orexin

Introduction

orexin (aka hypocretin) are a pair of peptide neurotransmitters derived from the cleavage of prepro-orexin that were discovered in 1998
orexin-A consists of 33 amino acids with two disulfide bridges
orexin-B is a linear peptide of 28 amino acids
they are exclusively produced by a cluster of “orexin neurons” in the hypothalamus that encircles the fornix and extends across the lateral hypothalamus

there are less than 80,000 orexin neurons but fibers reach nearly all parts of the central nervous system, influencing multiple arousal and reward centers
some of the heaviest projections are to nuclei that regulate arousal and motivation, including the noradrenergic neurons of the locus coeruleus, the histaminergic neurons of the tuberomammillary nucleus (TMN), the serotonergic neurons of the raphe nuclei, and the dopaminergic neurons of the ventral tegmental area (VTA) ¹⁾
they receive strong inputs from brain regions that mediate responses to stress and autonomic tone such as the amygdala and insular cortex, as well as from nuclei that regulate reward and motivation such as the nucleus accumbens and VTA
information related to circadian rhythms and the timing of wakefulness may influence the orexin neurons via the dorsomedial nucleus of the hypothalamus (DMH)

stabilize wakefulness and prevent inappropriate transitions into sleep or REM states
- become silent during REM and non-REM sleep
- loss of these neurons results in Type 1 narcolepsy
  - dual orexin receptor antagonists (dual orexin-A and orexin-B antagonists (Doras)) block orexin signaling to help patients with insomnia fall and stay asleep
  - stimulate appetite, drive food intake, and influence energy expenditure
  - increase heart rate, blood pressure, and behavioral reactions to acute stress
  - in is thought that inappropriate activation of the orexin neurons at night could contribute to insomnia because people with insomnia frequently exhibit signs of hyperarousal such as increased metabolic rate and sympathetic tone
moderate motivation and reward-seeking behaviors
- it seems the more effort required to obtain a reward, the stronger the orexin neuron activity becomes and this may reflect how the brain links reward expectation to the effort required to pursue them, and it seems orexin neurons are necessary for sustaining motivated behavior, though simply raising their activity may not be sufficient to increase it²⁾

two orexin receptors - OX1R and OX2R - one for each type of orexin
these are strongly conserved across mammals, with 94% identity in the amino acid sequences between humans and rats
OX1R and OX2R mRNA is widely expressed in the brain in a pattern similar to that of orexin nerve terminals

those with the full narcolepsy phenotype have a ~90% loss of the orexin-producing neurons in addition to a marked reduction in CSF levels of orexin-A

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