Mu Opioid Receptor–Expressing Neurons in the Dorsal Raphe Nucleus Are Involved in Reward Processing and Affective Behaviors

Welsch, Lola; Colantonio, Esther; Frison, Mathilde; Johnson, Desiree A.; McClain, Shannan P.; Mathis, Victor; Banghart, Matthew R.; Ben Hamida, Sami; Darcq, Emmanuel; Kieffer, Brigitte L.

doi:10.1016/j.biopsych.2023.05.019

Cited by 8 publications

(4 citation statements)

References 51 publications

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“…In all studies, mice were placed in behavioural tests 30 min after naloxone injection on experimental days 6, 7 and 8. In all studies; on day 6, mice were placed in a social preference test (SPT) 12 , 13 , on day 7 an open field test (OFT) 14 , and on day 8 a tail suspension test (TST) 15 . Additionally, on day 6, mice were scored for somatic withdrawal signs for 15-min after naloxone.…”

Section: Methodsmentioning

confidence: 99%

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Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice

Ozdemir,

Meyer,

Kieffer

et al. 2024

Sci Rep

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Opioid use disorder (OUD) is a chronic relapsing disorder that is a major burden for the lives of affected individuals, and society as a whole. Opioid withdrawal is characterized by strong physical symptoms, along with signs of negative affect. Negative affect due to opioid withdrawal is a major obstacle to recovery and relapse prevention. The mechanisms behind negative affect due to either spontaneous or antagonist-precipitated opioid withdrawal are not well known, and more animal models need be developed. Here, we present behavioral models of negative affect upon naloxone-precipitated morphine withdrawal in adult male mice. Social, anxiety, and despair-like deficits were investigated following naloxone administration in mice receiving morphine under three dosing regimens; acute, chronic constant dose and chronic escalating doses. Social behaviour in the three-chamber social preference test was decreased following withdrawal from chronic and escalating but not acute morphine. Anxiety-like behaviour in the open field was increased for all three treatments. Despair-like behaviour was increased following withdrawal from chronic and escalating but not acute morphine. Altogether, these animal models will contribute to study behavioural and neuronal circuitries involved in the several negative affective signs characterizing OUD.

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Section: Methodsmentioning

confidence: 99%

“…Additionally, on day 6, mice were scored for somatic withdrawal signs for 15-min after naloxone. Detailed descriptions of behavioural procedures are in the Supplementary Information and as described 12 – 15 . This includes the description of precipitated withdrawal sign scoring, SPT, OFT, and TST.…”

Section: Methodsmentioning

confidence: 99%

Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice

Ozdemir,

Meyer,

Kieffer

et al. 2024

Sci Rep

Self Cite

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“…Mu-opioids activate the DRN serotonergic release (Welsch et al, 2023). I propose that mu-opioids increase the well-being and safety signal in the vACC/IL disynaptically, via its serotonergic receptors: mu-opioids→DRN serotonin →vACC up→CeA down.…”

Section: Figure1mentioning

confidence: 99%

Circuits for anesthesia, unawareness, OIRD, sleep and memory replay: MHb→IPN→ PAG + DRN + MRN→claustrum→ cortical slow-waves.

