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Review

Role of the Dorsal Raphe Nucleus in Pain Processing

by
Huijie Zhang
1,†,
Lei Li
1,†,
Xujie Zhang
2,
Guanqi Ru
3 and
Weidong Zang
1,*
1
Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
2
Department of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China
3
Department of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Brain Sci. 2024, 14(10), 982; https://doi.org/10.3390/brainsci14100982 (registering DOI)
Submission received: 17 August 2024 / Revised: 20 September 2024 / Accepted: 26 September 2024 / Published: 28 September 2024
(This article belongs to the Section Neuroscience of Pain)
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Abstract

:
The dorsal raphe nucleus (DRN) has gained attention owing to its involvement in various physiological functions, such as sleep–awake, feeding, and emotion, with its analgesic role being particularly significant. It is described as the “pain inhibitory nucleus” in the brain. The DRN has diverse projections from hypothalamus, midbrain, and pons. In turn, the DRN is a major source of projections to diverse cortex, limbic forebrain thalamus, and the midbrain and contains highly heterogeneous neuronal subtypes. The activation of DRN neurons in mice prevents the establishment of neuropathic, chronic pain symptoms. Chemogenetic or optogenetic inhibition neurons in the DRN are sufficient to establish pain phenotypes, including long-lasting tactile allodynia, that scale with the extent of stimulation, thereby promoting nociplastic pain. Recent progress has been made in identifying the neural circuits and cellular mechanisms in the DRN that are responsible for sensory modulation. However, there is still a lack of comprehensive review addressing the specific neuron types in the DRN involved in pain modulation. This review summarizes the function of specific cell types within DRN in the pain regulation, and aims to improve understanding of the mechanisms underlying pain regulation in the DRN, ultimately offering insights for further exploration.

1. Structure of Dorsal Raphe Nucleus

The dorsal raphe nucleus (DRN), located in the ventromedial part of the midbrain periaqueductal gray, has a fan-shaped structure that is symmetrically distributed along the midline. It is highly heterogeneous in anatomical distribution, molecular markers, synaptic connectivity, and function and consists of various cell types, mainly including serotonergic neurons (5-HT neurons), GABAergic neurons (GABA neurons), dopaminergic neurons (DA neurons), glutamatergic neurons, and peptidergic neurons [1,2]. Among these, the 5-HT neurons are the most abundant, constituting approximately two-thirds of the neurons in the DRN [3,4]. They exhibit a clustered distribution and are predominantly found in the midline region. GABA neurons are second, accounting for about 25%. They predominantly are scattered on both sides of the wing [5]. DRN neurons exhibit heterogeneity and corelease neurotransmitters. For example, DRN 5-HT neurons corelease glutamate and serotonin [6], and some DA neurons co-release dopamine and glutamate [1]. In addition, the presence of glutamic acid decarboxylase 1 (GAD1) and GAD2, which are enzymes responsible for GABA synthesis, in 5-HT and glutamate neurons further demonstrates how the DRN neurons synthesize and release GABA as a neurotransmitter [7] (Figure 1).

2. Neurons within DRN Involved in Pain Control

As early as 1993, the DRN was described as the “pain inhibitory nucleus” in the brain [8]. A recent study found that implanting microelectrodes into the DRN and utilizing deep brain stimulation provided analgesia in patients [9,10], emphasizing the pivotal regulatory function of the DRN in pain management.

2.1. 5-HT Neurons

5-HT neurons within DRN are the main source of forebrain 5-HT. In previous research, 5-HT neurons have been commonly labeled using markers such as tryptophan hydroxylase (TPH), serotonin transporter (SERT), Pet1, or Sl6a4 expression genes. 5-HT released by these neurons can regulate the input of pain signals and influence pain processing. During inflammation, it interacts with proinflammatory factors and is introduced along the sensory afferent fibers (Aδ and C fibers), releasing nociceptive neurotransmitters to the dorsal horn of the spinal cord. The pain signals are then transmitted through ascending pathways to the cortex [11]. Studies have shown that the 5-HT knockout mice could increase pain sensitivity and reduced analgesic effects of opioids [12,13]. Additionally, acute traumatic stimulation has been reported to increase the activity of 5-HT neurons in the DRN [14], suggesting that 5-HT neurons in DRN may be an important target for pain treatment. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for depression clinically by blocking serotonin reuptake. Although SSRI have been suggested as an alternative treatment for chronic pain, the safety and effectiveness of SSRIs for pain condition is still uncertain [15].
5-HT receptors comprise 7 families (5-HT1-5-HT7) and approximately 15 receptor subtypes, which modulate neuronal activity [16,17]. Research reported that 5-HT modulates analgesic effects through 5-HT1 [18,19], 5-HT2 [20], and 5-HT7 [21] receptors, which are coupled to the Gq or Gi protein to reduce levels of cAMP and increase IP3 and DG levels. The 5-HT1A receptor appears to be involved in a variety of pain and mood disorders [22]. Hirvonen found an inverse correlation between 5-HT1A receptors binding potential and neuroticism [23]. 5-HT3 receptors depolarize the neuronal membrane [24]. In the central regulation of descending pain facilitation/inhibition from the DRN, various brain regions, such as the cortex, thalamus, and midbrain, are involved in the central regulation of descending pain facilitation/inhibition of DRN [25]. In a sciatic nerve ligation model, the activity of DRN 5-HT neurons increased and the levels of 5-HT released in the PFC increased. Optical stimulation of DRN5-HT–PFC alleviated sleep dysregulation induced by chronic pain [26]. Some research found a neural circuit between DRN and ACC modulated chronic pain-induced dysfunction. Activation of the ACC-DRN5-HT pathway reversed chronic pain-induced anxiety-like behaviors [27], and activation of the DRN5-HT–ACC pathway reversed sociability deficits [28]. Studies have measured serotonin release in the CeA and ACC. The neural activity of 5-HT neurons increased after formalin injection and increased 5-HT concentrations in the CeA and ACC [29]. In mice with spared nerve injury, the firing of 5-HT neurons in the DRN decreased and resulted in the disinhibition of CeASOM neurons. Activation of the DRN5-HT–CeASOM pathway relieved pain and depression-like behaviors. The study also used resting state fMRI to assess the neural circuit mechanisms for patients with chronic pain comorbid with depressive symptoms. The results showed that the functional connectivity of the DRN–CM pathway was decreased [30]. One such region is the lateral habenula (LHb), which can enhance the activity of 5-HT neurons in DRN through damaging LHb. This leads to an increased pain threshold in rats with neuropathic pain models [31]. These findings showed that 5-HT neurons in the DRN encode chronic pain by distinct pathway (Figure 2).
5-HT, referred to as the “mood boosters”, contributes to chronic pain comorbid anxiety and depression [32]. In inflammatory pain models and neuropathic pain models, the 5-HT levels in hippocampal and cortical regions increased significantly in the brain and the mice showed anxiety and depression-related behaviors, indicating a connection between reduced 5-HT levels and the development of anxiety and depression in the context of chronic pain [33,34]. Additionally, two brain regions, the bed nucleus of the stria terminalis (BNST) and the ventral tegmental area (VTA), are involved in encoding negative emotions and reward information, respectively [7]. These regions have been implicated in the modulation of anxiety and depression related to chronic pain. Furthermore, many small molecules have been identified that can influence the 5-HT system and participate in the regulation of pain-related negative emotions. For example, prostaglandin E2 [35], adiponectin [36], and cannabidiol [37,38] have been found to regulate the release of serotonin through 5-HT receptors. These molecules have the potential to be targeted for the treatment of chronic pain comorbid with anxiety and depression

