Wakefulness and vigilance levels are required for maintaining purposeful activities and motivated behaviours, which are often triggered by sensory information conveying external cues. An increasing body of work has suggested that orexins (also known as hypocretins)--a pair of neuropeptides that are crucial for maintaining wakefulness - are also involved in the regulation of motivated behaviours, including feeding, emotional behaviour and reward seeking, and that these functions are mediated by two subtypes of orexin receptors. Autonomic and endocrine responses, which accompany these motivated behaviours, are also influenced by the orexin system. Orexin-producing neurons act as a hub that links information about the internal and external environments of an animal to vigilance levels and internal bodily functions to support various motivated behaviours.

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The role of orexin in motivated behaviours

Distribution of orexin neurons in the adult rat brain

Orexin deficiency results in narcolepsy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. However, orexin neurons are ‘multi-tasking’ neurons that regulate sleep/wake states as well as feeding behavior, emotion, and reward processes. Orexin deficiency causes abnormalities in energy homeostasis, stress-related behavior, and reward systems. Orexin excites waking-active monoaminergic and cholinergic neurons in the hypothalamus and brain stem regions to maintain a long, consolidated waking period. Orexin neurons also have reciprocal links with the hypothalamic nucleus, which regulates feeding. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues suggests that these neurons have an important role as a link between energy homeostasis and vigilance states. The link between orexin and the ventral tegmental nucleus serves to motivate an animal to engage in goal-directed behavior. This review focuses on the interaction of orexin neurons with emotion, reward, and energy homeostasis systems. These connectivities are likely to be highly important to maintain proper vigilance states.

Role of orexin in modulating arousal, feeding, and motivation

The hypocretins (Hcrts), also known as orexins, are two peptides derived from a single precursor produced in the posterior lateral hypothalamus. Over the past decade, the orexin system has been associated with numerous physiological functions, including sleep/arousal, energy homeostasis, endocrine, visceral functions and pathological states, such as narcolepsy and drug abuse. Here, we review the discovery of Hcrt/orexins and their receptors and propose a hypothesis as to how the orexin system orchestrates these multifaceted physiological functions.

Linked ArticlesThis article is part of a themed section on Orexin Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-2

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The hypocretins/orexins: integrators of multiple physiological functions

Orexin signaling is essential for normal regulation of arousal and behavioral state control and represents an attractive target for therapeutics combating insomnia. Alternatively termed hypocretins, these neuropeptides were named to reflect sequence similarity to incretins and their potential to promote feeding. Current nomenclature reflects these molecular and biochemical discovery approaches in which HCRT, HCRTR1, and HCRTR2 genes encode prepro-orexin, the orexin 1 receptor (OX(1)) and the orexin 2 receptor (OX(2))-gene names designated by the Human Genome Organization and receptor names designated by the International Union of Basic and Clinical Pharmacology. Orexinergic neurons are most active during wakefulness and fall silent during inactive periods, a prolonged disruption in signaling most profoundly resulting in hypersomnia and narcolepsy. Hcrtr2 mutations underlie the etiology of canine narcolepsy, deficiencies in orexin-producing neurons are observed in the human disorder, and ablation of mouse orexin neurons or the Hcrt gene results in a narcolepsy-cataplexy phenotype. The development of orexin receptor antagonists and genetic models targeting components of the orexin pathway have elucidated the OX(2) receptor-specific role in histamine-mediated arousal and the contribution of both receptors in brainstem pathways involved in vigilance state gating. Orexin receptor antagonists of varying specificity uncovered additional roles beyond sleep and feeding that include addiction, depression, anxiety, and potential influences on peripheral physiology. Combined genetic and pharmacological approaches indicate that orexin signaling may represent a confluence of sleep, feeding, and reward pathways. Selective orexin receptor antagonism takes advantage of these properties toward the development of novel insomnia therapeutics.

https://pharmrev.aspetjournals.org/content/pharmrev/64/3/389.full.pdf

International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin Receptor Function, Nomenclature and Pharmacology

The crude methanolic extract of the bark of Cerbera odollam Gaertn. was evaluated for its possible antinociceptive and neuropharmacological activities in animal models. At the dose of 250 and 500 mg/kg body weight, the extract showed a significant antinociceptive effect in acetic acid induced writhing in mice comparable to that produced by aspirin, used as standard drug (P

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Antinociceptive and sedative effects of the bark of Cerbera odollam Gaertn.

