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Gene & Protein in Disease Orexin in depression

pathways in the pathogenesis of neurological conditions. awakening. Stimulating OX2R improves resilience to
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Reportedly, the orexin/receptor system can be investigated social stress, anxiety, and depression, whereas inhibiting
as a promising treatment focus for substance use OX2R promotes susceptibility to these conditions. OX2R
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disorders. Moreover, the pathophysiology of MDD agonists have been demonstrated to promote psychological
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involves increased orexin signaling, although the precise elasticity and antianxiety and antidepressant behaviors.
relationship between the orexinergic system and depressive Insomnia is often related to depression, and considering
symptoms remains unclear. OXA is related to the HPA axis, insomnia is a prevalent symptom of depression, OX2R
which regulates the stress system and response. A study antagonists may provide valuable therapeutic options for
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investigated the potential antidepressant-like effects of individuals with MDD. Seltorexant is a selective OX2R
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treating mice exposed to unanticipated chronic moderate antagonist, developed for treating MDD, and possesses
stress by blocking orexin receptors, as well as the underlying sleep-promoting properties. 115,116 The pathophysiology of
mechanisms. The findings indicate that the drug blocking MDD includes overawakening. By selectively blocking the
the orexin system can exert strong antidepressant effects human OX2R, seltorexant can reduce the symptoms of
and induce the recovery of stress-related HPA axis defects depression by normalizing excessive arousal. Seltorexant
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independent of neurogenic effects. 50 is a potential option for treating depression and anxiety
considering that its use is safe and that it exerts no
As mentioned earlier, the orexin system includes two
neuropeptides (OXA and OXB) and two G-protein- obvious or substantial adverse effects from a therapeutic
viewpoint.
To assess whether a potent selective OX2R
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coupled receptors (OX1R and OX2R). Orexin receptor
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antagonists are a novel class of psychotropic drugs for antagonist – TCS OX2 29 (TCS) – exerts a positive effect
treating insomnia and other psychiatric disorders such as in an animal model of detrusor overactivity coexisting
depression. Moreover, orexin receptor antagonists have with depressive-like states in male rats, a related study
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conducted FST to measure the spontaneous locomotor
therapeutic potential for mood disorders by modulating activity, conscious cystometry, and c-Fos expression in
the expression of neuropeptides in the hypothalamus central micturition areas of rats and performed several
and limbic system. The potential of orexin receptor biochemical analyses. Therefore, TCS (3 mg/kg/
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antagonists, including dual OX1/2R antagonists (DORAs), day, subcutaneous injection) administered for 7 days
selective OX1R antagonists (SORA1s), and selective normalized the cystometric parameters corresponding
OX2R antagonists (SORA2s), in treating depression to the overactivity of the detrusor and reversed the
will be reviewed subsequently. An analysis of preclinical predepressive responses; this finding opens up a novel
and clinical data demonstrated that although SORA1s perspective on the role of the orexin system in bladder
have the potential to treat drug addiction and anxiety, function and the pathophysiology of depression.
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SORA2s and DORAs exhibit great efficacy in treating sleep
disorders and even depression. 108 DORAs treat insomnia 119,120 by inducing drowsiness,
which is achieved by blocking the wake-up-promoting
Existing evidence shows that for emotional behavior,
OX1R and OX2R may have opposite functions. OX1R effect of orexin neuropeptides. Several randomized clinical
trials have demonstrated the effectiveness of DORAs in
primarily promotes anxiety and depression, and the major effectively treating chronic insomnia. 121,122 Suvorexant –
potential of drug treatment related to OX1R is to block which acts as an antagonist of orexin receptors – is used
anxiety and depressive behaviors through antagonists. in clinical practice for treating insomnia. This treatment
The effect of the intraperitoneal injection of the OX1R is based on the association between hyperactivity of the
antagonist SB334867 on depression in mice was explored orexin system and sleep disorders. A novel dual orexin
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using the number of crossings of FST, tail suspension receptor antagonist – daridorexant (ACT-541468) – is
experiment, and wilderness experiment, revealing that being investigated for treating sleeplessness, a common
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SB334867 exerted an antidepressant-like effect because co-occurring condition with anxiety and depression. 124-127
it reduced the immobility duration in the FST without In addition to treating insomnia, it treats cardiovascular
affecting the locomotor behavior. problems, chronic obstructive pulmonary disease, and
Orexin neuropeptides stabilize arousal, and several Alzheimer’s disease. Existing evidence provides valuable
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orexin receptor antagonists have been approved for insights into the real-world safety profile of daridorexant,
treating insomnia in adults. OX2R is gaining recognition supporting the presence of safety concerns related to
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as a novel therapeutic target for addressing persistent nightmares, depression, and hangovers. Almorexant is
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insomnia in individuals with depression. OX2R is deeply a DORA that exerts sleep-enabling effects in humans.
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involved in controlling alertness, arousal, and sleep–wake Almorexant can inhibit the effects of OXA, which improves
cycles. Insomnia is often the result of physiological over with its increasing concentrations. In a previous study,
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Volume 4 Issue 2 (2025) 13 doi: 10.36922/gpd.4210