Orexin plays a role in promoting wakefulness, regulates sleep-wake homeostasis, and contributes to circadian rhythm control. Orexin signaling peaks during wakefulness and subsequently decreases during slow-wave and REM sleep (27). PSG studies have demonstrated that orexin-A has a stabilizing effect on nocturnal sleep in a large clinical sample of patients with hypersomnia, and different cerebrospinal fluid (CSF) orexin-A levels correlate with nocturnal sleep/wake rhythms (28). Deficiency, loss, and disruption of signaling in orexin neurons can lead to sleep disorders. Research indicates that patients with reduced CSF orexin-A levels showed shortened mean sleep latency (29) and orexin-A deficiency leads to REM sleep disturbances in patients with narcolepsy (30). Narcolepsy type 1 (NT 1) results from the loss of orexin neurons, leading to low levels of orexin neuropeptides in the brain. In a clinical trial investigating this disorder, Evans et al. found that the OX2R agonist danavorexton significantly improved subjective somnolence in NT 1 participants, dose-dependently increased arousal in NT 1 patients, and effectively treated drowsiness symptoms, although the study noted mild side effects associated with the treatment (31). Suvorexant is a novel orexin receptor antagonist that induces and maintains sleep clinically used in treating insomnia. Herring et al. found that patients treated with suvorexant exhibited greater improvements in subjective and objective PSG measures of sleep onset and sleep maintenance compared to the placebo group in a clinical trial for insomnia treatment. However, in assessing drug safety, patients treated with suvorexant presented mild to moderate somnolence (32). Whether it is suvorexant for insomnia or danavorexton for drowsiness, these findings provide evidence for the role of orexin in the treatment of sleep disorders.

In animal studies, Hung et al. found that the ablation of orexin neurons in the mice brain reduced arousal and resulted in a narcolepsy-like phenotype (33). Murillo-Rodriguez et al. damaged orexin neurons with a neurotoxin in rats and observed that these rats woke up less during the night and had more REM sleep, which is consistent with reduced orexin function (34). Mieda et al. discovered that orexin neuron-ablated mice exhibited narcolepsy, and central administration of orexin-A significantly suppressed cataplectic behavioral arrests and increased wakefulness in these mice (35). Evans et al. (31) found that danavorexton administration increased arousal and reduced arousal fragmentation in orexin/ataxin-3 mice (a narcoleptic mouse model with postnatal hypocretin/orexin cell death) during the active/wakeful period. Furthermore, observations on its pharmacodynamics have informed study design and dose selection for NT 1 cohorts in human studies using intravenous infusion. Additionally, the orexin receptor antagonist suvorexant can promote sleep by blocking OX1R and OX2R (36). Orexin receptor antagonists and agonists provide a novel treatment for sleep disorders, opening new therapeutic avenues in the treatment of PMS/PMDD. The pharmacological role of these drugs in treating sleep disorders in patients with PMS warrants further exploration. These studies offer insights into the treatment of PMS sleep disorders, suggesting that orexin may be a potential target for therapy. However, the distribution and specific mechanisms of orexin and its receptors in PMS/PMDD have not been fully elucidated and may be related to the interaction of orexin with neurotransmitters, such as 5-HT, noradrenaline, acetyl-choline, GABA, and dopamine, etc. Large-scale preclinical and clinical trials are needed to further explore the relevant mechanisms.

Patients with PMS and PMDD are characterized by affective disorders, including anxiety and depression, with depressed mood being the main symptom in patients with PMDD (37). Therefore, alleviating mood symptoms is crucial for PMS. The current drugs of choice for the treatment of PMS/PMDD are first-line antidepressants, namely selective serotonin reuptake inhibitors (SSRIs). However, these drugs’ tolerability and dose-dependent nature of adverse effects limit their widespread clinical use (38). In recent years, research on orexin’s ability to alleviate depressive symptoms has been increasingly recognized and validated in preclinical trials (39). Reduced orexin levels are associated with depressed mood in depressed patients (40). Lu et al. also revealed significant gender-related changes in orexin in the hypothalamus of depressed patients, with female patients showing more pronounced orexin immunoreactivity (41). Research and development of drugs targeting orexin signaling is well established (42, 43) and has shown promise in animal experiments. The Orexin system appears to be a promising target for treating the symptoms of PMS/PMDD.

