Sleep-waking states and the endogenous opioid system

In the general introductory part of this thesis (Chapters and 2) a review of some pertinent literature related to sleep-waking states and opioid peptides is offered. A global view of the neurochemical mechanisms and theories of functions of sleep, as well as the physiological and possible clinical consequences of total or selective REM sleep deprivation is given in Chapter 1. In Chapter 2, which is concerned with the role of endogenous opioid peptides, particular attention is paid to the possible modulatory role of endogenously released opioid peptides in the regulation of some behavioural states in physiological and pathological conditions. It is generally known that exogenously administered opiates and opioid peptides can alter sleep pattern and decrease REM sleep. A possible interaction between sleep-waking states and endogenous opioid system is suggested by the report that the episodic release of plasma humoral endorphins during sleep is associated with the REM sleep phase (Chapter 1, section 1.1 .7). In addition, the concentrations of opioid peptides in some brain nuclei of the rat which are known to be important in sleep-waking regulation, are highest in the dark (active) phase, during which wakefulness is high and lowest in the light (rest) phase, when the propensity to sleep is at its highest (Chapter section 1 .3.2). Thus in order to clarify the effect of endogenously released opioid peptides in the regulation of sleep-waking pattern, we studied the effects of phosphoramidon, an inhibitor of enkephalinase A on sleep-waking states (Chapter 3). Several clinical studies suggest that the sleep-waking cycle may modulate the occurence of some types of epileptic phenomena in human subjects (Chapter 1, section 1 .5.2, iii). In addition, some studies indicate a similarity between enkephalin induced epileptic Therefore, phenomena and we studied petit the mal epilepsy effects of (Chapter 4 discussion). different sleep stages on enkephalin-induced epileptic phenomena using electrophysiological parameters (Chapter 4). These initial studies (Chapters 3 and 4) suggested an interaction between sleep-waking states and endogenous opioid system. The observation that REM sleep deprivation (REMSD) reduced the pain threshold to noxious electrical stimulation (Chapter 1 section 1 .5.2d i) was an indication of the importance of REM sleep in the regulation of nociception. Therefore in Chapters 5 and 6, the experiments were designed to explore a direct effect of REMSD on the analgesic effects of morphine, an enkephalinase inhibitor phosphoramdion and cold-water-swim. The profound antagonistic effect of REMSD on opiate/opioid peptide induced analgesia stimulated further interest to investigate the relationship between REMSD and other opiate/opioid peptide modulated behavioural phenomena. Therefore the following opioid modulated behaviours were investigated: akinetic-cataleptic syndrome, spontaneous vertical motor activity, convulsions, (Chapters 7-9). (Chapter 10) grooming, wet-dog-shakes and morphine withdrawal symptoms Additional experiments with nitrous oxide were performed since it is known that this anaesthetic agent can stimulate the release of endogenous enkephalins and induce opiate-like withdrawal symptoms (Chapter 2, section 2.5.2, iv). Finally, the possible clinical consequences of our findings are described in the relevant chapters.