Opioids, sleep, analgesia and respiratory depression: Their convergence on Mu (μ)-opioid receptors in the parabrachial area

Abstract

Opioids provide analgesia, as well as modulate sleep and respiration, all by possibly acting on the μ-opioid receptors (MOR). MOR's are ubiquitously present throughout the brain, posing a challenge for understanding the precise anatomical substrates that mediate opioid induced respiratory depression (OIRD) that ultimately kills most users. Sleep is a major modulator not only of pain perception, but also for changing the efficacy of opioids as analgesics. Therefore, sleep disturbances are major risk factors for developing opioid overuse, withdrawal, poor treatment response for pain, and addiction relapse. Despite challenges to resolve the neural substrates of respiratory malfunctions during opioid overdose, two main areas, the pre-Bötzinger complex (preBötC) in the medulla and the parabrachial (PB) complex have been implicated in regulating respiratory depression. More recent studies suggest that it is mediation by the PB that causes OIRD. The PB also act as a major node in the upper brain stem that not only receives input from the chemosensory areas in medulla, but also receives nociceptive information from spinal cord. We have previously shown that the PB neurons play an important role in mediating arousal from sleep in response to hypercapnia by its projections to the forebrain arousal centers, and it may also act as a major relay for the pain stimuli. However, due to heterogeneity of cells in the PB, their precise roles in regulating, sleep, analgesia, and respiratory depression, needs addressing. This review sheds light on interactions between sleep and pain, along with dissecting the elements that adversely affects respiration.

Keywords: analgesia; opioid induced respiratory depression; opioid tolerance; opioid use disorder; sleep-loss.

FIGURE 1

Schematic showing the possible role of the parabrachial μ-opioid receptor (MOR) expressing neurons (PB^Oprm1) in regulating opioid induced respiratory depression (OIRD), analgesia, and sleep: The neurons in the centro lateral sub-nucleus of parabrachial area (PBcl) and Kölliker Fuśe (KF) that express FoxP2 (PBcl^FoxP2) and those that express pro-dynorphin (PBcl^pdyn) may critically modulate respiration through their descending projections to the medullary ventral respiratory group (VRG). Opioids at incrementally higher dose (due to developing opioid tolerance) may act by inhibiting the PBcl^FoxP2/PBcl^pdyn neurons resulting in a continuous cycle of progressively depressed respiration that can prove to be fatal. Both hypercapnia and hypoxia stimuli (during apneic events) are conveyed to the PB via the retrotrapezoid (RTN) and nucleus of solitary tract (NTS), and these pathways are also inhibited by opioids use and tolerance. The interconnectivity of the PB^Oprm1 neurons, specifically between the PBcl^FoxP2/PBcl^pdyn and PBel^CGRP subpopulations may explain cortical arousal that results from respiratory stress during sleep apnea. The PB neurons that express CGRP (PBel^CGRP) regulate waking up in response to pain, hypercapnia and aversive stimuli through their projections to the forebrain arousal areas such as, central nucleus of amygdala (CeA); the bed nucleus of stria terminalis (BNST); the basal forebrain (BF) and the lateral hypothalamus (LH). Opioids may provide analgesia and prevent sleep disruption (SD) by inhibiting the PBel^CGRP neurons that act as relay node for the pain stimulus which is transmitted to these neurons via the spinal cord. In contrast, inadequate sleep over-activate this cortical arousal circuit, inclusive of the PBel^CGRP neurons, which causes decreased sensitivity to inhibition from opioids, also known as opioid tolerance. Sleep disruption, in itself, also cause increased pain sensitivity, with decreasing levels of opioid induced analgesia. The resulting continuous cycle accelerates opioid tolerance while progressively reducing opioid analgesia.