2.2. GABA Neurons

A genetic study of pain intensity showed that gene expression has significant tissue-group enrichment, such as histone modification in the human midbrain, specifically in GABAergic neurons [39]. GABA neurons in the midbrain serve as a modulator of pain [40]. Functionally, GABA neurons have been reported to be antianalgesic in the DRN. Some studies have indicated that GABA neurons in the DRN are activated by noxious stimuli, such as plantar electrical stimulation and tail pinch [41]. Conversely, other research demonstrated that chemogenetic inhibition of GABA neurons in the DRN promoted nociceptive sensitivity, and activation of GABA neurons alleviated hyperalgesia induced by inflammatory pain or ovarian hormone withdrawal [40,42]. However, a contradiction is presented regarding the involvement of GABA neurons in pain modulation within the DRN. Given that synapses between GABA and 5-HT neurons are inhibitory, it has been hypothesized that the activation of GABA neurons may actually promote pain sensitization, revealing a potential contradiction in their role. Additionally, in vivo electrophysiological studies have shown that morphine directly activates 5-HT neurons without altering GABA neuron activity [43]. However, local GABAergic afferents can exert strong inhibitory postsynaptic currents on 5-HT neurons, potentially suppressing their activity [44,45]. These finding suggest that different neuronal microcircuits may be active in different states. This behavioral outcome may be attributed to the dynamic network activity during progressive pain. Because it is closely associated with some pain-related brain regions such as CeA, BNST, VTA, and ventrolateral periaqueductal gray (vlPAG) [5,46], future research should place greater focus on the role of GABA neurons within the DRN.

2.3. DA Neurons

DA neurons are the smaller population in the DRN, which do not overlap with 5-HT and GABA neurons and project to several brain regions, including the BNST, CeA, and VTA, through D1 and D2 dopamine receptors [47,48]. In addition to memory expression, drug addiction, and sleep rhythm, DA neurons are also involved in pain modulation [49,50]. DA neurons in DRN contribute to sex differences in pain-related behaviors [51]. Activation of DA neurons within DRN or vlPAG/DRN DA+ terminals in the BNST reduces nociceptive sensitivity induced by inflammatory pain in male mice, whereas activation of this pathway in female mice leads to increased locomotion in the presence of salient stimuli [52]. DA neurons corelease glutamate, and their role is similar to glutamatergic neurons in antinociception [53]. In addition, DA neurons within DRN play a role in opioid-related processes. They are disinhibited by opioid receptor agonists to attenuate nociceptive sensitivity [49,54,55] and activated by ethanol to reduce nociceptive sensitivity [52]. Opioids can directly activate mu-opioid receptors (MOR) or inhibit GABA release to disinhibit the activity of DA neurons. This modulation ultimately increases the release of dopamine and glutamate, which act on downstream targets such as the BNST to mediate analgesic effects [56,57]. Results have shown that the activity of DA neurons in DRN changes in response to pain, and these changes can mediate pain-related hyperalgesia by affecting dopamine synthesis and downstream neuronal circuits.

2.4. Glutamatergic Neurons

Cells within the DRN are glutamatergic, expressing the mRNA of either vesicular glutamate transporter 2 (VGLUT2) or VGLUT3. Among these, VGLUT3 is primarily found in 5-HT neurons within DRN. It has been observed that the basolateral amygdala (BA) receives dense innervation from DRN 5-HT neurons and is VGLUT3-positive. The DRN5-HT∩vGluT3-BA pathway is associated with social stimuli and anxiety-related stimuli [58]. VTA, as an award center, receives dense glutamatergic and serotonergic input from the DRN [59]. However, chronic pain increased the activity of DRN VGLUT3-positive glutamatergic, but not 5-HT neurons, projecting to the VTA in male mice, and inhibition of the DRNGlu-VTA pathway produced an analgesic effect in male mice [60,61]. In addition, there are SP receptors on glutamatergic neurons [62]. Substance P released from central terminals in the brain may act on these receptors, leading to the direct or indirect modulation of glutamate release. This interaction between SP and glutamate systems potentially plays a role in the regulation of pain.

2.5. Other Types of Neurons

In addition to glutamate and substance P, acetylcholine and mygalin have been reported to be involved in pain modulation. Specifically, microinjection of the cholinergic agonist carbachol into the DRN has been shown to produce a strong analgesic effect [63]. Additionally, a low concentration of mygalin into DRN can increase the threshold, while a high concentration of mygalin could decrease it. The mechanism behind this modulation may involve the polyamines acting on excitatory and inhibitory neurotransmission simultaneously [64].

3. Afferent and Efferent Connections

Since 5-HT and GABA neurons constitute approximately 90% of the total neuronal population in the DRN, our focus has been on the afferent and efferent connections of these two neuron types. The findings are as follows.

3.1. Afferent Connections

Whole-brain screening studies in mice identified that GABA neurons in DRN receive fiber input mainly from the hypothalamus, midbrain, and pons, including the somatic motor area (MO), NAc, BNST, lateral stiff nucleus (LH), CeA, vlPAG, midbrain reticular and nucleus (MRN), VTA, SNc, and pons-motor-related area (P-mot) [5,65,66]. Interestingly, several researchers have found that 5-HT neurons mainly received projections from PAG, MRN, LH, P-mot, substantia nigra pars reticulata (SNr), zona incerta (ZI), and IC [7,67], which are similar to the afferent brain regions of GABA neurons in the DRN, indicating that the two types of neurons may encode and regulate the same function. However, there are some differences between these two types of neurons. 5-HT neurons in the DRN receive preferential projections from cerebral cortex regions such as the medial prefrontal cortex (mPFC) and ACC [27,68]. On the other hand, GABA neurons in the DRN receive preferential projections from the CeA and VTA, reflecting the heterogeneity of neurons [59]. These differences indicate the heterogeneity of neurons within the DRN and suggest that the 5-HT and GABAergic systems may play distinct roles in pain processing and related functions.

