scholarly journals Neuron Type-Dependent Synaptic Activity in the Spinal Dorsal Horn of Opioid-Induced Hyperalgesia Mouse Model

2021 ◽  
Vol 13 ◽  
Author(s):  
Austin Kearns ◽  
Jazmine Jayasi ◽  
Xin Liu ◽  
Jigong Wang ◽  
Yuqiang Shi ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Pain Sensitivity ◽  
Specific Cell ◽  
Dependent Manner ◽  
Neuronal Circuit ◽  
Morphine Treatment ◽  
Tonic Firing ◽  
Spinal Dorsal ◽  
Opioid Induced Hyperalgesia

Opioids are widely used for pain relief; however, chronic opioid use causes a paradoxical state of enhanced pain sensitivity, termed “Opioid-induced hyperalgesia (OIH).” Despite the clinical importance of OIH, the detailed mechanism by which it enhances pain sensitivity remains unclear. In this study, we tested whether repeated morphine induces a neuronal circuit polarization in the mouse spinal dorsal horn (SDH). Transgenic mice expressing GFP to neurokinin 1 receptor-expressing neurons (sNK1Rn) and GABAergic interneurons (sGABAn) that received morphine [20 mg/kg, once daily for four consecutive days (i.p.)] developed mechanical hypersensitivity. Repeated morphine altered synaptic strengths in the SDH as a specific cell-type but not in a gender-dependent manner. In sNK1Rn and non-tonic firing neurons, repeated morphine treatment significantly increased frequency of spontaneous excitatory postsynaptic current (sEPSC) and evoked EPSC (eEPSC). In addition, repeated morphine treatment significantly decreased evoked inhibitory postsynaptic current (eIPSC) in sNK1Rn. Conversely, in sGABAn and tonic firing neurons, repeated morphine treatment significantly decreased sEPSC frequency and eEPSC, but had no change of eIPSC in sGABAn. Interestingly, repeated morphine treatment significantly decreased neuronal rheobase of sNK1Rn but had no effect on sGABAn. These findings suggest that spinal neuronal circuit polarization maybe the mechanism of OIH and identify a potential therapeutic mechanism to prevent or treat opioid-induced pain.

scholarly journals α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

2019 ◽  
Vol 130 (5) ◽  
pp. 804-819 ◽  
Author(s):  
Meichun Deng ◽  
Shao-Rui Chen ◽  
Hong Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Spinal Dorsal Horn ◽  
Receptor Activity ◽  
Morphine Treatment ◽  
Chronic Morphine ◽  
Analgesic Tolerance ◽  
Spinal Dorsal ◽  
Aspartate Receptor ◽  
C Terminus ◽  
Opioid Induced Hyperalgesia

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-d-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-d-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-d-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1–bound N-methyl-d-aspartate receptors contribute to presynaptic N-methyl-d-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance. Methods Rats (5 mg/kg) and wild-type and α2δ-1–knockout mice (10 mg/kg) were treated intraperitoneally with morphine twice/day for 8 consecutive days, and nociceptive thresholds were examined. Presynaptic N-methyl-d-aspartate receptor activity was recorded in spinal cord slices. Coimmunoprecipitation was performed to examine protein–protein interactions. Results Chronic morphine treatment in rats increased α2δ-1 protein amounts in the dorsal root ganglion and spinal cord. Chronic morphine exposure also increased the physical interaction between α2δ-1 and N-methyl-d-aspartate receptors by 1.5 ± 0.3 fold (means ± SD, P = 0.009, n = 6) and the prevalence of α2δ-1–bound N-methyl-d-aspartate receptors at spinal cord synapses. Inhibiting α2δ-1 with gabapentin or genetic knockout of α2δ-1 abolished the increase in presynaptic N-methyl-d-aspartate receptor activity in the spinal dorsal horn induced by morphine treatment. Furthermore, uncoupling the α2δ-1–N-methyl-d-aspartate receptor interaction with an α2δ-1 C terminus–interfering peptide fully reversed morphine-induced tonic activation of N-methyl-d-aspartate receptors at the central terminal of primary afferents. Finally, intraperitoneal injection of gabapentin or intrathecal injection of an α2δ-1 C terminus–interfering peptide or α2δ-1 genetic knockout abolished the mechanical and thermal hyperalgesia induced by chronic morphine exposure and largely preserved morphine’s analgesic effect during 8 days of morphine treatment. Conclusions α2δ-1–Bound N-methyl-d-aspartate receptors contribute to opioid-induced hyperalgesia and tolerance by augmenting presynaptic N-methyl-d-aspartate receptor expression and activity at the spinal cord level.

Spike Frequency Adaptation and Signaling Properties of Identified Neurons in Rodent Deep Spinal Dorsal Horn

2003 ◽  
Vol 90 (1) ◽  
pp. 245-258 ◽  
Author(s):  
S. P. Schneider
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Neuronal Morphology ◽  
Differential Sensitivity ◽  
Current Application ◽  
Tonic Firing ◽  
Spinal Dorsal ◽  
Current Steps ◽  
Whole Cell Recordings ◽  
Linear Decline

