Part one of this three-part article published previously in Medical News described the double jeopardy of glucocorticoid-induced sleep debt. Here, Part 2 describes the action of adenosine on the homeostatic regulation of slow-wave, non-REM activity, and the perturbations of the highly structured architecture of normal sleep caused by adenosine modulation leading to sleep debt.
The neuroscience of sleep describes the role of adenosine as it relates to the depth of sleep. According to the homeostatic model of sleep, delta power is a measure of the depth of sleep. Delta power is expressed by the dominance of slow waves in the EEG (1-4 Hz), and linked to sleep need and prior wakefulness. The action of adenosine on delta power is twofold: First, extracellular adenosine inhibits wake-promoting neurons in an area of the basal forebrain (BF) called the ascending reticular activating system (ARAS). Second, the release of intracellular adenosine from glial cells, and the binding of adenosine to its neuronal receptor begins a chain of events that leads to the generation of slow wave non-REM activity.
One function of sleep is considered to be the restoration of energy reserves in the brain. The brain is responsible for 25 percent of total energy consumption of the body. Interestingly, CNS neurons are incapable of storing more than 30 seconds of energy. Thus, glial cells play a restorative role in providing energy to cortical neurons. The following paragraph is dedicated to briefly unpacking the neuroglial process of energy restoration. This process begins with the principal intracellular metabolic pathway of adenosine in glial cells followed by complex interactions between 4 different membrane-bound neuronal receptors:
When glial cells become energy challenged and glycogen reserves are diminished, glial cells scavenge two ADP molecules to make one high energy ATP molecule and one residual AMP molecule. AMP is degraded to adenosine which is released from glial cells and immediately has a direct effect on cortical neurons. The effect of adenosine on cortical neurons promotes very high delta power that aids in characterizing the depth of stage N3 slow-wave synchronized non-REM sleep. Adenosine binds with high affinity to its A1 neuronal receptor and activates it. Next, activated adenosine receptors intracellularly phosphorylate what are called slow-leak potassium (K) channels, causing an outflow of positively charged K ions, making the inside of the neuron more negative, thus hyperpolarizing the inside of the neuron. As a consequence of intracellular hyperpolarization, what follows is de-inactivation of T-type voltage-gated calcium (Ca) channels that have special properties. One property is that these special Ca channels have a lower threshold of activation than voltage-gated sodium (Na) channels at the normal resting membrane potential. De-inactivation of these Ca channels allow any small rise in resting membrane potential to open these Ca channels. Positively charged Ca ions rush into the cell making the inside of the neuron more positive, thus depolarizing it, thereby reaching the higher activation threshold for Na channels that open and generate a burst of low-voltage, high-amplitude Na action potentials (see Figure 1). In slow-wave non-REM sleep, these action potentials are recognized as the complex, synchronized, EEG wave forms. Multitudes of these wave forms, through time, have slower frequency and higher amplitude causing greater depth of delta power density in stage N3 slow-wave sleep. Thus, the binding of adenosine to its neuronal receptor begins a chain of events that promotes quiet sleep with high delta power in non-REM deep stage. The end result is restoration of energy reserves in the brain.
Restoration of energy reserves will not occur completely in the setting of fragmented sleep. Examples of fragmented sleep include obstructive sleep apnea/hypopnea syndrome (OSA) or upper airway resistance syndrome (UARS). Both cause frequent fracturing of delta power density in non-REM sleep resulting in multiple micro-arousal intrusions occurring in alpha sleep stage, or awakenings showing beta EEG wave forms.
In addition, in the setting of fragmented sleep, ATP levels decrease in wake-active regions of the BF due to increased energy consumption. As a result, extracellular adenosine accumulates selectively in the ARAS. As a homeostatic sleep regulatory agent, adenosine promotes the transition from wakefulness to sleep by inhibition wake-promoting BF neurons. Administration of A1 receptor agonists promote sleep and enhance deep delta power density necessary for restorative sleep. Thus, at accumulated levels, adenosine is available in the ARAS to, at least temporarily, compensate for micro-arousals and awakenings by the inhibition of wake-generating neurons.
Moreover, what antagonizes sleep with high delta power in non-REM activity, and antagonizes the inhibition of wake-promoting ARAS neurons is caffeine. Caffeine is used by 85 percent of Americans, many to ward off daytime somnia. Caffeine is a nonspecific adenosine receptor antagonist for both A1 and A2a receptors. Thus, caffeine acts to promote wakefulness by binding to adenosine receptors on cortical neurons and shutting down the cascade of molecular events reducing slow wave sleep described above. Finally, caffeine will compete with adenosine for receptor sites in the ARAS and increase the activity of wake-promoting neurons in the BF and decrease total sleep time.
Brian D. Fuselier, DDS, is a member of the International Association for the Study of Pain, and the American Pain Society.
Barry A. Loughner, DDS, MS, PhD is a member of the International Association for the Study of Pain, the American Pain Society, the American Dental Association, and the Ethics Committee of the American Association for the Study of Headache.
Dr. Fuselier and Dr. Loughner are actively practicing at Central Florida Oral and Maxillofacial Surgery, a unique service with both oral surgeons and facial pain specialists practicing together. For more information visit www.cforalsurgery.com