Anesthesiology & Pain Medicine >> Research >> Focus Areas >> Pain Medicine & Neuroscience >> Cytokine and Neurotransmitter Interactions in Sleep Regulation
section identifcation image

Research Focus Areas:
Pain Medicine & Neuroscience

Cytokine and Neurotransmitter Interactions in Sleep Regulation

Principal Investigators

M. R. Opp, Ph.D., L. Imeri, M.D.


Sleep presents a conundrum for neurobiology: we do not know what function(s) sleep serves for the brain (or the body). We do know, however, that adequate sleep is essential for physical and mental health. In addition to effects on cognition and performance, lack of sleep, or sleep disruption due to sleep disorders may be a contributing factor to multiple pathologies, including but not limited to hypertension, coronary artery disease, cerebrovascular disease, and hyperglycemia. Numerous studies demonstrate that sleep loss impairs immune function and that immune activation from infection alters sleep. Responsiveness to infection varies widely: in the extreme, some will live and others will die in response to the same pathogen(s). Numerous systematic pre-clinical studies demonstrate infection-induced alterations in sleep. Most infections increase non-rapid eye movements sleep (NREMS) and decrease rapid eye movements sleep (REMS). Our functional hypothesis is that the manner in which sleep is altered during infection is a critical determinant of clinical outcome. Indeed, one retrospective study demonstrates that specific sleep patterns of rabbits are associated with survival from infection. To further our understanding of central nervous system responses that result in good clinical outcome, we focus on the cytokine interleukin (IL)-1 as one mediator of altered sleep during immune activation. Data indicate IL-1 increases NREMS and suppresses REMS. We propose in this application to focus effort on IL-1-induced suppression of REMS, an effect that has been universally ignored. IL-1 inhibits ACh synthesis and release. Cholinergic neurons of the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei are involved in EEG desynchronization and thalamocortical activation during REMS. REMS-generating structures are under GABAergic inhibition: IL-1 enhances GABA inhibitory effects at multiple levels. Studies proposed in this application will test the mechanistic hypothesis that IL-1 suppresses REMS by opposed, yet complementary actions on brainstem cholinergic and GABAergic systems. Our preliminary data indicate: IL-1 microinjected into the LDT reduces REMS of rats; IL-1 reduces firing rates of cholinergic neurons in LDT slice preparations; and IL-1 increases the number of c-Fos+ neurons in the ventrolateral periaqueductal grey (vlPAG), a GABA-rich area that projects to the pontine reticular formation and the LDT. In this application, we propose to determine: 1) the impact on sleep of IL-1 microinjection into brainstem cholinergic / cholinoceptive nuclei, 2) in vitro effects of IL-1 on electrophysiological properties of cholinergic neurons, and 3) the impact of IL-1 on REMS-relevant brainstem nuclei and neurotransmitter systems using immuno-fluorescence techniques. Successful completion of these aims will provide novel data critical for our understanding of mechanisms by which REMS is suppressed during infection. Determination of whether alterations in sleep contribute to good clinical outcome will only be possible when the neuroanatomic and neurochemical substrates targeted by immune responses to infection are clearly understood.

Pain Medicine & Neuroscience:
Research Projects

An Internet CBT Intervention for Pediatric Chronic Pain and Disability
T. Palermo, Ph.D.
Cervical Sympathetic Block in Patients with Cerebral Vasospasm following Aneurysmal Subarachnoid Hemmorhage
M. DePinto, M.D., M.M. Treggiari, M.D., Ph.D., M.P.H.
Controlling Pain After Trauma
D. Patterson, Ph.D., S. R. Sharar, M.D., M. Jensen, Ph.D., H. Hoffman, Ph.D., et al.
Cytokine and Neurotransmitter Interactions in Sleep Regulation
M. R. Opp, Ph.D., L. Imeri, M.D.
Disability from Pediatric Traumatic Brain Injury
P Rivara, M.D., M. S. Vavilala, M.D.
Drug Interactions at the Human Blood-Brain Barrier
J. D. Unadkat, Ph.D., K. B. Domino, M.D., M.P.H., A. Collier, M.D., et al.
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
Rozet, M.D.
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
S. Flack, M.D.
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.