302 Chapter 10 Several studies have investigated the role of opioids in the context of hypocretin transmission. Work in mice hypothalamus slices showed that opioids decreased hypocretin-producing neuronal activity and, conversely, that opioid receptor blocking increased hypocretin-producing neuronal activity [357]. Yet, in vivo, morphine administration resulted in increased hypocretin activity in rats lasting for 3 h [125]. The conflicting results of opioids on hypocretin-producing neuronal activity that were reported in in vitro and in vivo studies remain unexplained but could be caused by secondary effects of the complex neuronal circuit in vivo. Significantly more and smaller hypocretin-producing cells were previously found in both the lateral and medial hypothalamus after long-term opioid administration in mice and humans [125]. Hypocretin-producing neuron size alterations are hypothesized to result directly from opioid administration, as opioids have been identified as changing plasma membrane receptors, endosome transporters, and Golgi apparatus functioning [347, 358]. Opioids as a potential treatment for narcolepsy type 1 Investigations into opioids and narcolepsy are scarce. Opioids were first mentioned in relation to improvement of hypersomnolence symptoms in 1981 [359]. After this, several case reports described effects of opioids on hypersomnolence, but an overarching overview is lacking. Recent publications have described both clinical [126] and physiological [125] observations that support a possible beneficial effect of opioids for treatment of hypersomnolence disorders. Importantly, other reports address the possible dangers of combining opioids with sodium oxybate, often prescribed to people with hypersomnolence [360-362]. Multiple case reports describe anaesthetic management of people with hypersomnolence and show that careful monitoring is needed when using opioids in anaesthetizing people with hypersomnolence disorders, in part because of possible interactions with medication for their sleep disorder [359, 363-369]. Following up on previous work, we aimed to investigate further the possible therapeutic effects of opioids for people with narcolepsy type 1. The objective of this study was to assess opioid use and its self-reported effect on narcolepsy symptom severity by conducting a combined systematic literature review and questionnaire study. We expected to observe improvements in narcolepsy symptom severity related to opioid use, mainly in people taking morphine or codeine as was described in earlier reports [125, 129-131]. Previous improvements in symptom severity were mainly reported for excessive daytime
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