Vadovičová

2024

Preprint

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Opiates are fast pain relievers that can cause respiratory arrest. I show new mechanisms how mu-opioids and high prenatal nicotine cause respiratory slowdown linked to slow wave sleep. Mu-opioids activate the medial habenula which activates the interpeduncular nucleus. The MHb-IPN system decreases respiration and alarm/arousal response to hypercapnia by projections to PAG, DRN, MRN and MRN→LPO→RMTg→vPAG. The same MHb-IPN circuit that causes respiratory slowdown, likely causes ventilatory deficits in mammalian neonates, known as sudden infant death syndrome (SIDS), linked to high fetal nicotine intake. Natural slowdown of respiration and heart rate is caused by slow wave sleep, when body is not moving. The MHb and rostromedial tegmental nucleus are known for high amount of mu-opioid receptors. Both were claimed to be activated by the MHb→IPN→MRN circuit that activates serotonin release, promotes slow SWS, rest, immune defense, recovery, sharp wave ripples, cortical spindles, replay of temporaly, spatialy and relationally bound memories, synaptogenesis, BDNF linked growth and DG neurogenesis, but inhibits theta states, arousal, alert wakefulness, awareness and REM sleep linked circuits (Vadovičová, 2015).This updated circuit model explains role of the MHb→IPN→MRN→hippocampus + claustrum→cortical slow wave activity (SWA) in anesthesia, memory replay, loss of awareness, SWS and in theta states suppression. I proposed new mechanisms for anesthetic ketamine effect: activation of the IPN→MRN→claustrum→cortical SWA circuit by the 5-HT2a IPN and claustrum receptors. I show why are ketamine and hallucinogens anxiolytic and antidepressant, andhow activation of 5-HT2a receptors in vACC/infralimbic cortex increases the safety, well-beingsignal, and cognitive flexibility.

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“…Mu-opioids activate the DRN serotonergic release (Welsch et al, 2023). Thus, I think mu-opioids increase the well-being and safety signal in the vACC/IL disynaptically, via its serotonergic receptors: mu-opioids→DRN serotonin →vACC up→CeA down.…”

mentioning

confidence: 99%

Circuits for anesthesia, unawareness, OIRD, sleep and memory replay: MHb→IPN→PAG + DRN + MRN→claustrum→cortex.

Vadovičová

2024

Preprint

View full text Add to dashboard Cite

Opiates are fast pain relievers that can cause respiratory arrest.I show new mechanisms how mu-opioids and high prenatal nicotine cause respiratory slowdownlinked to slow wave sleep. Mu-opioids activate the medial habenula which activates theinterpeduncular nucleus. The MHb-IPN system decreases respiration and alarm/arousal response tohypercapnia by projections to PAG, DRN, MRN and LPO→RMTg→vPAG. The same MHb-IPNcircuit that causes respiratory slowdown, likely causes ventilatory deficits in mammalian neonates,known as sudden infant death syndrome (SIDS), linked to high fetal nicotine intake.Natural slowdown of respiration and heart rate is caused by slow wave sleep, when body is notmoving. The MHb and rostromedial tegmental nucleus are known for high amount of mu-opioidreceptors. Both were claimed to be activated by the MHb→IPN→MRN circuit that activatesserotonin release, promotes slow SWS, rest, immune defense, recovery, sharp wave ripples, corticalspindles, replay of temporaly, spatialy and relationally bound memories, synaptogenesis and BDNFlinked growth, but inhibits theta states, arousal, alert wakefulness, awareness and REM sleep linkedcircuits (Vadovičová, 2015).This updated circuit model explains role of the MHb→IPN→MRN→hippocampus + claustrum→cortical slow wave activity (SWA) in anesthesia, memory replay, loss of awareness, SWS and intheta states suppression. I propose new mechanisms for anesthetic ketamine and hallucinogenseffect: activation of the IPN→MRN→claustrum→cortical SWA circuit by the 5-HT2a IPN andclaustrum receptors. I show why are ketamine and hallucinogens anxiolytic and antidepressant, andhow activation of 5-HT2a receptors in vACC/infralimbic cortex increases the safety, well-beingsignal, and cognitive flexibility.

show abstract

Mu Opioid Receptor–Expressing Neurons in the Dorsal Raphe Nucleus Are Involved in Reward Processing and Affective Behaviors

Cited by 8 publications

References 51 publications

Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice

Model of negative affect induced by withdrawal from acute and chronic morphine administration in male mice

Circuits for anesthesia, unawareness, OIRD, sleep and memory replay: MHb→IPN→ PAG + DRN + MRN→claustrum→ cortical slow-waves.

Circuits for anesthesia, unawareness, OIRD, sleep and memory replay: MHb→IPN→PAG + DRN + MRN→claustrum→cortex.

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