319 Therapeutic Potential of Opioids in Narcolepsy Type 1 instructions when initiating sodium oxybate and strongly discourage concurrent use with opioids. The mechanisms underlying opioid-induced symptom changes in people with narcolepsy type 1 remain to be further studied, especially in humans. From rodent studies it is known that opioid receptor expression is substantial in the hypocretin neurons of the lateral hypothalamus and hypocretin mRNA levels can be manipulated by administration of opioids and its antagonists [375-377]. Chronic opioid use is hypothesized to activate the ascending arousal system by increasing hypothalamic hypocretin innervation of the locus coeruleus, where elevated tyrosine hydroxylase levels have been reported [378]. Tyrosine hydroxylase is necessary for the synthesis of catecholamines including norepinephrine, which is key for arousal promotion throughout the neuraxis [379]. This cascade of opioid-induced effects was not present in hypocretin depleted mice [378], and this could potentially also explain the mixed effects that were seen in our study as opioids are hypothesized to be a modulator of the (remaining) number of available hypocretin-producing neurons. This interaction possibly only works when individuals are not fully hypocretin deficient and still have some functioning hypocretin-producing neurons present. This is supported by the results from Thannickal et al. [125] where mice with 30% reduced hypocretin-producing neuron counts returned to normal hypocretin-producing neuron numbers after morphine administration. Human postmortem analyses in people addicted to heroin and one person with narcolepsy taking opioids showed significantly increased hypocretinproducing neuron numbers compared to brains from non-opioid using controls and people with narcolepsy, respectively [125]. Hypocretin levels were unfortunately only available in a few people in our sample and not included in previous publications in humans. The sedative and analgesic properties of opioids could also play a role in the positive effects of opioid use in our study. This seems specifically plausible for the observed improvements in nocturnal sleep given the sedative effects of opioids. Future studies should aim to correlate hypocretin levels with opioid-related narcolepsy symptom changes and include polysomnography measurements to objectively investigate a potential relationship between opioid use and improved nocturnal sleep. Another potential working mechanism could be related to a recent study that suggests that hypocretin deficiency in narcolepsy type 1 is not caused by cellular destruction but by loss-of-function mutations or epigenetic silencing of the hypocretin neurons [380]. This entails that the hypocretin neurons of people with narcolepsy type 1 are present but inactivated. Opioids are known to alter DNA methylation [381, 382] and could hereby play a role in reactivating 10
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