3.2. Efferent Connections

The upstream fiber of the DRN is the main part of the efferent fiber. They are divided into three groups: dorsal group, middle group, and ventral group [69]. The dorsal group of efferent fibers from the DRN travels through the PAG and paraventricular thalamic nucleus (PVT). The medial bundle of DRN in the middle group is radially distributed through the ventrolateral side, and the ventral group travels in the VTA and the medial forebrain. 5-HT neurons can project upward to VTA and SNc in the midbrain. They also project along the medial forebrain tract (MFB) to many forebrain regions such as hypothalamus, thalamus, CeA, striatum (Str), Nac, and cortex [1,70,71], and can also project downward to the posterior brain region. The upstream efferent fibers of GABA neurons are more concentrated. Most of them establish local connections such as PAG and MRN. Some have long-range projections reaching distant brain structures, such as CeA and PVT, which, in turn, innervate back the DRN neurons. Studies have demonstrated that DRN 5-HT neurons can project to VTA, ACC, IC, and CeA to modulate pain [30,72,73]. They also can inhibit the activity of the spinal dorsal horn through synaptic relations with the nucleus raphe magnus (NRM) and also reach the spinal dorsal horn directly to inhibit the transmission of pain information [74]. DRNs are also related to opioids. Green light exposure would activate the projections from the ventral lateral geniculate nucleus (vLGN) proenkephalin (Penk)-positive neurons to the DRN by u-receptor producing analgesic effects [75].

4. Interaction between GABA Neurons and 5-HT Neurons

The activity of 5-HT neurons is adjusted by three main inhibitory mechanisms. The first one is that GABA neurons act on 5-HT neurons through GABAA receptors (GABAARs) and GABAB receptors (GABABRs) to suppress the activity of 5-HT neurons. The GABAARs are mainly distributed in the dorsal and dorsolateral fibers and terminus, while GABABRs are mainly located in the neuronal cell bodies and dendrites [76]. Optogenetic activation of GABA neurons in DRN and 5-HT neurons produced inhibitory postsynaptic currents (IPSCs), which were completely abolished by the tetrodotoxin (TTX) or GABAARs antagonists (gabazine), but then reappeared when 4-aminopyridine (4-AP) was used in the presence of TTX, confirming that the direct synaptic connections between 5-HT and GABA neurons and GABA acted on 5-HT neurons through GABAARs [77]. Interestingly, knockout of alpha 1-GABAARs of DRN, as the most highly expressed subunit in 5-HT DRN neurons, increased the sensitivity of anxiety-like behaviors [78]. In addition, recent researchers have detected that GABABRs were found on the synaptic membrane containing 5-HT granules under immunoelectron microscopy, and after microinjection of baclofen into the DRN, the 5-HT release decreased significantly [79,80]. This suggests that GABA can regulate 5-HT neurons through GABABRs. The second is a negative feedback mechanism. The axon branches or dendrites of 5-HT neurons release serotonin, which then activates potassium channels via the 5-HT1A autoreceptors to reduce the excitability of 5-HT neurons [81,82]. 5-HT KO mice also showed increased responsiveness of DRN 5-HT1A autoreceptors [83]. The third is regulated by some neuropeptides such as corticotropin-releasing factor (CRF). When animals cope with environmental challenges like pain, stress, or drug withdrawal, CRF levels increase in the brain, indirectly inhibiting 5-HT neurons by acting on CRF-1 receptors located on GABA neurons [84,85]. The activation mechanisms are regulated by glutamate and norepinephrine (NE). In most animals, 5-HT neurons spontaneously discharge in vivo, but they are silent in vitro. However, they can be evoked in vitro by glutamate and NE released from the locus coeruleus (LC). This activation occurs by inhibiting certain types of potassium (K+) channels, such as KCNQ/M and SK-type channels [86].
5-HT neurons also modulate the activity of GABA neurons [70]. GABA neurons express various serotonin receptors, including 5-HT1ARs, 5-HT2Rs, and 5-HT7Rs. Electrophysiological studies have revealed that the activation of 5-HT1ARs reduces the firing frequency of GABA neurons, whereas the activation of 5-HT2Rs and 5-HT7Rs increases the firing frequency of GABA neurons [66,87,88].
Functionally, studies have shown that GABA neurons and 5-HT neurons have opposing behavioral responses. For example, the calcium signal of GABA neurons decreased and the activity of 5-HT neurons increased in rewarding behavior [89]. Conversely, the activity of GABA neurons increased sharply when exposed to aversive stimulation such as plantar shock, whereas the activity of 5-HT neurons showed an inhibited tendency [40]. PFC to DRN would reach GABA neurons preferentially, and produce a rapid inhibition of 5-HT neurons to modulate depression-related behaviors [90]. These also prove that GABA regulates 5-HT expression.
5-HT neurons in DRN also have fiber connections with DA neurons. Research has found that dopamine could cause the depolarization of 5-HT neurons in DRN, and this effect could be antagonized by the D2 receptor antagonist sulpride [91]. Guiard [92] used 6-hydroxydopamine (6-OHDA) to selectively injure DA neurons, and observed that the spontaneous discharge rate of DRN 5-HT neurons in rats was significantly reduced. Therefore, we conclude that the excitation of DA to DRN 5-HT neurons is due to the facilitation of D2 receptors.
In summary, the excitability of DRN neurons is affected by local and external factors, but determining what kind of pathophysiological mechanism it uses in pain regulation needs further study.

5. Conclusions

In summary, the past decade has seen exponentially growing interest in the DRN in exploring the neural circuits and regulation of pain information. The DRN is a key hub for transmitting nociceptive signals from the spinal cord, ascending through the specific pathways to the cerebral cortex via the thalamus, and it plays a crucial role in inhibiting pain transmission. The detailed investigations into the molecular biological mechanism of GABA neurons’ interaction with 5-HT neurons have provided new insights into the dysfunction of the DRN. Despite these advancements, many important questions still remain unanswered. For instance, what is the relationship between the DRN and other pain-regulating brain regions such as the vlPAG, VTA, and thalamus? How does the excitability of 5-HT neurons change during the transition from acute to chronic pain? Future research that combines the identification of neuronal subtypes with project-specific targeting and in vivo single-cell recording hold promise for shedding new light on these unresolved questions, potentially leading to a deeper understanding of the DRN’s complex role in pain regulation.

