Symposium 8 – The orexinergic system of the brain and its importance for neuropsychiatry

Chaired by: Professor Elemer Szabadi (Nottingham)

Professor Jyrki Kukkonen (Helsinki): Neuroanatomy and physiology of the orexinergic system.

Professor Kukkonen kicked-off this session on Wednesday morning by giving us a comprehensive overview of the orexinergic system. We learned that orexins were discovered by 2 groups independently, within weeks of each other, around 20 years ago, in 1998. Orexinergic neurons are found in the hypothalamus, in the lateral, dorsomedial and perifornical areas. Their projections reach the hypothalamus, thalamus, brain stem and spinal cord.

We were then guided through the history of research into the orexinergic system. As previously stated, orexins were first identified by Sakurai et al. in a paper published in Cell, and were described as a novel target for appetite suppression. Almost simultaneously, de Lecea, Kilduff and colleagues described the hypocretin system.

It has since been discovered, owing to work from Dr. Emmanuel Mignot and others, that the condition narcolepsy is associated with a lack of orexins in the CSF. Mignot showed that a murine knockout of preproorexin, a precursor for orexin, causes narcolepsy in mice.

From a pharmacological perspective, Suvorexant, an orexin antagonist, can induce sleep. The story seems promising so far, but as Professor Kukkonen said, there is still much we want to know. There is plenty more to understand about the orexin signalling pathway. Furthermore, is it possible that orexin peptides kill some cancer cells? Can orexin levels be affected in other diseases? There is a lot of potential in the orexinergic system, so watch this space in the next few years!

Professor Daniel Hoyer (Melbourne): Development of orexin receptor antagonists and agonists.

Professor Hoyer then gave us a fascinating lecture on pharmacological manipulation of the orexinergic system, using orexin receptor agonists and antagonists. We were presented with a collection of the current compounds that are, or have been, in trials. We started with Almorexant, a dual OX1 and OX2 antagonist, with was stopped due to its hepatotoxicity. Further investigations using this compound showed that it increases REM sleep, and that its action is fully present in OX1 receptor knockout animals, but that OX2 receptor knockout abrogates this effect. This suggests that Almorexant’s effects on sleep are underpinned by antagonism at the OX2 receptor, therefore paving the way for developing specific OX2 receptor antagonists.

We then moved onto Suvorexant, a drug which is currently approved in Japan, the US and Australia for insomnia. We learned how it was originally approved in the US, to subsequently be ‘scrapped’ by the FDA due to its indicated high-dose which led to driving impairment 11h after administration, owing to its 12-hour half-life. Interestingly, patients were entirely unaware that they were impaired the morning after. After further testing, Suvorexant was re-approved by the FDA for insomnia in 2014, at a lower dose.

Professor Anne Lingford-Hughes (London): Relevance of orexins for addiction.

Our next speaker was Professor Lingford-Hughes, who works clinically in addiction services. In this talk, she focused on addiction and the “journey out, rather than vulnerability in”. Studies show that orexin A increases neuronal firing in the ventral tegmental area and increases consumption of ethanol, without associated increases in food or water consumption. This effect is blocked by an OX1/OX2 antagonist, Almorexant. Similar observations are reported for cocaine and heroin. For example, Suvorexant, an orexin antagonist, reduces use of cocaine pre-clinically.

In addition, low-dose ethanol increases orexin mRNA in the perifornical lateral hypothalamus, however higher-dose ethanol has no effect, perhaps suggesting that there is a negative feedback mechanism in play.

Furthermore, OX1 antagonists have been shown to block operant responding for alcohol, and can also block olfactory-cue-induced responding.

Encouragingly, orexins are included on NIDA’s ‘top 10 most wanted for addiction treatment’, a compilation of promising targets to tackle the opioid crisis. This is supported by evidence in mice that shows orexin knockout animals show far reduced opiate withdrawal symptoms. Taken together, this evidence suggests that the orexinergic system is a promising area for development in the field of addiction treatment.

Dr Paul Reading (Middlesbrough): Relevance of orexins for sleep disorders.

This symposium ended with Dr Reading describing the condition of narcolepsy and its clinical presentation. We were pointed towards a paper published in Nature in 2018 by Latorre and colleagues, providing the best evidence to-date that narcolepsy is an auto-immune condition, as it showed that CD4+ memory T-cells, specific for antigens found on orexinergic neurons, are found in patients with narcolepsy.

Dr Reading described that narcolepsy is a dysregulation of sleep architecture, without an overall increase in time taken sleeping. Other characteristics include an increased prevalence of parasomnia (talking or walking in sleep), and of restless legs syndrome. In addition, many patients report very vivid or disturbing dreams, which become confused with reality and are typically well-remembered.

The final, most specific symptom of narcolepsy is cataplexy, an abrupt loss of muscle tone due to intrusion of REM paralysis. During these episodes, awareness if fully maintained, and it is quite often induced by laughter or by excited anticipation. Dr Reading showed us some fascinating examples of this symptom occurring in patients of varying ages.

Bringing the topic back to orexins, Dr Reading told us that narcolepsy (particularly type 1), is diagnosed primarily by very low CSF levels of orexins. Healthy controls would have orexin levels of around or above 300 pg/mL, however patients with narcolepsy would show levels below 100 pg/mL, or even 50 pg/mL. This is not surprising given that narcolepsy is an almost complete loss of the 70,000 orexinergic cells in the human nervous system, and requires further understanding to develop effective treatments.

This symposium gave us some very interesting insights into the orexinergic system and its potential benefits in a wide range of conditions. This seems to be an exciting area for drug discovery, and I look forward to seeing what happens over the coming years.

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