BACKGROUND AND PURPOSE The rostral ventrolateral medulla (RVLM) maintains sympathetic nerve activity (SNA), and integrates adaptive reflexes. Orexin A-immunoreactive neurones in the lateral hypothalamus project to the RVLM. Microinjection of orexin A into RVLM increases blood pressure and heart rate. However, the expression of orexin receptors, and effects of orexin A in the RVLM on splanchnic SNA (sSNA), respiration and adaptive reflexes are unknown.



EXPERIMENTAL APPROACH The effect of orexin A on baseline cardio-respiratory variables as well as the somato-sympathetic, baroreceptor and chemoreceptor reflexes in RVLM were investigated in urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats (n= 50). orexin A and its receptors were detected with fluorescence immunohistochemistry.



KEY RESULTS Tyrosine hydroxylase-immunoreactive neurones in the RVLM were frequently co-localized with orexin 1 (OX1) and orexin 2 (OX2) receptors and closely apposed to orexin A-immunoreactive terminals. Orexin A injected into the RVLM was pressor and sympatho-excitatory. Peak effects were observed at 50 pmol with increased mean arterial pressure (42 mmHg) and SNA (45%). Responses to orexin A (50 pmol) were attenuated by the OX1 receptor antagonist, SB334867, and reproduced by the OX2 receptor agonist, [Ala11, D-Leu15]orexin B. Orexin A attenuated the somato-sympathetic reflex but increased baroreflex sensitivity. Orexin A increased or reduced sympatho-excitation following hypoxia or hypercapnia respectively.



CONCLUSIONS AND IMPLICATIONS Although central cardio-respiratory control mechanisms at rest do not rely on orexin, responses to adaptive stimuli are dramatically affected by the functional state of orexin receptors.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2011.01694.x

Orexin A in rat rostral ventrolateral medulla is pressor, sympatho- excitatory, increases barosensitivity and attenuates the somato- sympathetic reflex

BACKGROUND Intrathecal (i.t.) injection of orexin A (OX-A) increases blood pressure and heart rate (HR), but the effects of OX-A on sympathetic and phrenic, nerve activity, and the baroreflex(es), somato-sympathetic and hypoxic chemoreflex(es) are unknown.



EXPERIMENTAL APPROACH Urethane-anaesthetized, vagotomized and artificially ventilated male Sprague-Dawley rats were examined in this study. The effects of i.t. OX-A (20 nmol 10 µL−1) on cardiorespiratory parameters, and responses to stimulation of the sciatic nerve (electrical), arterial baroreceptors (phenylephrine hydrochloride, 0.01 mg kg−1 i.v.) and peripheral (hypoxia) chemoreceptors were also investigated.



KEY RESULTS i.t. OX-A caused a prolonged dose-dependent sympathoexcitation, pressor response and tachycardia. The peak effect was observed at 20 nmol with increases in mean arterial pressure, HR and splanchnic sympathetic nerve activity (sSNA) of 32 mmHg, 52 beats per minute and 100% from baseline respectively. OX-A also dose-dependently increased respiratory drive, as indicated by a rise in phrenic nerve amplitude and a fall in phrenic nerve frequency, an increase in neural minute ventilation, a lengthening of the expiratory period, and a shortening of the inspiratory period. All effects of OX-A (20 nmol) were attenuated by the orexin receptor 1 antagonist SB 334867. OX-A significantly reduced both sympathoexcitatory peaks of somato-sympathetic reflex while increasing baroreflex sensitivity. OX-A increased the amplitude of the pressor response and markedly amplified the effect of hypoxia on sSNA.