Author Contributions

H.Z. and L.L. wrote the paper. X.Z. and G.R. analyzed and interpreted data. W.Z. supervised the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the grants from the National Natural Science Foundation of China (grant number 82371237) and the Program for Innovative Research Team in Universities of Henan Province (22IRTSTHN028).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Huang, K.W.; Ochandarena, N.E.; Philson, A.C.; Hyun, M.; Birnbaum, J.E.; Cicconet, M.; Sabatini, B.L. Molecular and anatomical organization of the dorsal raphe nucleus. eLife 2019, 8, e46464. [Google Scholar] [CrossRef] [PubMed]
  2. Monti, J.M. The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness. Sleep Med. Rev. 2010, 14, 307–317. [Google Scholar] [CrossRef] [PubMed]
  3. Dorocic, I.P.; Fürth, D.; Xuan, Y.; Johansson, Y.; Pozzi, L.; Silberberg, G.; Carlén, M.; Meletis, K. A Whole-Brain Atlas of Inputs to Serotonergic Neurons of the Dorsal and Median Raphe Nuclei. Neuron 2014, 83, 663–678. [Google Scholar] [CrossRef]
  4. Luo, M.M.; Li, Y.; Zhong, W.X. Do dorsal raphe 5-HT neurons encode “beneficialness”? Neurobiol. Learn Mem. 2016, 135, 40–49. [Google Scholar] [CrossRef]
  5. Xu, Z.C.; Feng, Z.; Zhao, M.T.; Sun, Q.T.; Deng, L.; Jia, X.Y.; Jiang, T.; Luo, P.; Chen, W.; Tudi, A.; et al. Whole-brain connectivity atlas of glutamatergic and GABAergic neurons in the mouse dorsal and median raphe nuclei. eLife 2021, 10, e65502. [Google Scholar] [CrossRef]
  6. Wang, H.L.; Zhang, S.L.; Qi, J.; Wang, H.K.; Cachope, R.; Mejias-Aponte, C.A.; Gomez, J.A.; Mateo-Semidey, G.E.; Beaudoin, G.M.J.; Paladini, C.A.; et al. Dorsal Raphe Dual Serotonin-Glutamate Neurons Drive Reward by Establishing Excitatory Synapses on VTA Mesoaccumbens Dopamine Neurons. Cell Rep. 2019, 26, 1128–1142. [Google Scholar] [CrossRef]
  7. Paquelet, G.E.; Carrion, K.; Lacefield, C.O.; Zhou, P.C.; Hen, R.; Miller, B.R. Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors. Neuron 2022, 110, 2664–2679. [Google Scholar] [CrossRef]
  8. Wang, Q.P.; Nakai, Y. The Dorsal Raphe—An Important Nucleus in Pain Modulation. Brain Res. Bull. 1994, 34, 575–585. [Google Scholar]
  9. Forni, M.; Thorbergsson, P.T.; Thelin, J.; Schouenborg, J. 3D microelectrode cluster and stimulation paradigm yield powerful analgesia without noticeable adverse effects. Sci. Adv. 2021, 7, eabj2847. [Google Scholar] [CrossRef]
  10. Forni, M.; Thorbergsson, P.T.; Gällentoft, L.; Thelin, J.; Schouenborg, J. Sustained and potent analgesia with negligible side effects enabled by adaptive individualized granular stimulation in rat brainstem. J. Neural Eng. 2023, 20, 036014. [Google Scholar] [CrossRef]
  11. Sommer, C. Serotonin in pain and analgesia. Mol. Neurobiol. 2004, 30, 117–125. [Google Scholar] [CrossRef] [PubMed]
  12. Zhao, Z.Q.; Chiechio, S.; Sun, Y.G.; Zhang, K.H.; Zhao, C.S.; Scott, M.; Johnson, R.L.; Deneris, E.S.; Renner, K.J.; Gereau, R.W.; et al. Mice lacking central serotonergic neurons show enhanced inflammatory pain and an impaired analgesic response to antidepressant drugs. J. Neurosci. 2007, 27, 6045–6053. [Google Scholar] [CrossRef] [PubMed]
  13. Perrin, F.E.; Noristani, H.N. Serotonergic mechanisms in spinal cord injury. Exp. Neurol. 2019, 318, 174–191. [Google Scholar] [CrossRef] [PubMed]
  14. Moriya, S.; Yamashita, A.; Nishi, R.; Ikoma, Y.; Yamanaka, A.; Kuwaki, T. Acute nociceptive stimuli rapidly induce the activity of serotonin and noradrenalin neurons in the brain stem of awake mice. IBRO Rep. 2019, 7, 1–9. [Google Scholar] [CrossRef] [PubMed]
  15. Lian, Y.N.; Wang, Y.; Zhang, Y.; Yang, C.X. Duloxetine for pain in fibromyalgia in adults: A systematic review and a meta-analysis. Int. J. Neurosci. 2020, 130, 71–82. [Google Scholar] [CrossRef] [PubMed]
  16. Yang, C.L.; Jing, J.J.; Fu, S.Y.; Zhong, Y.L.; Su, X.Z.; Shi, Z.M.; Wu, X.Z.; Yang, F.; Chen, G.Z. Ropivacaine-induced seizures evoked pain sensitization in rats: Participation of 5-HT/5-HT3R br. Neurotoxicology 2022, 93, 173–185. [Google Scholar] [CrossRef] [PubMed]
  17. Liu, Q.Q.; Yao, X.X.; Gao, S.H.; Li, R.; Li, B.J.; Yang, W.; Cui, R.J. Role of 5-HT receptors in neuropathic pain: Potential therapeutic implications. Pharmacol. Res. 2020, 159, 104949. [Google Scholar] [CrossRef]
  18. Cortes-Altamirano, J.L.; Olmos-Hernández, A.; Jaime, H.B.; Carrillo-Mora, P.; Bandala, C.; Reyes-Long, S.; Alfaro-Rodríguez, A. Review: 5-HT1, 5-HT2, 5-HT3 and 5-HT7 Receptors and their Role in the Modulation of Pain Response in the Central Nervous System. Curr. Neuropharmacol. 2018, 16, 210–221. [Google Scholar] [CrossRef]
  19. Zhang, L.Q.; Zhou, Y.Q.; Li, J.Y.; Sun, J.; Zhang, S.; Wu, J.Y.; Gao, S.J.; Tian, X.B.; Mei, W. 5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation. Front. Pharmacol. 2022, 13, 834570. [Google Scholar] [CrossRef]
  20. Okumura, T.; Nozu, T.; Ishioh, M.; Igarashi, S.; Kumei, S.; Ohhira, M. 5-HT receptors but not cannabinoid receptors in the central nervous system mediate levodopa-induced visceral antinociception in conscious rats. Naunyn-Schmiedeberg Arch. Pharmacol. 2020, 393, 1419–1425. [Google Scholar] [CrossRef]
  21. Yang, J.; Bae, H.B.; Ki, H.G.; Oh, J.M.; Kim, W.M.; Lee, H.G.; Yoon, M.H.; Choi, J.I. Different role of spinal 5-HT(hydroxytryptamine)7 receptors and descending serotonergic modulation in inflammatory pain induced in formalin and carrageenan rat models. Br. J. Anaesth. 2014, 113, 138–147. [Google Scholar] [CrossRef] [PubMed]
