal Cannabinoids
G. W. Terman, M.D.,Ph.D.
Molecular Mechanisms of Sleep Responses to Viral Infection
James Krueger, PhD (WSU: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)
Neonatal Pain, Depression and Pain Susceptibility at Maturity in Rats
Gayle Page, DNSc, RN (Johns Hopkins: PI); Mark R. Opp, PhD (co-investigator/subcontract PI)
Neurologic Injury after Non-Supine Surgery Registry
L. A. Lee, M.D., L. Stephens, Ph.D., K. B. Domino, M.D., M.P.H., K. L. Posner, Ph.D.
Neuron-glial communication and brain aging
Paula Bickford, PhD (University of South Florida: PI); Carmelina Gemma, PhD (co-investigator/subcontract PI)
Neuronal-Glial Dialogue and Cognition
Carmelina Gemma, PhD (PI)
Neurotoxic Effects of Volatile Anesthetics in C. Elegans
P.G. Morgan, M.D.
Open Label Study of the Safety and Efficacy of Conivaptan (Vaprisol) to raise serum sodium levels in patients with severe traumatic brain injury
M. M. Treggiari, M.D., Ph.D., M.P.H., S. A. Deem, M.D., N.D. Yanez III, Ph.D.
Optimizing the Control of Pain from Severe Burns
D. Patterson, Ph.D.; S R. Sharar, MD; D. Heimbach, MD., J Doctor, Ph.D.
Patient Perceptions of the Benefits of Long-Term Opioid Therapy (PLOT) Initiative-Beliefs and Behaviors
D. C. Turk, Ph.D., J. P. Robinson., M.D., R. Landau, M.D.
Sepsis Outcomes and Aging: Role of Sleep Disruption and the Blood Brain Barrier
Mark R. Opp, PhD (PI); William A. Banks, MD (co-investigator); Richard M. Raymond, PhD (co-investigator)
Shared Decision Making in Orthopaedic Spine Surgery to Improve Patient Safety
K. B. Domino,M.D, M.P.H.; K. L. Posner, Ph.D. et al.
Sleep-Wake Disturbances in Adolescents with Chronic Pain Research
T. Palermo, Ph.D.
Subgroups of FMS: Symptoms, Beliefs & Tailored Treatments
D.C. Turk, Ph.D., J. Robinson, M.D., Ph.D.
Subjective and Neuroimaging Assessment of Combined Opioid and Virtual Reality Analgesia
S. R. Sharar, M.D., T. Richards, Ph.D.
Ultrasound Guided Rectus Sheath Block for Post-Operative Pain Control Following Umbilical Hernia Repair
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University of Washington Urologic Chronic Pelvic Pain Syndromes Discovery Center
D. S. Buchwald, M.D., N. Jimenez, M. D., et al.
Web-based CBT for Opioid-treated Chronic Pain Patients With Aberrant Behavior
Rosenblum, Ph.D., D.C. Turk, Ph.D.