The coexistence of VGluT2 and neurotensin or leu-enkephalin in the medullary dorsal horn: A confocal and electron microscopic immunohistochemical study in the rat

Liu, Tao; Li, Jinlian; Liu, Hui; Wang, Xin; Fan, Feiyan; Zhang, Pengxing; Tu, Yanyang; Zhang, Yongsheng

doi:10.1016/j.neulet.2014.11.008

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…In situ hybridization experiments confirmed Cre activity in the majority of Penk+ neurons (tdTomato: 78% ± 1.6%; n = 4; YFP: 88% ± 2.5%; n = 6) (Figure S1C; Figure 1B), with very limited Penk expression in DRG neurons (Figure S1B), consistent with previous reports (Harlan et al, 1987;Marvizó n et al, 2009;Pohl et al, 1994;Seybold and Elde, 1980). Immunohistochemical and electrophysiological analyses indicated that Penk+ dorsal horn neurons consist of a mixed population of GABAergic and glutamatergic neurons (Figure S1D; Figures 1C and 1D) throughout spinal laminae I to III (37% ± 2.7% of all neurons in LI-III express Penk) (Figure S1E), as shown previously (Chen et al, 2014;Harlan et al, 1987;Huang et al, 2008;Liu et al, 2015;Todd et al, 2003).…”

Section: Spinal Enkephalinergic Neurons Controlling Nociception Receive Inputs From the Rvmsupporting

confidence: 91%

A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins

François¹,

Low²,

Sypek³

et al. 2017

Neuron

256

226

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Pain thresholds are, in part, set as a function of emotional and internal states by descending modulation of nociceptive transmission in the spinal cord. Neurons of the rostral ventromedial medulla (RVM) are thought to critically contribute to this process; however, the neural circuits and synaptic mechanisms by which distinct populations of RVM neurons facilitate or diminish pain remain elusive. Here we used in vivo opto/chemogenetic manipulations and trans-synaptic tracing of genetically identified dorsal horn and RVM neurons to uncover an RVM-spinal cord-primary afferent circuit controlling pain thresholds. Unexpectedly, we found that RVM GABAergic neurons facilitate mechanical pain by inhibiting dorsal horn enkephalinergic/GABAergic interneurons. We further demonstrate that these interneurons gate sensory inputs and control pain through temporally coordinated enkephalin- and GABA-mediated presynaptic inhibition of somatosensory neurons. Our results uncover a descending disynaptic inhibitory circuit that facilitates mechanical pain, is engaged during stress, and could be targeted to establish higher pain thresholds. VIDEO ABSTRACT.

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Section: Spinal Enkephalinergic Neurons Controlling Nociception Receive Inputs From the Rvmsupporting

confidence: 91%

A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins

François¹,

Low²,

Sypek³

et al. 2017

Neuron

256

226

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“…Given the plethora of different glutamatergic receptors present on enteric neurons, it is likely that glutamate has multiple functional roles, depending on circuit state and whether it is released from VGLUT2 Long or VGLUT2 Circ . Glutamate release from a source that is extrinsic to the ENS may also have played a role in disrupting GI transit in the cell-type specific KO experiments, due to Penk/VGLUT2 co-expression in areas of the hindbrain and spinal cord, both of which can modulate GI motility 17,[39][40][41][42] . Finally, optogenetic activation will result in release not only of glutamate but of co-expressed signalling molecules as well, including ACh, enkephalin and substance P, all of which may modulate circuit activity in different manners.…”

Section: Discussionmentioning

confidence: 99%

Enteric glutamatergic interneurons regulate intestinal motility

Hamnett,

Bendrick,

Robertson

et al. 2024

Preprint

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The enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown. Here, we identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon, in addition to a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes, and signal with a variety of neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons profoundly disrupts gastrointestinal transit, while ex vivo optogenetic stimulation of glutamatergic neurons initiates propulsive motility in the colon. This motility effect is reproduced when stimulating only the descending interneuron class, marked by Calb1 expression. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.