  22. Li, Y.; Zhu, J.; Zheng, Q.; Qian, Z.; Zhang, L.; Wei, C.; Han, J.; Liu, Z.; Ren, W. 5-HT1A autoreceptor in dorsal raphe nucleus mediates sensitization of conditioned place preference to cocaine in mice experienced with chronic pain. Neuroreport 2019, 30, 681–687. [Google Scholar] [CrossRef] [PubMed]
  23. Hirvonen, J.; Tuominen, L.; Någren, K.; Hietala, J. Neuroticism and serotonin 5-HT1A receptors in healthy subjects. Psychiatry Res. Neuroimaging 2015, 234, 1–6. [Google Scholar] [CrossRef] [PubMed]
  24. Cornelison, L.E.; Woodman, S.E.; Durham, P.L. 5-HT3/7 and GABA receptors mediate inhibition of trigeminal nociception by dietary supplementation of grape seed extract. Nutr. Neurosci. 2022, 25, 1565–1576. [Google Scholar] [CrossRef]
  25. Khan, K.M.; de la Rosa, G.B.; Biggerstaff, N.; Selvakumar, G.P.; Wang, R.X.; Mason, S.; Dailey, M.E.; Marcinkiewcz, C.A. Adolescent ethanol drinking promotes hyperalgesia, neuroinflammation and serotonergic deficits in mice that persist into adulthood. Brain Behav. Immun. 2023, 107, 419–431. [Google Scholar] [CrossRef]
  26. Ito, H.; Yanase, M.; Yamashita, A.; Kitabatake, C.; Hamada, A.; Suhara, Y.; Narita, M.; Ikegami, D.; Sakai, H.; Yamazaki, M.; et al. Analysis of sleep disorders under pain using an optogenetic tool: Possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons. Mol. Brain 2013, 6, 59. [Google Scholar] [CrossRef]
  27. Wu, Z.M.; Shen, Z.; Xu, Y.L.; Chen, S.Z.; Xiao, S.Q.; Ye, J.Y.; Zhang, H.Y.; Ma, X.Y.; Zhu, Y.C.; Zhu, X.X.; et al. A neural circuit associated with anxiety-like behaviors induced by chronic inflammatory pain and the anxiolytic effects of electroacupuncture. CNS Neurosci. Ther. 2024, 30, e14520. [Google Scholar] [CrossRef]
  28. Li, L.; Zhang, L.-Z.; He, Z.-X.; Ma, H.; Zhang, Y.-T.; Xun, Y.-F.; Yuan, W.; Hou, W.-J.; Li, Y.-T.; Lv, Z.-J.; et al. Dorsal raphe nucleus to anterior cingulate cortex 5-HTergic neural circuit modulates consolation and sociability. eLife 2021, 10, e67638. [Google Scholar] [CrossRef]
  29. Akbar, L.; Castillo, V.C.G.; Olorocisimo, J.P.; Ohta, Y.; Kawahara, M.; Takehara, H.; Haruta, M.; Tashiro, H.; Sasagawa, K.; Ohsawa, M.; et al. Multi-Region Microdialysis Imaging Platform Revealed Dorsal Raphe Nucleus Calcium Signaling and Serotonin Dynamics during Nociceptive Pain. Int. J. Mol. Sci. 2023, 24, 6654. [Google Scholar] [CrossRef]
  30. Zhou, W.J.; Jin, Y.; Meng, Q.; Zhu, X.; Bai, T.J.; Tian, Y.H.; Mao, Y.; Wang, L.K.; Xie, W.; Zhong, H.; et al. A neural circuit for comorbid depressive symptoms in chronic pain. Nat. Neurosci. 2019, 22, 1649–1658, Erratum in Nat. Neurosci. 2019, 22, 1945. [Google Scholar] [CrossRef]
  31. Li, Y.H.; Wang, Y.M.; Xuan, C.L.; Li, Y.; Piao, L.H.; Li, J.C.; Zhao, H. Role of the Lateral Habenula in Pain-Associated Depression. Front. Behav. Neurosci. 2017, 11, 31. [Google Scholar] [CrossRef] [PubMed]
  32. Bacqué-Cazenave, J.; Bharatiya, R.; Barrière, G.; Delbecque, J.P.; Bouguiyoud, N.; Di Giovanni, G.; Cattaert, D.; De Deurwaerdère, P. Serotonin in Animal Cognition and Behavior. Int. J. Mol. Sci. 2020, 21, 1649. [Google Scholar] [CrossRef] [PubMed]
  33. Saffarpour, S.; Nasirinezhad, F. The CA1 hippocampal serotonin alterations involved in anxiety-like behavior induced by sciatic nerve injury in rats. Scand. J. Pain 2021, 21, 135–144. [Google Scholar] [CrossRef] [PubMed]
  34. Zhou, Y.S.; Meng, F.C.; Cui, Y.; Xiong, Y.L.; Li, X.Y.; Meng, F.B.; Niu, Z.X.; Zheng, J.X.; Quan, Y.Q.; Wu, S.X.; et al. Regular Aerobic Exercise Attenuates Pain and Anxiety in Mice by Restoring Serotonin-Modulated Synaptic Plasticity in the Anterior Cingulate Cortex. Med. Sci. Sports Exerc. 2022, 54, 566–581. [Google Scholar] [CrossRef] [PubMed]
  35. Singh, A.K.; Zajdel, J.; Mirrasekhian, E.; Almoosawi, N.; Frisch, I.; Klawonn, A.M.; Jaarola, M.; Fritz, M.; Engblom, D. Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain. J. Clin. Investig. 2017, 127, 1370–1374. [Google Scholar] [CrossRef]
  36. Li, C.; Meng, F.T.; Garza, J.C.; Liu, J.; Lei, Y.; Kirov, S.A.; Guo, M.; Lu, X.Y. Modulation of depression-related behaviors by adiponectin AdipoR1 receptors in 5-HT neurons. Mol. Psychiatr. 2021, 26, 4205–4220. [Google Scholar] [CrossRef]
  37. Colangeli, R.; Teskey, G.C.; Di Giovanni, G. Endocannabinoid-serotonin systems interaction in health and disease. In Progress in Brain Research; 5-Ht Interaction with Other Neurotransmitters: Experimental Evidence and Therapeutic Relevance, Part A; Elsevier: Amsterdam, The Netherlands, 2021; Volume 259, pp. 83–134. [Google Scholar] [CrossRef]
  38. De Gregorio, D.; McLaughlin, R.J.; Posa, L.; Ochoa-Sanchez, R.; Enns, J.; Lopez-Canul, M.; Aboud, M.; Maione, S.; Comai, S.; Gobbi, G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain 2019, 160, 136–150. [Google Scholar] [CrossRef]
  39. Toikumo, S.; Vickers-Smith, R.; Jinwala, Z.; Xu, H.; Saini, D.; Hartwell, E.E.; Pavicic, M.; Sullivan, K.A.; Xu, K.; Jacobson, D.A.; et al. A multi-ancestry genetic study of pain intensity in 598,339 veterans. Nat. Med. 2024, 30, 1075–1084. [Google Scholar] [CrossRef]
  40. Xie, L.H.; Wu, H.; Chen, Q.; Xu, F.; Li, H.; Xu, Q.; Jiao, C.C.; Sun, L.H.; Ullah, R.; Chen, X.Z. Divergent modulation of pain and anxiety by GABAergic neurons in the ventrolateral periaqueductal gray and dorsal raphe. Neuropsychopharmacology 2023, 48, 1509–1519. [Google Scholar] [CrossRef]
  41. Ren, S.; Zhang, C.; Yue, F.; Tang, J.; Zhang, W.; Zheng, Y.; Fang, Y.; Wang, N.; Song, Z.; Zhang, Z.; et al. A midbrain GABAergic circuit constrains wakefulness in a mouse model of stress. Nat. Commun. 2024, 15, 2722. [Google Scholar] [CrossRef]
