The pathophysiology of opioid-induced respiratory depression

Montandon, Gaspard

doi:10.1016/b978-0-323-91534-2.00003-5

Cited by 7 publications

(6 citation statements)

References 125 publications

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“…By contrast, Oprm1 À/À mice did not show any significant changes in respiratory rate and relative tidal volume following fentanyl injection compared with saline. This is consistent with fentanyl inhibiting neuronal activity by acting on MORs (Montandon, 2022). There were also significant differences in respiratory rates in response to saline during the early postinjection response between wild-type and Oprm1 À/À mice, despite no differences in baseline breathing rates before injection.…”

Section: Role Of Mors In Opioid-induced Respiratory Rate Depressionsupporting

confidence: 81%

“…Most opioid ligands are selective for a wide-range of opioid receptors (Montandon, 2022). For example, fentanyl and morphine bind strongly to the MOR, while morphine also moderately binds to k -opioid receptors.…”

Section: Role Of Mors In Opioid-induced Respiratory Rate Depressionmentioning

confidence: 99%

“…Opioid drugs are widely used as pain medications because of their potent analgesic effects. Opioid drugs act on m-opioid receptors (MORs) in spinal and brainstem regions involved in pain, but also on regions regulating breathing (Stein, 2016;Montandon, 2022). Through their actions on MORs in respiratory circuits, opioid drugs can cause respiratory depression, characterized by slow and shallow breathing, with severe cases involving inhibition of the hypoxic and hypercapnic ventilatory responses and even death with overdose (Dahan et al, 2001;Ramirez et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

Furdui

Scarpellini²,

Montandon

2023

eNeuro

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Opioid drugs are widely used as analgesics but cause respiratory depression, a potentially lethal side-effect with overdose, by acting on µ-opioid receptors (MORs) expressed in brainstem regions involved in the control of breathing. Although many brainstem regions have been shown to regulate opioid-induced respiratory depression, the types of neurons involved have not been identified. Somatostatin is a major neuropeptide found in brainstem circuits regulating breathing, but it is unknown whether somatostatin-expressing circuits regulate respiratory depression by opioids. We examined the co-expression ofSst(gene encoding somatostatin) andOprm1(gene encoding MORs) mRNAs in brainstem regions involved in respiratory depression. Interestingly,Oprm1mRNA expression was found in the majority (> 50%) ofSst-expressing cells in the preBötzinger Complex, the nucleus tractus solitarius, the nucleus ambiguus, and the Kölliker-Fuse nucleus. We then compared respiratory responses to fentanyl between wild-type andOprm1full knockout mice and found that the lack of MORs prevented respiratory rate depression from occurring. Next, using transgenic knockout mice lacking functional MORs specifically inSst-expressing cells, we compared respiratory responses to fentanyl between control and the conditional knockout mice. We found that respiratory rate depression by fentanyl was preserved when MORs were deleted only inSst-expressing cells. Our results show that despite co-expression ofSstandOprm1in respiratory circuits and the importance of somatostatin-expressing cells in the regulation of breathing, these cells do not mediate opioid-induced respiratory rate depression. Instead, MORs found in respiratory cell populations other thanSst-expressing cells likely contribute to the respiratory effects of fentanyl.Significance statementOpioid drugs cause respiratory depression, a potentially lethal side-effect with overdose, by acting on µ-opioid receptors in brainstem regions regulating breathing, therefore limiting their effective use as analgesics. Somatostatin is a major neuropeptide found within these brainstem circuits, but it is unknown whether somatostatin circuits regulate respiratory depression by opioids. We found that somatostatin-expressing neurons co-express µ-opioid receptors in respiratory circuits but that respiratory rate depression by fentanyl was preserved despite genetic deletion of µ-opioid receptors in somatostatin-expressing cells. Our results suggest that somatostatin-expressing cells are resistant to the rate-depressive effects of opioids and that other cells contribute to the effects of fentanyl on breathing. Somatostatin-expressing cells may constitute a cell population that can be targeted to stimulate breathing when it fails with opioids.

