High-frequency spinal cord stimulation produces long-lasting analgesic effects by restoring lysosomal function and autophagic flux in the spinal dorsal horn

Metabotropic glutamate (mGlu) receptors play important roles in the modulation of nociception. Previous studies demonstrated that mGlu5 modulates nociceptive plasticity via activation of ERK signaling. We have reported recently that the Kv4.2 K+ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKCγ, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

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Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Journal of Neurophysiology ◽

10.1152/jn.00423.2001 ◽

2002 ◽

Vol 87 (2) ◽

pp. 732-739 ◽

Cited By ~ 24

Author(s):

Guo-Du Wang ◽

Min Zhuo

Keyword(s):

Spinal Cord ◽

Nmda Receptors ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Adult Mouse ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Afferent Fibers ◽

Primary Afferent Fibers ◽

Spinal Dorsal Horn Neurons

Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-d-aspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. Here we show that in sensory synapses of adult mouse, some synaptic responses (26.3% of a total of 38 experiments) between primary afferent fibers and dorsal horn neurons are almost completely mediated by NMDA receptors. Dorsal root stimulation did not elicit any detectable AMPA/kainate receptor-mediated responses in these synapses. Unlike young spinal cord, serotonin alone did not produce any long-lasting synaptic enhancement in adult spinal dorsal horn neurons. However, co-application of the adenylyl cyclase activator forskolin and serotonin (5-HT) produced long-lasting enhancement, including the recruitment of functional AMPA receptor-mediated responses. Calcium-sensitive, calmodulin-regulated adenylyl cyclases (AC1, AC8) are required for the enhancement. Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.

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Xenon Has Greater Inhibitory Effects on Spinal Dorsal Horn Neurons than Nitrous Oxide in Spinal Cord Transected Cats

Anesthesia & Analgesia ◽

10.1213/00000539-199904000-00038 ◽

1999 ◽

Vol 88 (4) ◽

pp. 893-897 ◽

Cited By ~ 22

Author(s):

Yoshiya Miyazaki ◽

Takehiko Adachi ◽

Jun Utsumi ◽

Tsutomu Shichino ◽

Hajime Segawa

Keyword(s):

Spinal Cord ◽

Nitrous Oxide ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Inhibitory Effects ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Spinal Dorsal Horn Neurons

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Changes in Properties of Spinal Dorsal Horn Neurons and Their Sensitivity to Morphine after Spinal Cord Injury in the Rat

Anesthesiology ◽

10.1097/00000542-200501000-00024 ◽

2005 ◽

Vol 102 (1) ◽

pp. 152-164 ◽

Cited By ~ 23

Author(s):

Jungang Wang ◽

Mikito Kawamata ◽

Akiyoshi Namiki

Keyword(s):

Spinal Cord ◽

Spontaneous Activity ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

High Threshold ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Cord Injury ◽

Spinal Dorsal Horn Neurons ◽

Wdr Neurons

Background To gain a better understanding of spinal cord injury (SCI)-induced central neuropathic pain, the authors investigated changes in properties of spinal dorsal horn neurons located rostrally and caudally to the lesion and their sensitivity to morphine in rats after SCI. Methods The right spinal cord of Sprague-Dawley rats was hemisected at the level of L2. At 10 to 14 days after the SCI, when mechanical hyperalgesia/allodynia had fully developed, spontaneous activity and evoked responses to mechanical stimuli of wide-dynamic-range (WDR) and high-threshold neurons rostral and caudal to the lesion were recorded. Effects of cumulative doses of systemic (0.1-3 mg/kg) and spinal (0.1-5 microg) administration of morphine on spontaneous activity and evoked responses to the stimuli of the neurons were evaluated. Results Spontaneous activity significantly increased in WDR neurons both rostral and caudal to the SCI site, but high-frequency background discharges with burst patterns were only observed in neurons rostral to the SCI site. Significant increases in responses to the mechanical stimuli were seen both in WDR and high-threshold neurons located both rostrally and caudally to the lesion. The responses to nonnoxious and noxious stimuli were significantly greater in caudal WDR neurons than in rostral WDR neurons. In contrast, the responses to pinch stimuli were significantly higher in rostral high-threshold neurons than those in caudal high-threshold neurons. Systemically administered morphine had a greater effect on responses to nonnoxious and noxious stimuli of rostral WDR neurons than those of caudal WDR neurons. Spinally administered morphine significantly suppressed responses of WDR neurons in SCI animals to nonnoxious stimuli compared with those in sham-operated control animals. Conclusions The findings suggest that changes in properties of spinal dorsal horn neurons after SCI are caused by different mechanisms, depending on the classification of the neurons and their segmental locations.