In addition to changes in mood, patients with PMDD report impairments in cognitive abilities, including attention, memory, and motor coordination (56). Negative cognitive styles, such as a general negative expectancy for future events and the feeling of having no influence over them, are important factors in the pathogenesis of PMS/PMDD (57). PMDD shares similarities with major depression regarding cognitive vulnerability, and cognitive deficits are well-established in MDD. In a survey of 14 women with PMDD, Reed found that during the luteal phase, women with PMDD exhibited decreased performance on immediate and delayed word recall tasks, immediate and delayed digit recall tasks, and digit symbol replacement tests compared to controls (58). The working memory (WM) system temporally stores and processes information used to guide behavior and includes four subsystems: central execution, visuospatial storage, speech storage, and episode buffering. Yen et al. (59) first demonstrated reduced WM and cognitive control in PMDD patients during premenstrual GO/Nogo tasks, which was relieved during the follicular phase, consistent with abnormal mood and somatic symptoms. Slyepchenko et al. found persistent, subtle WM and selective attention difficulties during the follicular phase of the menstrual cycle in patients with moderate to severe PMS (60). There is also evidence that ovarian hormones are associated with emotional and cognitive processing and affect the cognitive abilities of women with PMDD during the menstrual cycle (61, 62).

Orexin plays an important role in cognitive regulation. It improves cognitive deficits in rats by addressing deficits in neurotransmission (63). Intranasal administration of [Ala11, D-Leu15]-OXB increased c-fos expression (a reliable marker for neural activity) in cortical and basal forebrain areas as well as medial septal cholinergic neurons. Orexin-A also activated a wider range of cortical areas and basal forebrain cholinergic neurons. In addition, intranasal orexin-A significantly reversed the changes produced by sleep deprivation on local brain changes in cerebral metabolic rate for glucose consumption (CMRglc) in rhesus monkeys during delayed match-to-sample task execution more effectively than intravenous injection (64). In orexin/ataxin-3 narcoleptic mice, Yang et al. found that they showed deficits in long-term social memory. Nasal administration of exogenous orexin-A restored social memory to some extent in AT mice, which was associated with enhanced hippocampal synaptic plasticity and cAMP response element binding protein phosphorylation (65). In conclusion, these findings provide strong evidence for the effectiveness of orexin in improving cognitive deficits.

During the menstrual cycle, estrogen levels are low during menstruation, gradually rise during ovulation, and then fall gradually during the luteal phase. On the other hand, progesterone levels remain low throughout the follicular phase, experience a rapid increase after ovulation, and then decrease quickly during the late luteal phase (66). These fluctuations in hormone levels may significantly contribute to mood swings experienced by women. Numerous studies have underscored the impact of estrogen and progesterone on depression, anxiety, and other mood disorders in women, implicating abnormal hormone fluctuations as crucial mechanisms in the development of premenstrual depression (67). Different from healthy women, those with PMS exhibit lower estrogen levels and higher progesterone levels. It has been found that the rapid withdrawal of ovarian hormones is likely pivotal in the pathogenesis of PMDD (68). Women with PMDD have demonstrated lower early luteal estrogen levels compared to controls, and covariate analysis demonstrates that the interaction between early luteal phase estrogen and progesterone levels correlates with PMDD severity (69). Both preclinical and human research have illustrated that the cessation of ovarian steroids (estrogen, progesterone, or both) can trigger emotional, cognitive, and behavioral symptoms associated with suicide in susceptible individuals (70). The link between allelic variants in the estrogen receptor alpha gene and PMDD demonstrated by Huo et al. was the first finding revealing genetic alteration in the background of this disorder. ERα’s involvement in the etiopathogenesis and treatment of PMDD, through its regulation of neurotransmitter system signal transduction, underscores its potential significance (71). In addition, Pakharenko et al. have verified that polymorphic variants in the estrogen receptor 1 (ESR1) A-351G gene can serve as markers for the development of PMS (72). Intriguingly, estrogen-mediated signaling also plays a significant role in the activation of neural circuits associated with social cognition and emotion regulation (62). In conclusion, these studies demonstrate the relevance of ovarian hormones to PMS/PMDD. However, it is important to acknowledge that the production of hormones and their actions in the body involve complex molecular mechanisms; consequently, ovarian hormone therapy is not merely about controlling estrogen and progesterone levels, necessitating further comprehensive investigations.

