Preventing the Inflammatory Response to Experimentally-induced Insomnia Symptoms

The main purpose of this study is to learn about the effects of sleep disruption (two days in a row where sleep is shortened and disrupted) on inflammation, mood (how you feel), and pain processing (your own experiences/perceptions of pain). In this research project, we are trying to figure out if we can change the effects of sleep disruption on inflammation, mood, and pain. Therefore, we will study whether taking a low-dose aspirin pill every day over 2 weeks can change how we respond to sleep disruption. For example, does the sensitivity to pain (e.g., how intense the feeling of pain is if we put our hand in very hot or very cold water) change with sleep disruption, and can low-dose aspirin influence this change. We are also interested in seeing how inflammation changes in relation to your own perceived experience of pain.

Sleep that is deficient in quantity or quality leads to upregulation of inflammatory markers (Mullington et al., 2010). In particular, interleukin (IL)-6 and prostaglandin (PG) E2 are elevated in experimental models of sleep restriction or total sleep deprivation, as well as in insomnia. Inflammation is thought to be a key mechanism through which insufficient sleep increases the risk of developing or exacerbating various disorders, including cardiovascular and metabolic disorders (Mullington et al., 2009), as well as pain-related disorders (Haack et al., 2009c). With respect to pain, markers such as IL-6 and PGE2 are able to sensitize pain transmission neurons, thereby increasing their responsiveness to stimulation. In the context of insufficient sleep, both IL-6 and PGE2 have been shown to be associated with increased spontaneous pain (Haack et al., 2007;Haack et al., 2009a), suggesting their mediating role in pain amplification as a consequence of insufficient sleep. These findings raise the question of whether pain amplification can be dampened by preventing the inflammatory increase in response to insufficient sleep. The primary goal of this pilot project is to gather preliminary support for the hypothesis that deficient sleep leads to pain amplification through an inflammatory mechanism. In addition to the primary goal of this proposal, the secondary goal is to gather preliminary data on the effects of aspirin on blood pressure regulation. Cardiovascular disease is the leading cause of death in the United States. A modest reduction of blood pressure (BP; i.e., 3 to 5 mmHg) in the population will produce a significant fall in serious cardiovascular events (Turnbull, 2003). It has been reported that low-dose aspirin may significantly reduce BP (i.e., 6 to 7 mmHg) when taken at bedtime (Hermida et al., 1994;Hermida et al., 1997;Hermida et al., 2003b;Hermida et al., 2003a;Hermida et al., 2005a;Hermida et al., 2005b). Aspirin, when taken at bedtime, may modulate 24h blood pressure by decreasing the nocturnal rise of renin-angiotensin-aldosterone system (RAAS) activity (Snoep et al., 2009) and attenuating the nocturnal drop in nitric oxide (NO) production (Hermida et al., 2005b). However, the underlying mechanisms are still unknown. Therefore, the second goal of this pilot project is to investigate the potential mechanisms contributing to BP reduction in response to aspirin taken at bedtime.

sleep, insomnia, inflammation, pain, Insomnia symptom induction/placebo, Insomnia symptom induction/aspirin

Measured in plasma and urine 3 times/day over the 5-day in-hospital stay (after 2 weeks of pill admin)

Thermode will be attached to the skin and participant has to rate the intensity of the heat or cold sensation via visual analog scales

Participant has to immerse foot into cold or hot water and rate the intensity of heat pain or cold stimuli applied to the arm on visual analog scales

Inclusion Criteria: Women and men between the ages 18-35 years Body mass index (BMI) between 18.5 and 30.0 kg/m2 For female participants: regular menstrual cycles, no significant discomfort during pre-menses/menses Daily sleep duration between 7.0-9.0 hours, verified by sleep log/actigraphy data for two weeks Habitual sleep period must begin within one hour of 2300h (to ensure normal entrainment) Blood chemistry in the normal range Exclusion Criteria: Active infection/disease. History of psychiatric, neurological, pain-related, immune, gastrointestinal, or cardiovascular disease; significant allergy; Raynaud's syndrome. History of intolerance or allergy to non-steroidal anti-inflammatory drugs (NSAID) Esophageal reflux; gastric or duodenal ulcers; or asthma Pregnant/nursing. Respiratory disturbance index of >5 events/hour on polysomnographic sleep study, periodic leg movement index (PLMI) >15/hour; sleep efficiency <80% (findings indicative of a sleep disorder). Regular medication use other than oral contraceptives. Donation of blood or platelets 3 month prior to or in-between in-hospital visits. Substance abuse.