Biology of Sleep Substances

Shojiro Inoue

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000141580
• Topic: Biological Sciences
• Subtopic: Pharmacology
• Index: Biological Sciences

All aspects of sleep sciences are included in this excellent resource text, with special reference to sleep substances and sleep modulators. The historical development of the theories of sleep are reviewed in conjunction with the technical problems. All candidate substances are overviewed as to their sites of presence, chemical nature, bioassay techniques, physiological and pharmacological effects. On the basis of a standardized methodology developed by the author, sleep-modulatory characteristics of some substances are compared and evaluated in quantitative terms. The sleep regulatory mechanisms, which are composed of complex neurohumoral subsystems, are analyzed from the results of recent neurophysiological and neuroendocrinological experiments. Furthermore, an evolutionary aspect of sleep substances is taken into consideration. Chapters Highlight: Techniques for isolation and evaluation Prostaglandins Paradoxical sleep factors Sleep-promoting substances and nucleosides

Chapter 1

CANDIDATE SUBSTANCES, RESEARCH BACKGROUND, AND BIOLOGICAL ROLES

I. WHAT IS AN ENDOGENOUS SLEEP SUBSTANCE?

Sleep, one of the most sophisticated integrative functions in higher animals, appears to be regulated by a variety of endogenous humoral factors. These factors are called “sleep substances”. However, it is still difficult to unanimously define an endogenous sleep substance since we cannot yet fully understand the mechanism involved in the regulation of sleep. Until several years ago, even those investigators who presumed the existence of a humorally transmitted somnogenic factor regarded that the number of the genuine factors must be solely one or at most two, i.e., one for the regulation of rapid-eye-movement (REM) sleep and the other for that of non-REM sleep. However, our recent increasing knowledge indicates that multiple factors are actually participating in the induction, maintenance, and termination of physiological sleep.^1,2 Thus, it seems unlikely that a single sleep hormone does regulate every aspect of sleep. As a consequence, the definition of a sleep substance and the concept of the humoral theory on sleep have been gradually revised.

Borbély and Tobler^3,4 first proposed criteria essential for a specific sleep substance. According to them, an endogenous sleep substance should satisfy the following six requirements: (1) the substance should reliably and distinctly induce and/or maintain physiological sleep, (2) a dose-effect relationship should prevail within a certain dosage range, (3) the action of the substance should be similar with respect to the time course and the effect on sleep states in different species, (4) the substance should be present in the organism, (5) spontaneous or induced changes in the vigilance level should be associated with alternations in the endogenous concentration and/or turnover of the substance, (6) the substance should be chemically identified.

Jouvet⁵-⁷ differentiated “sleep-inducing or sleep-promoting factors” from “sleep-facilitating factors”. According to him, the distinction is as follows:

Sleep-inducing (sleep-promoting) factors: (1) they should be endogenous, in the brain, cerebrospinal fluid (CSF) or blood; (2) they should increase during instrumental deprivation of sleep; (3) they act directly upon executive mechanisms of sleep; (4) they are probably different for slow-wave sleep (SWS) and paradoxical sleep (PS), but they may have the same ancestor molecule; (5) their administration at the receptor level should trigger and increase SWS and/or PS, provided that permissive systems are blocked; (6) inactivation of these factors (at the production or receptor level) should result in either total insomnia or selective suppression of SWS or PS; such suppression could be obtained for a long time and should not be followed by any secondary rebound; (7) insomnia provoked by suppression of sleep-inducing factors should not be reversed by sleep-facilitating factors; (8) they are probably identical in all mammals.

Sleep-facilitating factors: (1) they may be exogenous or endogenous; (2) they do not obligatorily increase during sleep deprivation; (3) they do not act directly upon executive mechanisms of sleep, but control the permissive mechanisms that impair sleep onset; (4) their administration should increase either SWS or PS or both; (5) in case of inactivation of sleep-inducing factors, the administration of sleep-facilitating factors may induce sedation or drowsiness, but not physiological sleep; (6) their facilitating effect upon sleep may be dose-dependent, but this is not obligatory; (7) inactivating these factors may delay sleep onset temporarily, but a secondary rebound of sleep should occur later; (8) they are probably different in different mammals according to their sleep ecology.

Ursin^8,9 defined an endogenous sleep factor as a substance that is produced by the organism and that affects sleep. Her definition allows a wide latitude of possibilities as to how such a factor may work. In addition to its primary or specific effect on sleep-waking mechanisms, its actions may include unusual or unspecific sleep modulations, which neither occur in natural sleep nor result from some secondary effect of the substance.

This author¹⁰ provisionally defined an endogenous sleep factor as an active substance which, under a high physiological demand for sleep in the organism, is produced in the brain and transferred to the whole brain via the body fluid (especially CSF) to induce or maintain sleep. Inoué¹¹ and Inoué et al.¹² also proposed that, if the physiological demand for sleep is achieved, an exogenously supplied sleep substance should not cause unnatural extra sleep.

Mendelson et al.,¹³ and more recently Gillin,¹⁴ modified the proposed criteria of Borbély and Tobler^3,4 as follows: (1) the sleep substance should be purified and identified; (2) the substance normally should be present in the organism: its synthetic system, location, storage form, and concentrations should be clarified; (3) it should be demonstrated convincingly that endogenous administration of the substance promotes sleep or a specific component such as delta electroencephalogram (EEG) activity or REM-sleep compared to adequate controls; (4) the sleep promoted by the substance should be physiologically and psychologically “normal” within a broadly defined range, i.e., autonomic function, body temperature, CSF pressure, EEG wave forms, cyclic succession of non-REM and REM sleep, behavioral arousal, dreaming, and so on; (5) the effects should occur at physiological concentrations at the critical receptor areas, and these concentrations should vary appropriately with the behavioral state, i.e., low in wakefulness and high in sleep; (6) tolerance should not develop with repeated,...

Table of contents

• Cover
• Title Page
• Copyright Page
• Dedication
• Preface
• Acknowledgments
• The Author
• Table of Contents
• Chapter 1: Candidate Substances, Research Background, and Biological Roles
• Chapter 2: Techniques for Isolation and Evaluation
• Chapter 3: Delta-Sleep-Inducing Peptide and Its Derivatives
• Chapter 4: Sleep-Promoting Substance (SPS) and Nucleosides
• Chapter 5: Muramyl Peptides and Immunoreactive Substances
• Chapter 6: Prostaglandins
• Chapter 7: Paradoxical Sleep (PS) Factors
• Chapter 8: Other Sleep Modulators
• Chapter 9: Interactions of Sleep Substances
• Chapter 10: Evolutionary Aspects
• Index