CONCLUSIONS Thus, activation of OX receptors in rat spinal cord alters cardiorespiratory function and differentially modulates sympathetic reflexes.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.2010.01102.x

Intrathecal orexin A increases sympathetic outflow and respiratory drive, enhances baroreflex sensitivity and blocks the somato-sympathetic reflex

The hypothalamic peptide orexin plays a role in many physiological systems including feeding behavior, sleep–wakefulness, reward system, stress, and nociception. In addition, it is now clear that orexin is involved in the central regulation of cardiorespiratory function. Here, we review the cardiorespiratory effects elicited by central orexin and consider the physiological role of this peptide in central cardiorespiratory control in normal and pathophysiological states. Orexin neurons are found exclusively in the hypothalamus but project to almost all brain regions including cardiorespiratory regulatory areas, where their receptors are also expressed. Administration of orexin into the nucleus tractus solitarius, rostral ventrolateral medulla, rostral ventromedial medulla, and spinal cord increases blood pressure, heart rate, and sympathetic nerve activity. Orexin neurons stimulate respiration and are sensitive to changes in pH. Orexin knockout mice have apnoeic episodes in sleep. Therefore, orexin may be a potentially important therapeutic target for the treatment of cardiorespiratory disorders.

Orexin and central regulation of cardiorespiratory system.

SUMMARY The MeOH extract of seeds of Cerbera odollam Gaertn. (Apocynaceae) was screened for its antibacterial,cytotoxic and neuropharmacological activities. The extract showed moderate anti-bacterialactivity against Salmonella typhi, Streptococcus saprophyticus, and Streptococcus pyogenes. It exhibitedhigh level cytotoxicity against brine shrimp (LC 50 : 3 µg/ml). The extract potentiated pentobarbitalinduced sleeping time in mice which was further supported by the exploratory behavior test atdose of 25 mg/kg. The overall results tend to suggest the antibacterial, cytotoxic and CNSdepressant activities of the extract. Key words: Cerbera odollam; Antibacterial activity; Cytotoxic activity; CNS depressant activity INTRODUCTION Cerbera odollam Gaertner (pink-eyed cerbera, yellow-eyed cerbera, odollam tree), also sometimes calledCerbera manghas L, belongs to the notoriously poisonousApocynaceae family, which also includes theyellow oleanders (Thevetia peruviana and Thevetianerifolia) and common oleanders (Nerium oleanderand Nerium indicum). The C. odollam tree grows toa height of 6 - 15 m and has dark green fleshylanceolate leaves. The large white flowers have adelicate perfume, reminiscent of jasmine. Thefruit, when still green, looks like a small mango,with a green fibrous shell enclosing an ovoidkernel measuring approximately 2 cm × 1.5 cmand consisting of two cross-matching white fleshyhalves. On exposure to air, the white kernel turnsviolet, then dark grey, and ultimately brown orblack. The plant as a whole yields a milky whitelatex. The tree grows in coastal salt swamps andcreeks in south India (particularly abundantlynear the canals and backwaters of Kerala) andalong riverbanks in southern and central Vietnam,Cambodia, Sri Lanka, Bangladesh and Myanmar.In Bangladesh the plant is known as Dabur,Dhakur or Um-dabur. The seeds have a longhistory as an ordeal poison in Madagascar, due tothe highly toxic cardiac glycosides they contain.The seeds contain non-siccative oil, producing ashining flame with a pleasant nut-like odour. TheBurmese use it for lighting, as a cosmetic, ormixed with other oils as an insecticide or insect-repellent (Chopra et al., 1956). The bark and leavesof the plant are traditionally used as emetic andcathartic; kernels are used as emetic; fruit is usedas a cure for hydrophobia (Kirtikar and Basu,1987). Its bark and fruits are purgative and used

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IZ Shahid

Papers

Antinociceptive and sedative effects of the bark of Cerbera odollam Gaertn.

Orexin A in rat rostral ventrolateral medulla is pressor, sympatho- excitatory, increases barosensitivity and attenuates the somato- sympathetic reflex

Intrathecal orexin A increases sympathetic outflow and respiratory drive, enhances baroreflex sensitivity and blocks the somato-sympathetic reflex

Orexin and central regulation of cardiorespiratory system.

Antibacterial, cytotoxic and neuropharmacological activities of Cerbera odollam seeds