Buprenorphine Disrupts Sleep and Decreases Adenosine Concentrations in Sleep-regulating Brain Regions of Sprague Dawley Rat

Abstract

Background Buprenorphine, a partial μ opioid receptor agonist and κ opioid receptor antagonist, is an effective analgesic. The effects of buprenorphine on sleep have not been well characterized. This study tested the hypothesis that an antinociceptive dose of buprenorphine decreases sleep and decreases adenosine levels in regions of the basal forebrain and pontine brain stem that regulate sleep. Methods Male Sprague Dawley rats were implanted with intravenous catheters and electrodes for recording states of wakefulness and sleep. Buprenorphine (1 mg/kg) was administered systemically via an indwelling catheter and sleep/wake states were recorded for 24 h. In additional rats buprenorphine was delivered by microdialysis to the pontine reticular formation and substantia innominata of the basal forebrain while simultaneously measuring adenosine. Results An antinociceptive dose of buprenorphine caused a significant increase in wakefulness (25.2%) and a decrease in both nonrapid eye movement sleep (−22.1%) and rapid eye movement sleep (−3.1%). Buprenorphine also increased electroencephalographic delta power during nonrapid eye movement sleep. Coadministration of the sedative/hypnotic eszopiclone diminished the buprenorphine-induced decrease in sleep. Dialysis delivery of buprenorphine significantly decreased adenosine levels in the pontine reticular formation (−14.6%) and substantia innominata (−36.7%). Intravenous administration of buprenorphine significantly decreased (−20%) adenosine in the substantia innominata. Conclusions Buprenorphine significantly increased time spent awake, decreased nonrapid eye movement sleep, and increased latency to sleep onset. These disruptions in sleep architecture were mitigated by coadministration of the nonbenzodiazepine sedative/hypnotic eszopiclone. The buprenorphine-induced decrease in adenosine levels in basal forebrain and pontine reticular formation is consistent with the interpretation that decreasing adenosine in sleep-regulating brain regions is one mechanism by which opioids disrupt sleep.

Opiate-induced changes in brain adenosine levels and narcotic drug responses

“…In rats, opioids have been shown to disrupt sleep, and to decrease adenosine levels in brain regions that regulate sleep (Nelson et al, 2009, Gauthier et al, 2011). Similarly, opioids disrupt human sleep (Kay et al, 1981), and major disruptions of sleep occur during human opiate withdrawal (Beswick et al, 2003) (Oyefeso et al, 1997).…”

Neuropharmacology of Sleep and Wakefulness

“…Intravenous administration of buprenorphine decreases adenosine levels in the basal forebrain and increases wakefulness. 66 Inactivating adenosine A 1 receptors in the basal forebrain decreases EEG delta power and NREM sleep time, 67 and immunohistochemical studies reveal that the basal forebrain contains A 1 receptors, but not A 2A receptors. 68 Cholinergic neurons in the basal forebrain project to the cortex and contribute to the EEG activation characteristic of wakefulness and REM sleep.…”

“…76 Studies examining the effects on sleep of adenosine receptor antagonists are required in order to conclude that endogenous adenosine within the pontine reticular formation modulates sleep. The finding that clinically used opioids, such as morphine, fentanyl and buprenorphine, decrease adenosine levels in the pontine reticular formation 66, 77 {added one reference} and disrupt REM sleep 66 (also reviewed in 78 ) suggests the possibility that adenosinergic transmission within the pontine reticular formation participates in REM sleep generation.…”

“…Sleep disruption, in turn, exacerbates pain 204–206 and increases the dose of opioids required for successful pain management (reviewed in 77, 78, 206 ). Clinically relevant doses of opioids given to naïve rats 66 or to otherwise healthy humans (reviewed in 207 ) disrupt sleep. For example, a single intravenous infusion of morphine in healthy volunteers decreases stages 3 and 4 NREM sleep, decreases REM sleep, and increases stage 2 NREM sleep.…”

Adenosine A1 Receptors in Mouse Pontine Reticular Formation Depress Breathing, Increase Anesthesia Recovery Time, and Decrease Acetylcholine Release

“…Long-standing evidence that the adenosine antagonist caffeine promotes wakefulness 3,4 prompted the more recent findings that adenosine promotes sleep (reviewed in 5 ) and that opioid-induced decreases in brain levels of adenosine contribute to sleep disruption caused by opioids. 6,7 The neuronal networks, neurotransmitters, and receptor systems by which adenosine alters behavioral arousal and control of breathing remain incompletely understood.…”