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Suppressive effect of spinal dorsal-horn neuronal activity by local spinal-cord cooling is reversed by naloxone in cats

Journal of Anesthesia ◽

10.1007/s005400200027 ◽

2002 ◽

Vol 16 (3) ◽

pp. 211-215 ◽

Cited By ~ 1

Author(s):

Min Dai ◽

Toshinobu Sumida ◽

Megumi Tagami ◽

Yasuo Ide ◽

Masaki Nagase ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Neuronal Activity ◽

Spinal Dorsal Horn ◽

Suppressive Effect ◽

Spinal Dorsal

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Xenon Has Greater Inhibitory Effects on Spinal Dorsal Horn Neurons than Nitrous Oxide in Spinal Cord Transected Cats

Anesthesia & Analgesia ◽

10.1097/00000539-199904000-00038 ◽

1999 ◽

Vol 88 (4) ◽

pp. 893-897 ◽

Cited By ~ 3

Author(s):

Yoshiya Miyazaki ◽

Takehiko Adachi ◽

Jun Utsumi ◽

Tsutomu Shichino ◽

Hajime Segawa

Keyword(s):

Spinal Cord ◽

Nitrous Oxide ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Inhibitory Effects ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Spinal Dorsal Horn Neurons

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A systematic review on descending serotonergic projections and modulation of spinal nociception in chronic neuropathic pain and after spinal cord stimulation

Molecular Pain ◽

10.1177/17448069211043965 ◽

2021 ◽

Vol 17 ◽

pp. 174480692110439

Author(s):

Lonne Heijmans ◽

Martijn R Mons ◽

Elbert A Joosten

Keyword(s):

Systematic Review ◽

Spinal Cord ◽

Neuropathic Pain ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Serotonergic System ◽

Chronic Neuropathic Pain ◽

Spinal Dorsal ◽

Important Target ◽

Serotonergic Modulation

Chronic neuropathic pain is a debilitating ordeal for patients worldwide and pharmacological treatment efficacy is still limited. As many pharmacological interventions for neuropathic pain often fail, insights into the underlying mechanism and role of identified receptors is of utmost importance. An important target for improving treatment of neuropathic pain is the descending serotonergic system as these projections modulate nociceptive signaling in the dorsal horn. Also with use of last resort treatments like spinal cord stimulation (SCS), the descending serotonergic projections are known to be involved in the pain relieving effect. This systematic review summarizes the involvement of the serotonergic system on nociceptive modulation in the healthy adult rodent and the chronic neuropathic rodent and summarizes all available literature on the serotonergic system in the SCS-treated neuropathic rodent. Medline, Embase and Pubmed databases were used in the search for articles. Descending serotonergic modulation of nociceptive signaling in spinal dorsal horn in normal adult rat is mainly inhibitory and mediated by 5-HT1a, 5-HT1b, 5-HT2c, 5-HT3 and 5-HT4 receptors. Upon injury and in the neuropathic rat, this descending serotonergic modulation becomes facilitatory via activation of the 5-HT2a, 5-HT2b and 5-HT3 receptors. Analgesia due to neuromodulatory intervention like SCS restores the inhibitory function of the descending serotonergic system and involves 5-HT2, 5-HT3 and 5-HT4 receptors. The results of this systematic review provide insights and suggestions for further pharmacological and or neuromodulatory treatment of neuropathic pain based on targeting selected serotonergic receptors related to descending modulation of nociceptive signaling in spinal dorsal horn. With the novel developed SCS paradigms, the descending serotonergic system will be an important target for mechanism-based stimulation induced analgesia.

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Neuroligins Facilitate The Development of Bone Cancer Pain via Regulating Synaptic Transmission

10.21203/rs.3.rs-991135/v1 ◽

2021 ◽

Author(s):

Xianqiao Xie ◽

Yang Li ◽

Shanchun Su ◽

Xiaohui Li ◽

Xueqin Xu ◽

...

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Cancer Pain ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Rat Spinal Cord ◽

Spinal Dorsal

Abstract Background The underlying mechanism of chronic pain involves the plasticity in synaptic receptors and neurotransmitters. This study aimed to investigate potential roles of neuroligins (NLs) within the spinal dorsal horn of rats in a newly established bone cancer pain (BCP) model. Methods Using our rat BCP model, we assessed pain hypersensitivity over time. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to investigate NL expression, and NLs were overexpressed in the rat spinal cord using lentiviral vectors. Immunofluorescence staining and whole-cell patch-clamp recordings were deployed to investigate the role of NLs in the development of BCP. Results We observed reduced expression levels of NL1 and NL2, but not NL3, within the rat spinal cord, which were found to be associated with and essential for the development of BCP in our model. Accordingly, NL1 or NL2 overexpression in the spinal cord alleviated mechanical hypersensitivity of rats. Electrophysiological experiments indicated that NL1 and NL2 are involved in BCP via regulating γ-aminobutyric acid-ergic interneuronal synapses and the activity of glutamatergic interneuronal synapses, respectively. Conclusions Our observations unravel the role of NLs in cancer-related chronic pain and further suggest that inhibitory mechanisms are central features of BCP in the spinal dorsal horn. These results provide a new perspective and basis for subsequent studies elucidating the onset and progression of BCP.

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