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Section: Role Of Mors In Opioid-induced Respiratory Rate Depressionsupporting

confidence: 81%

Section: Role Of Mors In Opioid-induced Respiratory Rate Depressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

Furdui

Scarpellini²,

Montandon

2023

eNeuro

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“…Opioid drugs present unwanted side effects such as respiratory depression. The respiratory properties of opioid drugs are due to their action on µ-opioid receptors (Heinricher et al ., 2009; Montandon, 2022). The preBötC expresses MORs and mediates a large component of respiratory rate depression by opioid drugs (Montandon et al ., 2011; Bachmutsky et al ., 2020; Varga et al ., 2020).…”

Section: Discussionmentioning

confidence: 99%

A tachykinin precursor 1 medullary circuit promoting rhythmic breathing

Rousseau

Furdui

Scarpellini

et al. 2023

Preprint

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Rhythmic breathing is generated by neural circuits located in the brainstem. At its core is the preBötzinger Complex (preBötC), a region of the medulla, necessary for the generation of rhythmic breathing in mammals. The preBötC is comprised of various neuronal populations expressing neurokinin-1 receptors, the cognate G-protein-coupled receptor of the neuropeptide substance P (encoded by the tachykinin precursor 1 orTac1). Neurokinin-1 receptors are highly expressed in the preBötC and destruction or deletion of neurokinin-1 receptor-expressing preBötC neurons severely impairs rhythmic breathing. Application of substance P to the preBötC stimulates breathing in rodents, however substance P is often associated with nociception and locomotion in various brain regions, suggesting thatTac1neurons found in the preBötC may have diverse functional roles. Here, we aim to characterize the role ofTac1-expressing preBötC neurons in the generation of rhythmic breathingin vivo, as well as motor behaviors. Using a cre-lox recombination approach, we injected adeno-associated virus containing the excitatory channelrhodopsin-2 ChETA in the preBötC region ofTac1-cre mice. Using a combination of histological, optogenetics, respiratory, and behavioral assays, we defined the identity and the role ofTac1preBötC neurons. These neurons are glutamatergic and their stimulation promotes rhythmic breathing in both anesthetized and freely moving/awake animals, but also triggers locomotion and overcomes respiratory depression by opioid drugs. Overall, our study identifies a new population of excitatory preBötC with major role in rhythmic breathing and behaviors.

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“…Interestingly, stimulation of Tac1 preBötC cells directly elicited a strong locomotor response suggesting that Tac1 preBötC cells play a dual role in promoting breathing and locomotion. Rhythmic breathing is dampened by opioid drugs and preBötC cells mediate a major component of respiratory depression by opioid drugs ( Montandon et al, 2011 ; Montandon, 2022b ). Because most Tac1 preBötC cells co-expressed µ-opioid receptors (encoded by the gene Oprm1 ) in the preBötC, their stimulation reversed the effects of opioid drugs on breathing, suggesting that Tac1 preBötC neurons constitute a robust excitatory neuronal population promoting breathing during calm states and that can overcome respiratory depression with narcotics.…”

Section: Introductionmentioning

confidence: 99%

Medullary tachykinin precursor 1 neurons promote rhythmic breathing

Rousseau¹,

Furdui²,

Scarpellini³

et al. 2023

eLife

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Rhythmic breathing is generated by neural circuits located in the brainstem. At its core is the preBötzinger Complex (preBötC), a region of the medulla, necessary for the generation of rhythmic breathing in mammals. The preBötC is comprised of various neuronal populations expressing neurokinin-1 receptors, the cognate G-protein-coupled receptor of the neuropeptide substance P (encoded by the tachykinin precursor 1 or Tac1). Neurokinin-1 receptors are highly expressed in the preBötC and destruction or deletion of neurokinin-1 receptor-expressing preBötC neurons severely impairs rhythmic breathing. Although application of substance P to the preBötC stimulates breathing in rodents, substance P is also involved in nociception and locomotion in various brain regions, suggesting that Tac1 neurons found in the preBötC may have diverse functional roles. Here, we characterized the role of Tac1-expressing preBötC neurons in the generation of rhythmic breathing in vivo, as well as motor behaviors. Using a cre‑lox recombination approach, we injected adeno-associated virus containing the excitatory channelrhodopsin-2 ChETA in the preBötC region of Tac1-cre mice. Employing a combination of histological, optogenetics, respiratory, and behavioral assays, we showed that stimulation of glutamatergic or Tac1 preBötC neurons promoted rhythmic breathing in both anesthetized and freely moving animals, but also triggered locomotion and overcame respiratory depression by opioid drugs. Overall, our study identified a population of excitatory preBötC with major roles in rhythmic breathing and behaviors.

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The pathophysiology of opioid-induced respiratory depression

Cited by 7 publications

References 125 publications

Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

A tachykinin precursor 1 medullary circuit promoting rhythmic breathing

Medullary tachykinin precursor 1 neurons promote rhythmic breathing

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