  42. Wu, H.; Xie, L.; Chen, Q.; Xu, F.; Dai, A.; Ma, X.; Xie, S.; Li, H.; Zhu, F.; Jiao, C.; et al. Activation of GABAergic neurons in the dorsal raphe nucleus alleviates hyperalgesia induced by ovarian hormone withdrawal. Pain 2024. online ahead of print. [Google Scholar] [CrossRef] [PubMed]
  43. Fu, B.; Yao, J.Q.; Lu, C.; Wang, B.; Li, Z.Q.; Huang, M.; Tian, T.; Peng, H.; Liu, S.J. Dorsal Raphe Nucleus Serotoninergic Neurons Mediate Morphine Rewarding Effect and Conditioned Place Preference. Neuroscience 2022, 480, 108–116. [Google Scholar] [CrossRef] [PubMed]
  44. Zhou, L.; Liu, M.Z.; Li, Q.; Deng, J.; Mu, D.; Sun, Y.G. Organization of Functional Long-Range Circuits Controlling the Activity of Serotonergic Neurons in the Dorsal Raphe Nucleus. Cell Rep. 2017, 20, 1991–1993. [Google Scholar] [CrossRef]
  45. Cai, P.; Wang, F.D.; Yao, J.; Wang, W.F.; Hu, Y.D.; Liu, R.F.; Li, Z.S.; Zhu, Z.H.; Cai, Y.T.; Lin, Z.H.; et al. Regulation of wakefulness by GABAergic dorsal raphe nucleus-ventral tegmental area pathway. Sleep 2022, 45, zsac235. [Google Scholar] [CrossRef]
  46. Paretkar, T.; Dimitrov, E. Activation of enkephalinergic (Enk) interneurons in the central amygdala (CeA) buffers the behavioral effects of persistent pain. Neurobiol. Dis. 2019, 124, 364–372. [Google Scholar] [CrossRef]
  47. Choi, J.E.; Choi, D.I.; Lee, J.; Kim, J.; Kim, M.J.; Hong, I.; Jung, H.; Sung, Y.; Kim, J.I.; Kim, T.; et al. Synaptic ensembles between raphe and D1R-containing accumbens shell neurons underlie postisolation sociability in males. Sci. Adv. 2022, 8, eabo7527. [Google Scholar] [CrossRef]
  48. Cai, X.; Liu, H.L.; Feng, B.; Yu, M.; He, Y.; Liu, H.S.; Liang, C.; Yang, Y.J.; Tu, L.L.; Zhang, N.; et al. A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice. Nat. Neurosci. 2022, 25, 646–658. [Google Scholar] [CrossRef]
  49. Lin, R.; Liang, J.W.; Wang, R.Y.; Yan, T.; Zhou, Y.T.; Liu, Y.; Feng, Q.R.; Sun, F.M.; Li, Y.L.; Li, A.A.; et al. The Raphe Dopamine System Controls the Expression of Incentive Memory. Neuron 2021, 106, 498–514.e8. [Google Scholar] [CrossRef]
  50. Lin, R.; Liang, J.W.; Luo, M.M. The Raphe Dopamine System: Roles in Salience Encoding, Memory Expression, and Addiction. Trends Neurosci. 2021, 44, 366–377. [Google Scholar] [CrossRef]
  51. Yu, W.; Pati, D.; Pina, M.M.; Schmidt, K.T.; Boyt, K.M.; Hunker, A.C.; Zweifel, L.S.; McElligott, Z.A.; Kash, T.L. Periaqueductal gray/dorsal raphe dopamine neurons contribute to sex differences in pain-related behaviors. Neuron 2021, 109, 1365–1380.e5. [Google Scholar] [CrossRef]
  52. Taylor, N.E.; Pei, J.Z.; Zhang, J.; Vlasov, K.Y.; Davis, T.; Taylor, E.; Weng, F.J.; Van Dort, C.J.; Solt, K.; Brown, E.N. The Role of Glutamatergic and Dopaminergic Neurons in the Periaqueductal Gray/Dorsal Raphe: Separating Analgesia and Anxiety. Eneuro 2019, 6, ENEURO.0018-0018. [Google Scholar] [CrossRef] [PubMed]
  53. Taylor, A.M.W.; Becker, S.; Schweinhardt, P.; Cahill, C. Mesolimbic dopamine signaling in acute and chronic pain: Implications for motivation, analgesia, and addiction. Pain 2016, 157, 1194–1198. [Google Scholar] [CrossRef]
  54. Li, C.; Kash, T.L. κ-Opioid Receptor Modulation of GABAergic Inputs onto Ventrolateral Periaqueductal Gray Dopamine Neurons. Complex Psychiatry 2019, 5, 190–199. [Google Scholar] [CrossRef]
  55. Flores, J.A.; El Banoua, F.; Galán-Rodríguez, B.; Fernandez-Espejo, E. Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: Critical role for D1 (not D2) dopamine receptors. Pain 2004, 110, 205–214. [Google Scholar] [CrossRef]
  56. Li, C.; Sugam, J.A.; Lowery-Gionta, E.G.; McElligott, Z.A.; McCall, N.M.; Lopez, A.J.; McKlveen, J.M.; Pleil, K.E.; Kash, T.L. Mu Opioid Receptor Modulation of Dopamine Neurons in the Periaqueductal Gray/Dorsal Raphe: A Role in Regulation of Pain. Neuropsychopharmacology 2016, 41, 2122–2132. [Google Scholar] [CrossRef]
  57. Poulin, J.F.; Zou, J.; Drouin-Ouellet, J.; Kim, K.Y.A.; Cicchetti, F.; Awatramani, R.B. Defining Midbrain Dopaminergic Neuron Diversity by Single-Cell Gene Expression Profiling. Cell Rep. 2014, 9, 930–943. [Google Scholar] [CrossRef]
  58. Yu, X.D.; Zhu, Y.; Sun, Q.X.; Deng, F.; Wan, J.X.; Zheng, D.; Gong, W.K.; Xie, S.Z.; Shen, C.J.; Fu, J.Y.; et al. Distinct serotonergic pathways to the amygdala underlie separate behavioral features of anxiety. Nat. Neurosci. 2022, 25, 1651. [Google Scholar] [CrossRef]
  59. McDevitt, R.A.; Tiran-Cappello, A.; Shen, H.; Balderas, I.; Britt, J.P.; Marino, R.A.M.; Chung, S.L.; Richie, C.T.; Harvey, B.K.; Bonci, A. Serotonergic versus Nonserotonergic Dorsal Raphe Projection Neurons: Differential Participation in Reward Circuitry. Cell Rep. 2014, 8, 1857–1869. [Google Scholar] [CrossRef]
  60. Liu, D.; Hu, S.-W.; Wang, D.; Zhang, Q.; Zhang, X.; Ding, H.-L.; Cao, J.-L. An Ascending Excitatory Circuit from the Dorsal Raphe for Sensory Modulation of Pain. J. Neurosci. 2024, 44, e0869232023. [Google Scholar] [CrossRef]
  61. Wang, X.Y.; Jia, W.B.; Xu, X.; Chen, R.; Wang, L.B.; Su, X.J.; Xu, P.F.; Liu, X.Q.; Wen, J.; Song, X.Y.; et al. A glutamatergic DRN-VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice. Nat. Commun. 2023, 14, 5124. [Google Scholar] [CrossRef]
  62. Ma, Q.P.; Bleasdale, C. Modulation of brain stem monoamines and γ-aminobutyric acid by NKI receptors in rats. Neuroreport 2002, 13, 1809–1812. [Google Scholar] [CrossRef] [PubMed]
  63. Klamt, J.G.; Prado, W.A. Antinociception and Behavioral-Changes Induced by Carbachol Microinjected into Identified Sites of the Rat-Brain. Brain Res. 1991, 549, 9–18. [Google Scholar] [CrossRef] [PubMed]