The transcription and translation of prepro-orexin mRNA take place in the hypothalamic region, a crucial locus for the generation of orexin neurons and the primary origin of the hypothalamic-pituitary-gonadal axis (HPG). Consequently, it is plausible that the regulation of behavioral and stress responses in the hypothalamus may be intricately linked to the coordinated interactions among the E2, progesterone, and orexin systems (73). Orexin neurons play an essential role in the regulation of the HPG axis and sexual behavior (74, 75). Research by Cataldi et al. indicates that both orexin-A and orexin-B diminish progesterone secretion in luteal cells, suggesting a modulatory role for the orexin system within the ovary (76). Notably, both in vivo and in vitro investigations have revealed that orexin-A inhibits luteinizing hormone-releasing hormone (LHRH)-stimulated LH release in the dispersed anterior pituitary of proestrus female rats in a dose-dependent manner (75). The hormonal secretion during the rodent estrous cycle appears to correlate with appropriate nutritional status and alertness. It has been demonstrated that orexin governs luteinizing hormone-releasing steroids, nutritional status, and alertness in an interdependent fashion, thus hinting at a possible coordinating function for orexin throughout the estrous cycle (77). Similarly, Kiezun et al. explored alterations in the estrous cycle and early pregnancy in the pig uterus concerning estrogen E1 and E2 emphasizing the orexin system’s role as a “molecular switch” for estrogen activation (78). In conclusion, this body of evidence suggests that orexin may have therapeutic effects in PMS/PMDD through its modulation of ovarian hormones. However, for PMS, there exists inconsistency in the results pertaining to hormone expression levels despite the increasing recognition of the trend toward lower estrogen levels and higher progesterone. Furthermore, the molecular activity and downstream signaling pathways of orexin in the context of intricate hormonal mechanisms remain largely unelucidated, necessitating comprehensive mechanistic studies.

Emerging trends in neuroendocrinology indicate a connection between inflammatory processes and both mental and somatic disorders sharing common features with PMS/PMDD. Low-level inflammation has been associated with alterations in mood and pain. In a study investigating the correlation between changes in physical and psychological symptoms and inflammatory markers during the menstrual cycle in normal weight and overweight women. Puder et al. discovered that variations in tumor necrosis factor-α (TNF-α) and high-sensitivity C-reactive protein serum concentrations were associated with physical and psychological symptoms experienced during the menstrual cycle (79). Another investigation focusing on the association between inflammatory markers and the severity of menstrual symptoms and PMS among young women revealed that mean levels of interleukin 4, interleukin 10 (IL-10), interleukin 12, and Interferon-gamma were significantly elevated in women meeting PMS criteria compared to healthy women (80). In a comprehensive review by Hantsoo et al. on the epidemiology and treatment of PMS, it was suggested that inflammatory molecules may contribute to the pathobiology of PMDD (81). Furthermore, in a survey involving 21 healthy women with regular menstrual cycles, plasma IL-10 levels were notably higher in women experiencing PMS compared to their healthy counterparts (82). Cumulatively, these findings provide substantial preliminary evidence supporting a potential link between neuroinflammation and the etiology of PMS (83).

