LAUSR

Over the past century, a huge amount of evidence has emerged pointing to the role of the neurotransmitter serotonin, the neuropeptides orexin A and B, and the small gaseous molecule nitric oxide (NO) (Fig. 1) as crucial regulators of both physiological functions and diseases of the central nervous system (CNS) and peripheral organs as well (Berger et al., 2009; Zhou and Zhu, 2009; Shekhar, 2012). Serotonin, orexins, and NO produced in the brain centrally regulate a great number of neural activities including synaptic plasticity, sleep–wake cycle, energy balance, food intake, hormone secretion, immune responses, cardiovascular functions, and others (Szczepanska-Sadowska et al., 2010; Hu and Zhu, 2014; Shan et al., 2015). Interestingly, these regulatory factors are even involved in the complex neurobiological phenomenon relying on trust, belief, pleasure, and reward activities such as love (Esch and Stefano, 2005). They play major roles in the control of partner preference, sexual desire, erection, copulation, ejaculation, orgasm, and sexual satiety. Serotonin, orexins, NO, and their synthetic and signaling machineries are not limited to the neural tissues and brain, but they are also expressed in peripheral tissues, where their prominent role begins from the time of the morphogenesis in utero and lasts through all of adult life. Peripheral locally produced serotonin, orexins, and NO regulate cardiovascular system physiology, bowel motility, steroidogenesis in the adrenal glands and the genital tract, urethrogenital reflex, vascular smooth muscle contractility, platelet aggregation, immunity, and many other physiological processes (F€ orstermann and Sessa, 2012; Amireault et al., 2013; Li et al., 2014). The regulatory activities of the three neuromodulators depend on the place of their release and the availability of specific receptors; thus, they may exert either stimulatory or inhibitory effects depending on the site of action. An elevated number of disorders affecting either CNS or peripheral organs including psychiatric (depression, alcoholism, suicidal behavior, schizophrenia, autism), neurological (Alzheimer, Huntington, and Parkinson diseases), neuroimmune, and cardiovascular diseases, metabolic pathologies (diabetes, obesity, anorexia), gastrointestinal diseases (e.g., irritable bowel syndrome, Crohn disease, functional dyspepsia), tumors, sexual dysfunctions, and many other human pathologies have been associated with deregulation of serotonin and/or orexin and/or NO systems. To date, the majority of studies aimed at investigating the pathogenesis of the above diseases have mainly focused on highlighting the critical role of a single neuromodulator of the three, well establishing the molecular mechanisms underlying its action. By contrast, a notably low number of studies have been devoted to clarifying the mutual interactions among the three players in a specific physiological and/or pathological condition. Few examples include the evidence of a functional link among serotonin, orexin, and NO systems in the regulation of sleep and wakefulness (Monti, 2010), sexual behavior and drug addiction (Hull, 2011), migraine (Goadsby, 2005; Tso and Goadsby, 2014), gastrointestinal disorders (Okumura and Nozu, 2011; Szlachcic et al., 2013; Vermeulen et al., 2014), and neuropathic pain (Gilron and Dickenson, 2014). On the other hand, the occurrence of an interplay among serotonin, orexin, and NO systems in human health and disease is supported by the recurrent coincidence of different disorders that are mainly ascribed to the dysfunction of one of the three neuromodulator action,