  64. Gao, N.; Shi, H.P.; Hu, S.; Zha, B.X.; Yuan, A.H.; Shu, J.H.; Fan, Y.Q.; Bai, J.; Xie, H.Y.; Cui, J.C.; et al. Acupuncture Enhances Dorsal Raphe Functional Connectivity in Knee Osteoarthritis With Chronic Pain. Front. Neurol. 2022, 12, 813723. [Google Scholar] [CrossRef] [PubMed]
  65. Weissbourd, B.; Ren, J.; DeLoach, K.E.; Guenthner, C.J.; Miyamichi, K.; Luo, L.Q. Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons. Neuron 2014, 83, 645–662. [Google Scholar] [CrossRef] [PubMed]
  66. Broadbelt, K.G.; Paterson, D.S.; Rivera, K.D.; Trachtenberg, F.L.; Kinney, H.C. Neuroanatomic relationships between the GABAergic and serotonergic systems in the developing human medulla. Auton. Neurosci. 2010, 154, 30–41. [Google Scholar] [CrossRef]
  67. Peyron, C.; Rampon, C.; Petit, J.M.; Luppi, P.H. Sub-regions of the dorsal raphe nucleus receive different inputs from the brainstem. Sleep Med. 2018, 49, 53–63. [Google Scholar] [CrossRef]
  68. Commons, K.G. Ascending serotonin neuron diversity under two umbrellas. Brain Struct. Funct. 2016, 221, 3347–3360. [Google Scholar] [CrossRef]
  69. Vasudeva, R.K.; Lin, R.C.S.; Simpson, K.L.; Waterhouse, B.D. Functional organization of the dorsal raphe efferent system with special consideration of nitrergic cell groups. J. Chem. Neuroanat. 2011, 41, 281–293. [Google Scholar] [CrossRef]
  70. Hernandez-Vazquez, F.; Garduno, J.; Hernandez-Lopez, S. GABAergic modulation of serotonergic neurons in the dorsal raphe nucleus. Rev. Neurosci. 2019, 30, 289–303. [Google Scholar] [CrossRef]
  71. Satija, R.; Farrell, J.A.; Gennert, D.; Schier, A.F.; Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 2015, 33, 495–502. [Google Scholar] [CrossRef]
  72. Santello, M.; Nevian, T. Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation. Neuron 2015, 86, 233–246. [Google Scholar] [CrossRef] [PubMed]
  73. Ng, A.J.; Vincelette, L.K.; Li, J.Y.; Brady, B.H.; Christianson, J.P. Serotonin modulates social responses to stressed conspecifics via insular 5-HT2C receptors in rat. Neuropharmacology 2023, 236, 529065. [Google Scholar] [CrossRef] [PubMed]
  74. Shen, L.; Qiu, H.B.; Xu, H.H.; Wei, K.; Zhao, L.; Zhu, C.C.; Li, C.J.; Lu, Z.J. Nicotine withdrawal induces hyperalgesia via downregulation of descending serotonergic pathway in the nucleus raphe magnus. Neuropharmacology 2021, 189, 108515. [Google Scholar] [CrossRef] [PubMed]
  75. Tang, Y.L.; Liu, A.L.; Lv, S.S.; Zhou, Z.R.; Cao, H.; Weng, S.J.; Zhang, Y.Q. Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus. Sci. Transl. Med. 2022, 14, eabq6474. [Google Scholar] [CrossRef]
  76. Suzuki, T.; Nurrochmad, A.; Ozaki, M.; Khotib, J.; Nakamura, A.; Imai, S.; Shibasaki, M.; Yajima, Y.; Narita, M. Effect of a selective GABA(B) receptor agonist baclofen on the μ-opioid receptor agonist-induced antinociceptive, emetic and rewarding effects. Neuropharmacology 2005, 49, 1121–1131. [Google Scholar] [CrossRef]
  77. Zhou, L.C.; Liu, D.; Xie, Z.D.; Deng, D.; Shi, G.Q.; Zhao, J.L.; Bai, S.S.; Yang, L.; Zhang, R.; Shi, Y.F. Electrophysiological Characteristics of Dorsal Raphe Nucleus in Tail Suspension Test. Front. Behav. Neurosci. 2022, 16, 893465. [Google Scholar] [CrossRef]
  78. Li, C.; Mcelroy, B.D.; Phillips, J.; Mccloskey, N.S.; Shi, X.D.; Unterwald, E.M.; Kirby, L.G. Role of α1-GABA receptors in the serotonergic dorsal raphe nucleus in models of opioid reward, anxiety, and depression. J. Psychopharmacol. 2024, 38, 188–199. [Google Scholar] [CrossRef]
  79. Liu, X.J.; Wang, H.J.; Wang, X.Y.; Ning, Y.X.; Gao, J. GABABR1 in DRN mediated GABA to regulate 5-HT expression in multiple brain regions in male rats with high and low aggressive behavior. Neurochem. Int. 2021, 150, 105180. [Google Scholar] [CrossRef]
  80. Liu, X.J.; Wang, H.J.; Wang, X.Y.; Ning, Y.X.; Liu, W.; Gao, J. Baixiangdan capsule and Shuyu capsule regulate anger-out and anger-in, respectively: GB1-mediated GABA can regulate 5-HT levels in multiple brain regions. Aging 2023, 15, 2046–2065. [Google Scholar] [CrossRef]
  81. Sun, N.; Qin, Y.J.; Xu, C.; Xia, T.; Du, Z.W.; Zheng, L.P.; Li, A.A.; Meng, F.; Zhang, Y.; Zhang, J.; et al. Design of fast-onset antidepressant by dissociating SERT from nNOS in the DRN. Science 2022, 378, 390–398. [Google Scholar] [CrossRef]
  82. Yaman, B.; Bal, R. Pindolol potentiates the antidepressant effect of venlafaxine by inhibiting 5-HT1A receptor in DRN neurons of mice. Int. J. Neurosci. 2022, 132, 23–30. [Google Scholar] [CrossRef] [PubMed]
  83. Mazzocco, M.T.; Guarnieri, F.C.; Monzani, E.; Benfenati, F.; Valtorta, F.; Comai, S. Dysfunction of the serotonergic system in the brain of synapsin triple knockout mice is associated with behavioral abnormalities resembling synapsin-related human pathologies. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2021, 105, 110135. [Google Scholar] [CrossRef]
  84. Li, C.; McCloskey, N.; Phillips, J.; Simmons, S.J.; Kirby, L.G. CRF-5-HT interactions in the dorsal raphe nucleus and motivation for stress-induced opioid reinstatement. Psychopharmacology 2021, 238, 29–40. [Google Scholar] [CrossRef] [PubMed]
  85. Kijima, T.; Muroi, Y.; Ishii, T. Regulation of Maternal Care by Corticotropin-Releasing Factor Receptors in the Dorsal Raphe Nucleus in Mice. Behav. Neurosci. 2021, 135, 359–368. [Google Scholar] [CrossRef]
  86. Wang, J.; Wang, Y.Z.; Du, X.A.; Zhang, H.L. Potassium Channel Conductance Is Involved in Phenylephrine-Induced Spontaneous Firing of Serotonergic Neurons in the Dorsal Raphe Nucleus. Front. Cell Neurosci. 2022, 16, 891912. [Google Scholar] [CrossRef]
