Systemically administered neurotensin receptor agonist produces antinociception through activation of spinally projecting serotonergic neurons in the rostral ventromedial medulla

Li, Yaqun; Kang, Dong Ho; Kim, Woong Mo; Lee, Hyung Gon; Kim, Seung Hoon; You, Hyun Eung; Choi, Jeong Il; Yoon, Myung Ha

doi:10.3344/kjp.2021.34.1.58

Cited by 3 publications

(4 citation statements)

References 24 publications

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“…This result agrees with evidence indicating that RVM activation induces analgesia, ameliorating acute or chronic pain. 13,18,19,24,30,39 However, the participation of the RVM in the pain chronification process in a depression-related context remained to be further explored. To the best of our knowledge, this is the first study highlighting the RVM as a mediator of depression-related behaviors, featuring it as a key structure to further the investigation of the comorbidity between chronic pain and depression.…”

Section: Discussionmentioning

confidence: 99%

The rostral ventromedial medulla modulates pain and depression-related behaviors caused by social stress

Pagliusi,

Amorim-Marques,

Lobo

et al. 2024

Pain

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The rostral ventromedial medulla (RVM) is a crucial structure in the descending pain modulatory system, playing a key role as a relay for both the facilitation and inhibition of pain. The chronic social defeat stress (CSDS) model has been widely used to study stress-induced behavioral impairments associated with depression in rodents. Several studies suggest that CSDS also causes changes related to chronic pain. In this study, we aimed to investigate the involvement of the RVM in CSDS-induced behavioral impairments, including those associated with chronic pain. We used chemogenetics to activate or inhibit the RVM during stress. The results indicated that the RVM is a vital hub influencing stress outcomes. Rostral ventromedial medulla activation during CSDS ameliorates all the stress outcomes, including social avoidance, allodynia, hyperalgesia, anhedonia, and behavioral despair. In addition, RVM inhibition in animals exposed to a subthreshold social defeat stress protocol induces a susceptible phenotype, facilitating all stress outcomes. Finally, chronic RVM inhibition—without any social stress stimulus—induces chronic pain but not depressive-like behaviors. Our findings provide insights into the comorbidity between chronic pain and depression by indicating the involvement of the RVM in establishing social stress–induced behavioral responses associated with both chronic pain and depression.

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Section: Discussionmentioning

confidence: 99%

The rostral ventromedial medulla modulates pain and depression-related behaviors caused by social stress

Pagliusi,

Amorim-Marques,

Lobo

et al. 2024

Pain

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“…To measure the extracellular level of 5‐HT in the spinal dorsal horn, microdialysis was carried out as previously described (Chae et al, 2020; Lee et al, 2014; Li et al, 2021). Under sevoflurane anaesthesia, a 24‐gauge cannula was inserted into the right femoral vein and Ringer's solution was infused at 1 mL/h.…”

Section: Methodsmentioning

confidence: 99%

Antinociceptive effects of nefopam activating descending serotonergic modulation via 5‐HT2 receptors in the nucleus raphe magnus

Li,

Kim,

Lee

et al. 2023

European Journal of Pain

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BackgroundNefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam.MethodsThe effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra‐nucleus raphe magnus (NRM) pre‐treatment with the serotonin (5‐HT) receptor antagonist or 5‐HT2 receptor antagonist. The change in extracellular 5‐HT levels was measured by spinal cord microdialysis.ResultsIntraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre‐treatment with 5‐HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5‐HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5‐HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra‐NRM cinanserin pre‐treatment. The increase in spinal level of 5‐HT by systemic nefopam was attenuated by intra‐NRM cinanserin pre‐treatment.ConclusionThe antinociceptive effects of systemically administered nefopam are mediated by 5‐HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5‐HT into the spinal dorsal horn.SignificanceThis study revealed supraspinal mechanisms of nefopam‐produced analgesia mediated by 5‐HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5‐HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.

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“…Neurotensin (NT) is mainly expressed in the RVM and exerts nociceptive or antinociceptive effects in different states of pain ( Feng et al, 2015 ). The low dose of NT in the RVM selectively activates the CCK2R in ON cells, increases the release of CCK, and produces thermal hyperalgesia, while high doses of NT recruit OFF cells and activate NT receptors, resulting in antinociception ( Neubert et al, 2004 ; Li et al, 2021 ). Both the high-affinity NT receptor (NTR1) and the low-affinity NT receptor (NTR2) are expressed in RVM, of which NTR1 is predominantly co-expressed with 5-HT, whereas NTR2 is rarely expressed in 5-HTergic neurons.…”

Section: Function and Molecular Characteristics Of Rvm On And Off Cellsmentioning

confidence: 99%

“…Both the high-affinity NT receptor (NTR1) and the low-affinity NT receptor (NTR2) are expressed in RVM, of which NTR1 is predominantly co-expressed with 5-HT, whereas NTR2 is rarely expressed in 5-HTergic neurons. Antinociception produced by PD149163 (NTR1 agonists) is blocked by methysergide (non-selective serotonergic receptor antagonists) and is partially blocked by intrathecal yohimbine (NA receptor antagonists), although β-LT (NTR2 agonists) induced antinociception is only inhibited by yohimbine ( Buhler et al, 2005 ; Buhler et al, 2008 ; Li et al, 2021 ). Taken together, it is plausible that NTR1-mediated antinociception is mediated by noradrenaline (NA) and 5-HT release, while NTR2-mediated antinociception involves spinal release of NE alone.…”

Section: Function and Molecular Characteristics Of Rvm On And Off Cellsmentioning

confidence: 99%

Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters

et al. 2023

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The rostral ventromedial medulla (RVM) is a bulbospinal nuclei in the descending pain modulation system, and directly affects spinal nociceptive transmission through pronociceptive ON cells and antinociceptive OFF cells in this area. The functional status of ON and OFF neurons play a pivotal role in pain chronification. As distinct pain modulative information converges in the RVM and affects ON and OFF cell excitability, neural circuits and transmitters correlated to RVM need to be defined for an in-depth understanding of central-mediated pain sensitivity. In this review, neural circuits including the role of the periaqueductal gray, locus coeruleus, parabrachial complex, hypothalamus, amygdala input to the RVM, and RVM output to the spinal dorsal horn are discussed. Meanwhile, the role of neurotransmitters is concluded, including serotonin, opioids, amino acids, cannabinoids, TRPV1, substance P and cholecystokinin, and their dynamic impact on both ON and OFF cell activities in modulating pain transmission. Via clarifying potential specific receptors of ON and OFF cells, more targeted therapies can be raised to generate pain relief for patients who suffer from chronic pain.

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Systemically administered neurotensin receptor agonist produces antinociception through activation of spinally projecting serotonergic neurons in the rostral ventromedial medulla

Cited by 3 publications

References 24 publications

The rostral ventromedial medulla modulates pain and depression-related behaviors caused by social stress

The rostral ventromedial medulla modulates pain and depression-related behaviors caused by social stress

Antinociceptive effects of nefopam activating descending serotonergic modulation via 5‐HT2 receptors in the nucleus raphe magnus

Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters

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