Naloxone Does Not Alter the Arousal Response Decrement after Repeated Exposure to Hypoxemia during Sleep in Lambs

Abstract

Arousal is an important protective response that may prevent severe hypoxemia and death during sleep. Hypoxemia may occur during sleep in indi viduals with chronic lun g disease ( 1-3). Th e usual respirato ry respon se to hypoxemia is an increase in ventilat ion, which tends to increase the alveolar and arterial oxygen ten sion . However, the ventilatory response to hypoxemi a is decreased during active sleep compared to quiet sleep in som e species that develop rib cage collapse during active sleep [e.g. lambs (4) and calves (5)]. T hus, the arousal respon se is an im portant protective respon se when we consider the overa ll cardiorespiratory response to hypoxemi a during sleep (6-9).Experiments were done on five lambs ranging in age from 10 to 19 d. Each lamb was separated from its ewe 1 to 3 dafter birth and was hou sed in our laboratory in a Plexiglas cage with continu ous access to milk (Iamb milk replacer, Land O'Lakes, Inc., Fort Dodge , IA). Th e lambs were among oth er lambs, fed and slept ad libitum, and soon became accustomed to the surroundings and laboratory personnel.S urgical preparation. Each lamb underwent one operation before study. Before the operation, each lamb was given atropine sulfate (0.2 mg/kg s.c.) and ketamine HCl (10 mg/k g intramuscularly) and its trachea was intubated with a cuffed endotracheal tube. The cuff was inflated to a gas tight fit and anesthesia was ma intain ed by ventilating th e lamb's lungs with I to 3% isoflurane (Fo rane, Anaquest, Mad ison , WI) in oxygen and nitrous oxide (3: I). An ECG and rectal temp erature were monitored du ring surgery, and core temperature was kept near 39°C with a heat ing pad.The operation was don e between 7 and 16 d of age when a double-lumen fiberopti c catheter oximeter (model U440 opticath, Oximetrix, Inc ., Mountain View, CA) was inserted into the thoracic aorta via a femor al artery for continuous measurement of arterial Hb oxygen satu ration and systemic blood pressure. Electrodes for the following recordings were also implanted: electrocorticogram, electro oculogram , nuchal electromyogram , and diaphragm electromyogram . A reference wire was sutured int o the s.c. tissue of the scalp. The electrodes were made in our 222ABSTRACT. Experiments were done to determine if endogenous opiates cause the arousal response decrement that follows repeated exposure to hypoxemia during sleep in lambs. Five lambs were anesthetized and instrumented for sleep staging and measurement of arterial Hb oxygen saturation. No sooner than 3 d after surgery, measurements were made in quiet sleep and active sleep during control periods when the lambs were breathing 21% oxygen and during experimental periods when the lambs were breathing 5% oxygen. The experimental period was terminated during each epoch by changing the inspired gas mixture back to 21% oxygen, once the lamb aroused from sleep. After each lamb had been exposed to 5% oxygen during 100 consecutive epochs of sleep, naloxone-an opiate antagonist-was given i.v, in a dose of 3 mgJkg as a bolus. T...

The carotid body and arousal in the fetus and neonate

“…Acute hypoxemia is associated with increases in the extracellular concentration (measured with microdialysis) of both excitatory and inhibitory neurotransmitters and/or neuromodulators in the brainstem, including opioids, glutamate, GABA, taurine, adenosine and serotonin in both anesthetized and conscious animals (Hoop et al , 1999; Richter et al , 1999; Tabata et al , 2001; Hehre et al , 2008). Studies in newborn lambs demonstrated that blockade of opioid receptors did not reverse the progressive blunting of arousal with repeated hypoxia exposure (Konduri & Fewell, 1992). Adenosine is a ubiquitous nucleoside that is released from cells into the extracellular space when oxygen supply no longer matches oxygen needs (Darnall & Bruce, 1987).…”

Arousal from sleep in response to intermittent hypoxia in rat pups is modulated by medullary raphe GABAergic mechanisms

“…There is little or no information linking these substances with arousal from sleep in response to hypoxia. One study in newborn lambs demonstrated that blockade of opioid receptors did not reverse the progressive lengthening of the time to arousal in response to repeated hypoxia exposures (48). Adenosine is released from cells into the extracellular space during hypoxia when oxygen needs no longer match oxygen supply (16) and activation of both GABA A and serotonin 1A (5-HT 1A ) receptors in this region disrupts sleep and promotes wakefulness (11,13,15,34).…”

The Autopsy and Pathology of Sudden Infant Death Syndrome

“…Acute hypoxemia is associated with increases in the extracellular concentration of both excitatory and inhibitory neurotransmitters and/or neuromodulators in the brainstem, including opioids, glutamate, GABA, taurine, adenosine, and 5-HT (253)(254)(255)(256). Blockade of opioid receptors did not reverse arousal habituation associated with repeated hypoxia exposure in newborn lambs (257). Adenosine is a ubiquitous nucleoside that is released from cells into the extracellular space when oxygen supply no longer matches oxygen needs (258), and it is a potential candidate that could directly inhibit excitatory neurons involved in arousal via A 1 receptors, or that could indirectly inhibit these neurons by acting on excitatory adenosine A 2A receptors located on GABAergic neurons.…”