Orexin Receptor Antagonists: A New Concept In CNS Disorders?

Gatfield, John; Brisbare‐Roch, Catherine; Jenck, F.; Boss, Christoph

doi:10.1002/cmdc.201000132

Cited by 67 publications

(51 citation statements)

References 115 publications

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“…Micro-injection of OX-A elicited an anti-nociceptive effect reducing A and C fiber responses to dural stimulation and spontaneous activity, in agreement with other analgesia studies whereas interestingly OX-B activation elicited the opposite "pro-nociceptive" effect enhancing nociceptive transmission and convergent sensory responses to facial thermal stimulation [71]. Most recently novel dual OX-1R/OX-2R receptor antagonists that have been developed for the treatment of primary insomnia [72] have been used to probe the pharmacology of the trigeminal system rather than the peptide orexin agonists. The dual orexin antagonists were shown [73] to inhibit electrically evoked trigeminal nociceptive transmission and neuronal activity in the trigeminocervical complex supporting a pro-nociceptive role for orexins in trigeminal pain pathways.…”

supporting

confidence: 85%

Erratum to: Why does Sleep Stop Migraine?

Bigal¹,

Hargreaves

2014

Curr Pain Headache Rep

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The section titled Subcortical Structures Relevant to Migraine involved in Sleep should read as follows:Our comprehension of the physiology of the daily cycles of sleep and wakefulness, as well as the neuronal circuitry and molecular basis of the biological clock that underpins human circadian rhythms (daily sleep-wake cycles), has increased substantially in recent years.The wake promotion systems and the sleep promotion system are temporally controlled by the endogenous circadian pacemaker contained within the suprachiasmatic nuclei (SCN) that functions autonomously as the brain's master clock. The SCN receives information about light and dark periods from melanopsin expressing retinal ganglion cells during the day (the light entrainment system) and melatonin from the pineal gland at night to reset the human 24.5 hour circadian rhythm to our 24 hour day length. The molecular basis of the clock function involves transcriptional and translational regulation of the expression of genes such as period, clock, Bmal and cryptochrome that when mutated or deleted disrupt circadian rhythm cycles [49].Daily oscillations in SCN activity signal through the subparaventricular zone and the dorsal medial hypothalamus to both GABA-ergic neurons of the ventrolateral pre-optic area of the hypothalamus (VLPO) and the wake promoting orexinergic neurons of the lateral hypothalamus. GABA-ergic neurons promote sleep by sending inhibitory projections both to orexin neurons as well as brain stem nuclei such as locus ceruleus (norepinephrine), Raphe nucleus (serotonin) and tuberomamillary nucleus (histamine) that together with cholinergic projections from the basal forebrain form the ascending arousal systems. Attenuation of this inhibitory signal and increased excitatory input from the SCN to orexin secreting neurons that innervate these monoaminergic brain stem arousal nuclei promotes waking and somatosensory function. [50]. Increasing evidence suggests that human circadian rhythms are regulated by a thalamic switch that can be activated or deactivated to regulate sensory information reaching the cerebral cortex and the degree of consciousness [51]. The transition from sleep to wakefulness comes as thalamocortical pathways activate the cortex that has been primed by neurotransmitters (serotonin, histamine, norepinephrine) released from ascending pathways originating in the brain stem. The extent of information passing to the cortex through the thalamus is "gated" based on the arousal level of the central nervous system that is in turn set by outputs from the reticulo-activating systems (RAS) of the brain stem and hypothalamus.Migraine is often triggered by stimuli that activate the RAS such as environmental stimuli, exercise, changes in levels of stress, fatigue, sleep deprivation or poor sleep hygiene [52,53] suggesting that the propensity to sleep during migraine could be an endogenous homeostatic response that can reduce the intensity or frequency of migraine headaches. The mechanisms through which physiological sleep achieves an an...

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confidence: 85%

Erratum to: Why does Sleep Stop Migraine?

Bigal¹,

Hargreaves

2014

Curr Pain Headache Rep

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“…This implies it is hypocretin that influences A . Therefore, hypocretin receptor antagonists, which selectively block hypocretin-1 signaling, may in humans decrease A levels and indirectly its accumulation, next to their effect on sleep [35]. We should note that a recent study verified the coexistence of narcolepsy and AD, which demonstrates that AD pathology can also develop in the absence of hypocretin [36].…”

Section: Hypocretin-1 Csf Levels In Relation To a Levelsmentioning

confidence: 90%

Association between Hypocretin-1 and Amyloid-β42 Cerebrospinal Fluid Levels in Alzheimer’s Disease and Healthy Controls

Slats

Claassen²,

Lammers³

et al. 2012

CAR

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Alzheimer's disease is associated with sleep disorders. Recently, animal studies demonstrated a link between hypocretin, a sleep-regulation neurotransmitter, and AD pathology. In this study, we investigated the circadian rhythm of hypocretin-1 in Alzheimer's Disease (AD) patients and controls. Moreover, we assessed the relation between CSF hypocretin-1 and amyloid-β. A continuous CSF sampling study via indwelling intrathecal catheter was performed to collect hourly CSF samples of six patients with AD (59-85 yrs, MMSE 16-26) and six healthy volunteers (64-77 yrs). CSF hypocretin-1 and Aβ42 concentrations were determined at 8 individual time points over 24 hours. A circadian pattern was assessed by fitting a 24 hour sine curve to the hypocretin-1 data using mixed model analysis. Clinical diagnosis and Aβ42 were entered into the model as time invariant covariates to determine differences between AD and controls, and correlate Aβ42 to hypocretin-1 levels. A hypocretin-1 circadian rhythm with an amplitude of 11.5 pg/ml was found in clinical AD patients, which did not differ from the control group (7.15 pg/ml). Lower mean CSF Aβ42 levels were related to lower hypocretin-1 levels; 1.6 pg/ml hypocretin-1 per 10 pg/ml Aβ42 (p=0.03), and a higher amplitude of the hypocretin-1 circadian rhythm (0.4 pg/ml, p=0.03). CSF hypocretin-1 has a circadian rhythm for which we could show no difference between AD and controls. However, the association between mean Aβ42 levels and mean hypocretin-1 levels and amplitude may suggest a relationship between AD pathology and hypocretin disturbance, which could hold possibilities for treatment of AD related sleep disorders.

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“…Suvorexant is able to block the effects of the orexin compounds and promote sleep. [8][9][10] In animal models, suvorexant dose-dependently reduced locomotor activity and promoted sleep. 9 In healthy human subjects, suvorexant was associated with a dose-dependent increase in sleepiness and decrease in alertness.…”

Section: Clinical Pharmacologymentioning

confidence: 99%