Orexin neurons play an important role in neuroprotection, primarily through the inhibition of inflammatory responses mediated by OX1R and OX2R (84). Experimental findings demonstrated that diminished orexin signaling plays a crucial role in mediating inflammation-induced drowsiness (85). Clark et al. proposed that the activity of orexin neurons is suppressed by the inflammatory cytokine TNF, which has the capacity to degrade orexin precursor mRNA in a time- and dose-dependent manner (86). In a study by Modi et al., utilizing intranasal orexin in a rat model of cardiac arrest (CA), it was revealed that CA led to increased pro-inflammatory markers across all brain regions. Treatment with orexin-A significantly ameliorated CA-induced neuroinflammatory markers in the hypothalamus, increased the production of OX1R and OX2R, exerted anti-inflammatory effects, and expedited cortical EEG and behavioral recovery (87). Additionally, Zhang et al. found that orexin-A effectively dampened endothelial cell inflammation by inhibiting mitogen-activated protein kinases p38 and nuclear factor kappa-B (NF-κB) inflammatory signaling pathways (88). In an investigation into the molecular mechanisms by which orexin-A reduces cerebral ischemia/reperfusion injury, Xu et al. observed that orexin-A confers neuroprotective effects by inhibiting OX1R-mediated NF-κB, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase, and MAPK/p38 signaling pathways, and by suppressing astrocyte apoptosis, activation, and the generation of inflammatory factors such as interleukin 1β (IL-1β), TNF-α, and interleukin 6 (IL-6) (89). Moreover, examining the physiological function of orexin-A in fibroblast-like synoviocytes, Sun et al. found that orexin-A treatment resulted in reduced secretion of IL-1β, IL-6, and interleukin 8, decreased production of reactive oxygen species, and inhibited TNF-α-induced activation of the NF-κB signaling pathway, thus demonstrating an important role in neuroprotection (84). This body of evidence reveals the antagonistic relationship between orexin and inflammatory cytokines, underscoring the potential of orexin’s anti-inflammatory effect as a promising new target for the treatment of PMS/PMDD.

Gamma-aminobutyric acid (GABA) serves as the predominant inhibitory neurotransmitter in the human cortex and plays a pivotal role in regulating salience plasticity, sleep, and mood (90–92). Patients diagnosed with PMS often demonstrate alterations in GABA-α receptor sensitivity and GABA concentration, exhibiting reduced plasma GABA levels during the late luteal phase, particularly in cases of premenstrual anxiety (93). Fluctuations in steroid hormone levels can influence the structure and function of the GABAA receptor (GABAAR), impacting the expression levels of GABAARγ-2 and delta subunits, which are closely associated with the pathophysiology of PMS (94, 95). In a study by Zhang et al., analysis of GABA receptor subunit expression patterns in a rat model simulating clinical PMDD symptoms revealed notable differences in the expression of GABAAR α1, α2, α4, α5, β2, β3, and δ subunits among PMDD rat models with distinct characteristics, suggesting their potential as biomarkers for PMDD pathogenesis (96). Furthermore, experimental findings by Iba et al. indicated that the Japanese herb Inochinohaha White increased the b2-subunit of the GABAA receptor in the amygdala, attenuating anxiety-like behavior in a rat model of progesterone withdrawal through augmentation of the GABAA receptor-mediated signaling pathway (97). Similarly, the Chinese medicinal preparation Shuyu capsule, utilized for treating PMS and comprising active ingredients extracted from four Chinese medicines (bupleurum chinense, white paeony root, radix glycyrrhizae, and rhizoma cyperi), reversed the decrease in glutamate to GABA ratio in the right hippocampus of a rat model of premenstrual depression (98). These investigations provide encouraging evidence for the relationship between the GABA system and PMS, warranting further exploration of GABA as an effective therapeutic target for PMS.

GABA and glutamate neurons are distributed in the reticular core of the brain, where they play a crucial role in regulating cortical activity and behavior during the wake-sleep state. These in turn are modulated by acetylcholine, noradrenaline, dopamine, serotonin, histamine, orexin, and the melanin-concentrating hormone neurons (99). The interplay between orexin and GABA neurotransmission is particularly significant in sleep and mood regulation. Ji et al. found that orexin neurons have direct projections to GABA neurons in the ventral pallidum, enabling them to modulate GABA depolarization via OX1R and OX2R. Knockdown or pharmacological blockade of orexin receptors led to a decrease in peak current in GABA neuron cells. Furthermore, exogenous orexin was found to activate GABA neurons via OX1R and OX2R thereby ameliorating depressive-like behavior in rats (46). Moreover, postsynaptic OX2R activation has been shown to stimulate Na/Ca2 exchange currents in GABA neurons, resulting in heightened membrane depolarization, increased firing rates, and augmented GABA release (100). Similarly, Brevig et al. demonstrated that intracerebral pontine reticular formation injection of orexin-A in rats led to an increase in consolidated wakefulness through the activation of GABAA receptors and OX1R, ultimately promoting arousal (101). Orexin has been found to enhance neuronal plasticity via its modulation of GABA neuron release, exerting selective influence on sleep/wake control within the brain (102), and contributing to the regulation of mood changes. This evidence suggests that the activation of GABA by orexin may represent a potential target for the treatment of PMS/PMDD.