Introduction For Sleep Deprivation

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Sleep is a necessary behavior for physiological allostasis that is common to all vertebrates. Allostasis refers to the set of intertwined neuroendocrine-immune processes of bodily adaptation to stressful challenges during the wake cycle. The summative effects of these challenges, the allostatic load, signifies the total cost of wear and tear to the body. A finely regulated neuroimmunology of the sleep component of the circadian patterns is critical to the physiological repair mechanism required in allostasis (Solomon and Moos 1964; Solomon 1987; Sterling and Eyer 1988; Chrousos and Gold 1992; Kiecolt-Glaser, McGuire, Robles, and Glaser 2002; Irwin 2002; McEwen and Wingfield 2003; Schulkin 2003; Chiappelli and Cajulis 2004; Chiappelli et al. in press-c).

It was long suspected (e.g., Engle 1960), and is now widely documented by research findings from our laboratory and others that oral biology and systemic medicine are intimately intertwined. Certain prokaryotes that contribute the flora of the oral cavity are known to migrate into the cardiovascular system, to lodge in the aortic and the pulmonary valves, and to lead to severe cardiac malfunction and bacterial endocarditis. Serious tegumentary diseases, such as lichen planus, have their corresponding pathology in the oral mucosa (i.e., oral lichen planus, OLP, vide infra) (Chiappelli and Cajulis 2004). Several systemic neuroendocrine and immune responses to stress, to the allostatic response, and to bacteriokines, bacterial cytokine inducers that are produced by infectious pathogens and that contribute to the control of the pathological inflammatory response, are monitored in peripheral fluids (e.g., plasma, serum, urine), including total or parotid saliva. Case in point, the cold pressor challenge, whose physiological mechanism underlying the response consists of temperature-dependent constriction to blood flow of both superficial and deep tissues of the hand, and associated strong perception of pain. This challenge test is an adequate model to study psychobiological responses to stressful discomfort and the associated allostatic response, because cold-induced vasospasms are frequently present in syndromes of chronic pain. The caveat of this test is that it may have adverse effects in subjects with cardiovascular dysfunctions. In normal subjects, the cold pressor test alters the glucocorticoids-cytokine axis response driven by the hypothalamus-pituitary-adrenocortical (HPA) cell mediated immune (CMI) feedback system (vide infra, Prolo and Chiappelli in press). This leads to a time-dependent pattern of change in the circadian patterns of salivary interleukin (IL)-6. Salivary

IL-6 rises two- to threefold during the 90 min following the challenge. This effect is more pronounced in female compared to male subjects (p < 0.05), suggesting modulatory effects by the HPGonadal hormones, themselves under biologically important rhythmicity (Chiappelli et al. in press-c; Prolo and Chiappelli in press; Chiappelli, Prolo, Cajulis, Harper, Sunga, and Concepcion 2004).

IL-6 is a central neuroimmunological factor, and is one of the proinflammatory cytokines produced following immune challenges that contribute to stimulate the hypothalamic secretion of corticotropin releasing factor (CRF), the factor responsible for inducing secretion of adrenocorticotropin hormone (ACTH) by the anterior pituitary. ACTH regulates production and secretion of glucocorticoids by the adrenal cortex (i.e., cortisol in fish and Homo sapiens, corticosterone in rodents), which down-regulate both the HPA axis, and immune inflammatory events mediated by CMI. Autonomic neural activity, which includes palmar skin conductance, brachial artery systolic blood pressure, electrocardiogram, interbeat duration between R spikes, finger photoplethysmograph pulse peak amplitude, and peripheral finger photoplethysmograph peak during the final 60 s of a 15-min resting period, expressed as the SD of each indicator about its mean under each assessment condition, also plays a significant role in mediating CMI (Solomon 1987; Chrousos and Gold 1992; Kiecolt-Glaser et al. 2002; Chiappelli et al. in press-c; Prolo and Chiappelli in Press; Chiappelli et al. 2004). Saliva and plasma IL-6 levels are characterized by distinctive patterns of circadian fluctuation, and show a significant positive correlation (Chiappelli et al. in press-c).

In addition to its somnogenic properties, IL-6 administration or elevation of its endogenous levels results in sleep disturbance when associated with HPA axis activation (Chiappelli et al. 2004). Changes in sleep physiology associated with aging, including elevations of sleep-disturbing hormones and increased sensitivity of the sleep-controlling target organ to the actions of these hormones, markedly increase insomnia prevalence with aging. IL-6 peripheral levels correlate negatively with sex steroid levels, are decreased after a restful night of sleep, and are elevated in chronic pain/inflammatory syndromes (Irwin 2002).

The allostatic response consists of a set of psychobiological process, whose relevance to the health disease continuum is long lasting. The fundamental mechanisms of allostasis are defined by underlying psychoneuroendocrine-immune pathways. The psychoneuroimmune interactive system consists of the overlay of the complexity of the psyche with the short and long feedback loops that directly and indirectly regulate neuroendocrine responses, and the modulation of cellular and humoral, innate and antigen-dependent immunity, with the intertwined process of physiological rhythmicity (Solomon 1987; Kiecolt-Glaser et al. 2002; Chiappelli et al. in press-c; Chiappelli et al. 2004).

We present the case of oral mucositis (OM), the pervasive condition that afflicts the large majority of patients undergoing aggressive cancer treatments, as a significant allostatic threat. OM is a condition with established immunological mechanisms, with severe sequelae that include, among others, disturbed sleep. We discuss the fundamental psychobiology of the etiology of OM, and current treatment interventions. We present the case for chronomodulated cancer treatment that is one that respects biorhythmicity, as an effective measure to minimize or to prevent OM. We suggest avenues for future research to better characterize the fundamental neuroimmunology of OM, and the potential palliative effects of sleep for this condition.

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