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“…NT-containing cell bodies and fibers are heterogeneously distributed throughout the pain modulation system, including the dorsal horn (Kalivas et al, 1982;Seybold and Elde, 1982;Shipley et al, 1987;Wang et al, 2014;Liu et al, 2015). The SDH neurons receive nociceptive messages from the periphery and transmit them to higher levels during these processing events, and the nociception in the dorsal horn receives multiple modulations from descending axons and local interneurons, making the dorsal horn a pivotal site for nociception processing and modulation (Todd, 2010).…”

Section: Nt-immunoreactivity and Ntr2-ir In Spinal Dorsal Hornmentioning

confidence: 99%

“…NT, consisting of thirteen amino acids (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH), is an endogenous neuropeptide with a strong opioid-independent analgesic function (Dobner, 2006;Feng et al, 2015). In the SDH, NTimmunoreactive (NT-ir) cell bodies, fibers and terminals are found in the superficial laminae (laminae I and II) (Seybold and Elde, 1982;Difiglia et al, 1984;Liu et al, 2015). In accordance with the distribution pattern, NT plays important roles in modulating nociception as a neuromodulator (Martin and Naruse, 1982).…”

Section: Introductionmentioning

confidence: 99%

Neurotensin Attenuates Nociception by Facilitating Inhibitory Synaptic Transmission in the Mouse Spinal Cord

Zhang

Feng

Qiu

et al. 2021

Front. Neural Circuits

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Neurotensin (NT) is an endogenous tridecapeptide in the central nervous system. NT-containing neurons and NT receptors are widely distributed in the spinal dorsal horn (SDH), indicating their possible modulatory roles in nociception processing. However, the exact distribution and function of NT, as well as NT receptors (NTRs) expression in the SDH, have not been well documented. Among the four NTR subtypes, NTR2 is predominantly involved in central analgesia according to previous reports. However, the expression and function of NTR2 in the SDH has not yet been directly elucidated. Specifically, it remains unclear how NT-NTR2 interactions contribute to NT-mediated analgesia. In the present study, by using immunofluorescent histochemical staining and immunohistochemical staining with in situ hybridization histochemical staining, we found that dense NT- immunoreactivity (NT-ir) and moderate NTR2-ir neuronal cell bodies and fibers were localized throughout the superficial laminae (laminae I-II) of the SDH at the light microscopic level. In addition, γ-aminobutyric acid (GABA) and NTR2 mRNA were colocalized in some neuronal cell bodies, predominantly in lamina II. Using confocal and electron microscopy, we also observed that NT-ir terminals made both close contacts and asymmetrical synapses with the local GABA-ir neurons. Second, electrophysiological recordings showed that NT facilitated inhibitory synaptic transmission but not glutamatergic excitatory synaptic transmission. Inactivation of NTR2 abolished the NT actions on both GABAergic and glycinergic synaptic release. Moreover, a behavioral study revealed that intrathecal injection of NT attenuated thermal pain, mechanical pain, and formalin induced acute inflammatory pain primarily by activating NTR2. Taken together, the present results provide direct evidence that NT-containing terminals and fibers, as well as NTR2-expressing neurons are widely distributed in the spinal dorsal horn, GABA-containing neurons express NTR2 mainly in lamina II, GABA coexists with NTR2 mainly in lamina II, and NT may directly increase the activity of local inhibitory neurons through NTR2 and induce analgesic effects.

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The coexistence of VGluT2 and neurotensin or leu-enkephalin in the medullary dorsal horn: A confocal and electron microscopic immunohistochemical study in the rat

Cited by 5 publications

References 38 publications

A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins

A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins

Enteric glutamatergic interneurons regulate intestinal motility

Neurotensin Attenuates Nociception by Facilitating Inhibitory Synaptic Transmission in the Mouse Spinal Cord

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