The Role of Adenosine in the Regulation of Sleep

Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
Current topics in medicinal chemistry (Impact Factor: 3.4). 03/2011; 11(8):1047-57. DOI: 10.2174/156802611795347654
Source: PubMed


This paper presents an overview of the current knowledge about the role of adenosine in the sleep-wake regulation with a focus on adenosine in the central nervous system, regulation of adenosine levels, adenosine receptors, and manipulations of the adenosine system by the use of pharmacological and molecular biological tools. The endogenous somnogen prostaglandin (PG) D(2) increases the extracellular level of adenosine under the subarachnoid space of the basal forebrain and promotes physiological sleep. Adenosine is neither stored nor released as a classical neurotransmitter and is thought to be formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The extracellular concentration of adenosine increases in the cortex and basal forebrain during prolonged wakefulness and decreases during the sleep recovery period. Therefore, adenosine is proposed to act as a homeostatic regulator of sleep and to be a link between the humoral and neural mechanisms of sleep-wake regulation. Both the adenosine A(1) receptor (A(1)R) and A(2A)R are involved in sleep induction. The A(2A)R plays a predominant role in the somnogenic effects of PGD(2). By use of gene-manipulated mice, the arousal effect of caffeine was shown to be dependent on the A(2A)R. On the other hand, inhibition of wake-promoting neurons via the A(1)R also mediates the sleep-inducing effects of adenosine, whereas activation of A(1)R in the lateral preoptic area induces wakefulness, suggesting that A(1)R regulates the sleep-wake cycle in a site-dependent manner. The potential therapeutic applications of agonists and antagonists of these receptors in sleep disorders are briefly discussed.

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Available from: Zhi-Li Huang, Apr 02, 2015
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    • "In addition, previous studies suggested that adenosine A 1 receptor (R, A 1 R) may play a vital role in the analgesic effect of paeoniflorin (Liu et al. 2006b; Liu et al. 2006c; Zhang et al. 2009). The A 1 Rs are widely expressed in the brain (Fredholm et al. 2011) and activation of A 1 Rs could inhibit wakepromoting neurons including orexinergic, histaminergic and cholinergic neurons and enhanced non-rapid eye movement (NREM) sleep (Liu and Gao 2007; Oishi et al. 2008; Rainnie et al. 1994), suggesting that A 1 Rs play a vital role in sleep regulation (Huang et al. 2011; 2014). Therefore, we hypothesized that paeoniflorin may be effective in treating neuropathic pain and the concomitant sleep disturbance and A 1 R may be responsible for the analgesic and somnogenic effects. "
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    ABSTRACT: Rational: Neuropathic pain is frequently comorbid with sleep disturbances. Paeoniflorin, a main active compound of total glucosides of paeony, has been well documented to exhibit neuroprotective bioactivity. Objective: The present study evaluated effects of paeoniflorin on neuropathic pain and associated insomnia and the mechanisms involved. Methods: The analgesic and hypnotic effects of paeoniflorin were measured by mechanical threshold and thermal latency, electroencephalogram (EEG) and electromyogram, and c-Fos expression in a neuropathic pain insomnia model. Results: The data revealed that paeoniflorin (50 or 100 mg/kg, i.p.) significantly increased the mechanical threshold and prolonged the thermal latency in partial sciatic nerve ligation (PSNL) mice. Meanwhile, paeoniflorin increased non-rapid eye movement (NREM) sleep amount and concomitantly decreased wakefulness time. However, pretreatment with l,3-dimethy-8-cyclopenthylxanthine, an adenosine A1 receptor (R, A1R) antagonist, abolished the analgesic and hypnotic effects of paeoniflorin. Moreover, paeoniflorin at 100 mg/kg failed to change mechanical threshold and thermal latency and NREM sleep in A1R knockout PSNL mice. Immunohistochemical study showed that paeoniflorin inhibited c-Fos overexpression induced by PSNL in the anterior cingulate cortex and ventrolateral periaqueductal gray. Conclusions: The present findings indicated that paeoniflorin exerted analgesic and hypnotic effects via adenosine A1Rs and might be of potential use in the treatment of neuropathic pain and associated insomnia.
    Psychopharmacology 10/2015; DOI:10.1007/s00213-015-4108-6 · 3.88 Impact Factor
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    • "Caffeine binds with very similar affinity to adenosine A 1 (A 1 Rs) and A 2A (A 2A Rs) receptors, and, at doses commonly consumed by humans, adenosine actions at both receptors are antagonized . Adenosine is an inhibitory neuromodulator involved in sleep–wake regulation (Porkka-Heiskanen et al., 1997; Huang et al., 2011). Using global genetic knock-outs of A 1 Rs and A 2A Rs, in which the receptor is deleted from the entire animal, we demonstrated previously that the A 2A R, but not the A 1 R, mediates the arousal effect of caffeine (Huang et al., 2005). "

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    • "evidence shows that extracellular concentrations of AD are enhanced in association with natural or prolonged alertness in multiple brain areas (Porkka-Heiskanen et al., 2000, 2002; Blanco- Centurión et al., 2006; Huang et al., 2011). Since CBD promotes waking and AD is increased during alertness, we tested the hypothesis that this cannabinoid increases extracellular levels of AD in rats. "
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    ABSTRACT: Cannabidiol (CBD) is a constituent of Cannabis sativa that promotes wakefulness as well as enhances endogenous levels of wake-related neurotransmitters, including dopamine. However, at this date, the effects of CBD on the sleep-inducing molecules, such as adenosine (AD), are unknown. Here, we report that intrahypothalamic injection of CBD (10μg/1μL) increases the extracellular levels of AD collected from nucleus accumbens. Furthermore, the pharmacodynamic of this drug shows that effects on the contents of AD last 2h post-injection. These preliminary findings suggest that CBD promotes the endogenous accumulation of AD.
    Neuroscience Research 05/2014; 84. DOI:10.1016/j.neures.2014.04.006 · 1.94 Impact Factor
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