355 Discussion in narcolepsy type 1 it would therefore be advisable to perform repeated CSF hypocretin assessments in those showing clinical improvement. Multiple studies have suggested that the hypocretin neurons are not destroyed in narcolepsy type 1. People after traumatic brain injury [464], hypothalamic brain lesions [185, 465, 466] or tumours [184] may for instance present with a transient narcolepsy type 1 phenotype, accompanied by temporary hypocretin deficiency. These findings indicate that hypocretin expression levels can fluctuate without necessarily resulting in permanent cell loss. Increased hypothalamus levels of pyroglutamylated RFamide peptide (QRFP) have recently been found in human postmortem narcolepsy type 1, a peptide that is known to be mainly produced by hypocretin neurons [380]. QRFP has a rather similar structure and possibly also function to hypocretin; also, elevated levels of QRFP in narcolepsy type 1 suggest preservation of hypocretin neurons [380]. The same study also found high methylation levels of the promotor of the hypocretin gene in narcolepsy type 1, which could be responsible for epigenetic silencing of hypocretin production [380]. As methylation is a reversible process, this opens doors to investigate possibly therapeutic demethylation interventions. The role of hypocretin in opioid addiction Hypocretin neurons have strong projections to the ventral tegmental area as an important hub in reward circuitry and have been found to mediate drugseeking behaviour in animal studies [349, 467]. Whether altered hypocretin signalling is a cause, sustaining factor or just an indirect effect in opioid dependence, remains unknown and should be further studied. Given the increase in hypocretin cell counts after chronic opioid administration [125] and the important modulatory role of hypocretin in reward processing, the question arises whether pharmaceutical interventions targeting the hypocretinergic system would be effective to treat opioid addiction. Hypocretin antagonists therefore offer a promising novel therapeutic option for opioid addiction and warrant further investigation in this context [349]. Multiple hypocretin antagonists have been approved by the U.S. Food and Drug Administration (FDA) for treating insomnia and are still under investigation by the European Medicines Agency (EMA) [468, 469]. 11
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