  87. Devroye, C.; Haddjeri, N.; Cathala, A.; Rovera, R.; Drago, F.; Piazza, P.V.; Artigas, F.; Spampinato, U. Opposite control of mesocortical and mesoaccumbal dopamine pathways by serotonin receptor blockade: Involvement of medial prefrontal cortex serotonin receptors. Neuropharmacology 2017, 119, 91–99. [Google Scholar] [CrossRef]
  88. Wang, S.; Zhao, Y.; Gao, J.; Guo, Y.; Wang, X.; Huo, J.; Wei, P.; Cao, J. In Vivo Effect of a 5-HT7 Receptor Agonist on 5-HT Neurons and GABA Interneurons in the Dorsal Raphe Nuclei of Sham and PD Rats: An Electrophysiological Study. Am. J. Alzheimers Dis. 2017, 32, 73–81. [Google Scholar] [CrossRef]
  89. Rahaman, S.M.; Chowdhury, S.; Mukai, Y.; Ono, D.; Yamaguchi, H.; Yamanaka, A. Functional Interaction Between GABAergic Neurons in the Ventral Tegmental Area and Serotonergic Neurons in the Dorsal Raphe Nucleus. Front. Neurosci. 2022, 16, 87705. [Google Scholar] [CrossRef]
  90. Lin, S.; Huang, L.; Luo, Z.C.; Li, X.; Jin, S.Y.; Du, Z.J.; Wu, D.Y.; Xiong, W.C.; Huang, L.; Luo, Z.Y.; et al. The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway. Biol. Psychiatry 2022, 92, 179–192. [Google Scholar] [CrossRef]
  91. Sellnow, R.C.; Newman, J.H.; Chambers, N.; West, A.R.; Steece-Collier, K.; Sandoval, I.M.; Benskey, M.J.; Bishop, C.; Manfredsson, F.P. Regulation of dopamine neurotransmission from serotonergic neurons by ectopic expression of the dopamine D2 autoreceptor blocks levodopa-induced dyskinesia. Acta Neuropathol. Com. 2019, 7, 8. [Google Scholar] [CrossRef]
  92. Guiard, B.P.; El Mansari, M.; Merali, Z.; Blier, P. Functional interactions between dopamine, serotonin and norepinephrine neurons: An in-vivo electrophysiological study in rats with monoaminergic lesions. Int. J. Neuropsychoph. 2008, 11, 625–639. [Google Scholar] [CrossRef] [PubMed]
Brainsci 14 00982 g001
Figure 1. Neurons of distribution in DRN. Neurons in the DRN mainly use serotonin as neurotransmitters, which are predominantly in the midline region. GABAergic neurons are second, being scattered on both sides of the wing. Dopaminergic neurons are close to the midbrain periaqueductal gray. Most glutamatergic neurons are colabeled with 5-HT neurons. There are interactions between GABAergic neurons and serotonergic neurons.
Figure 1. Neurons of distribution in DRN. Neurons in the DRN mainly use serotonin as neurotransmitters, which are predominantly in the midline region. GABAergic neurons are second, being scattered on both sides of the wing. Dopaminergic neurons are close to the midbrain periaqueductal gray. Most glutamatergic neurons are colabeled with 5-HT neurons. There are interactions between GABAergic neurons and serotonergic neurons.
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Figure 2. Afferent and efferent connectivity networks of DRN involved in pain regulation. On the output side, serotonergic neurons in the dorsal raphe nucleus (DRN) projecting to the prefrontal cortex (PFC), anterior cingulate cortex (ACC), central amygdala (CeA), and insular cortex (IC) modulate chronic pain comorbid anxiety and depression. Dopaminergic neurons in the DRN projecting to the bed nucleus of the stria terminalis (BNST) mediate analgesic effects. Glutamatergic neurons in the DRN project to the ventral tegmental area (VTA). In addition, DRN sends direct or indirect inputs to the dorsal horn of the spinal cord to inhibit the activity via the raphe magnus nucleus (NRM). On the input side, DRN preferentially receives inputs from GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG), glutamatergic neurons in the lateral habenula (LHb), and proenkephalin-positive neurons in the ventral lateral geniculate nucleus (vLGN) to regulate pain.
Figure 2. Afferent and efferent connectivity networks of DRN involved in pain regulation. On the output side, serotonergic neurons in the dorsal raphe nucleus (DRN) projecting to the prefrontal cortex (PFC), anterior cingulate cortex (ACC), central amygdala (CeA), and insular cortex (IC) modulate chronic pain comorbid anxiety and depression. Dopaminergic neurons in the DRN projecting to the bed nucleus of the stria terminalis (BNST) mediate analgesic effects. Glutamatergic neurons in the DRN project to the ventral tegmental area (VTA). In addition, DRN sends direct or indirect inputs to the dorsal horn of the spinal cord to inhibit the activity via the raphe magnus nucleus (NRM). On the input side, DRN preferentially receives inputs from GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG), glutamatergic neurons in the lateral habenula (LHb), and proenkephalin-positive neurons in the ventral lateral geniculate nucleus (vLGN) to regulate pain.
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Zhang, H.; Li, L.; Zhang, X.; Ru, G.; Zang, W. Role of the Dorsal Raphe Nucleus in Pain Processing. Brain Sci. 2024, 14, 982. https://doi.org/10.3390/brainsci14100982

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Zhang H, Li L, Zhang X, Ru G, Zang W. Role of the Dorsal Raphe Nucleus in Pain Processing. Brain Sciences. 2024; 14(10):982. https://doi.org/10.3390/brainsci14100982

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Zhang, Huijie, Lei Li, Xujie Zhang, Guanqi Ru, and Weidong Zang. 2024. "Role of the Dorsal Raphe Nucleus in Pain Processing" Brain Sciences 14, no. 10: 982. https://doi.org/10.3390/brainsci14100982

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