Using whole cell recordings, I analyzed the intrinsic discharge properties for 285 neurons in Rexed's laminae III–V of isolated hamster spinal cord preparations. Neurons were characterized by their responses to step-wise and ramp-hold depolarizing current applied through the recording pipettes. Tonic cells (133/285; 47%) fired repetitively during step-wise current application. Firing decayed linearly (–0.14 to –4.3 imp · s–1 · s–1) or was bimodal, with an initial exponential phase (τ ≈ 450 ms) followed by a linear decline (–0.02 to –6.3 imp · s–1 · s–1); discharge frequency was unrelated to current trajectory. Phasic-firing cells (108/285; 38%) responded with a burst discharge having an initial rapid, exponential decrease (τ ≈ 30 ms) and subsequent linear decline (–1 to –78 imp · s–1 · s–1). Phasic cells were activated preferentially by fast current ramps (slope, 70 pA/s–2.2 nA/s) with the number and frequency of impulses increasing with current slope. Delayed-firing cells (44/285; 15%), responded to current steps with an accelerating firing following a substantial latent period (0.5–4 s) and discharged during current ramps with slopes less than ≈100 pA/s. Intracellular staining revealed a significant association between electrophysiological profile and neuronal morphology. A majority of presumed projection cells (22/30; 73%) exhibited tonic firing to step-wise activation. The preponderance of phasic and delayed firing cells, 93% (42/45) and 71% (12/17), respectively, were interneurons with local or intersegmental terminations. Differential sensitivity to static and time-varying components of membrane current suggest differences in neuronal signaling properties that may have important implications for integration of mechanosensory information in the deep spinal dorsal horn.

scholarly journals Evans Blue Reduces Neuropathic Pain Behavior by Inhibiting Spinal ATP Release

2019 ◽  
Vol 20 (18) ◽  
pp. 4443 ◽  
Author(s):  
Yin ◽  
Hong ◽  
Phạm ◽  
Shin ◽  
Gwon ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Evans Blue ◽  
Spinal Dorsal Horn ◽  
Critical Role ◽  
Atp Release ◽  
Pain Behavior ◽  
Dependent Manner ◽  
Spinal Dorsal

Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1β and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL.

In vivo patch-clamp analysis of sensory neuronal circuit in the rat superficial spinal dorsal horn

2004 ◽  
Vol 1269 ◽  
pp. 69-72 ◽  
Author(s):  
Hidemasa Furue ◽  
Go Kato ◽  
Ji Hoon Kim ◽  
Byung-Il Min ◽  
Toshihiko Katafuchi ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Neuronal Circuit ◽  
Spinal Dorsal

scholarly journals Electrophysiological and Morphological Features of Rebound Depolarization Characterized Interneurons in Rat Superficial Spinal Dorsal Horn

2021 ◽  
Vol 15 ◽  
Author(s):  
Mengye Zhu ◽  
Yi Yan ◽  
Xuezhong Cao ◽  
Fei Zeng ◽  
Gang Xu ◽  
...  
Keyword(s):  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Morphological Characteristics ◽  
Substantia Gelatinosa ◽  
Morphological Properties ◽  
Specific Cell ◽  
Membrane Hyperpolarization ◽  
Spinal Dorsal ◽  
C Fibers ◽  
Somatosensory Information

Substantia gelatinosa (SG) neurons, which are located in the spinal dorsal horn (lamina II), have been identified as the “central gate” for the transmission and modulation of nociceptive information. Rebound depolarization (RD), a biophysical property mediated by membrane hyperpolarization that is frequently recorded in the central nervous system, contributes to shaping neuronal intrinsic excitability and, in turn, contributes to neuronal output and network function. However, the electrophysiological and morphological properties of SG neurons exhibiting RD remain unclarified. In this study, whole-cell patch-clamp recordings were performed on SG neurons from parasagittal spinal cord slices. RD was detected in 44.44% (84 out of 189) of the SG neurons recorded. We found that RD-expressing neurons had more depolarized resting membrane potentials, more hyperpolarized action potential (AP) thresholds, higher AP amplitudes, shorter AP durations, and higher spike frequencies in response to depolarizing current injection than neurons without RD. Based on their firing patterns and morphological characteristics, we propose that most of the SG neurons with RD mainly displayed tonic firing (69.05%) and corresponded to islet cell morphology (58.82%). Meanwhile, subthreshold currents, including the hyperpolarization-activated cation current (Ih) and T-type calcium current (IT), were identified in SG neurons with RD. Blockage of Ih delayed the onset of the first spike in RD, while abolishment of IT significantly blunted the amplitude of RD. Regarding synaptic inputs, SG neurons with RD showed lower frequencies in both spontaneous and miniature excitatory synaptic currents. Furthermore, RD-expressing neurons received either Aδ- or C-afferent-mediated monosynaptic and polysynaptic inputs. However, RD-lacking neurons received afferents from monosynaptic and polysynaptic Aδ fibers and predominantly polysynaptic C-fibers. These findings demonstrate that SG neurons with RD have a specific cell-type distribution, and may differentially process somatosensory information compared to those without RD.

scholarly journals Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn

2017 ◽  
Author(s):  
Alexander Chamessian ◽  
Michael Young ◽  
Yawar Qadri ◽  
Temugin Berta ◽  
Ru-Rong Ji ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Dorsal Horn ◽  
Spinal Dorsal Horn ◽  
Transcriptional Profiling ◽  
Expression Patterns ◽  
Specific Cell ◽  
Gene Repertoire ◽  
Rna Seq ◽  
Cell Type ◽  
Spinal Dorsal

AbstractThe spinal dorsal horn (SDH) is comprised of distinct neuronal populations that process different somatosensory modalities. Somatostatin (SST)-expressing interneurons in the SDH have been implicated specifically in mediating mechanical pain. Identifying the transcriptomic profile of SST neurons could elucidate the unique genetic features of this population and enable selective analgesic targeting. To that end, we combined the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) method and Fluorescence Activated Nuclei Sorting (FANS) to capture tagged SST nuclei in the SDH of adult male mice. Using RNA-sequencing (RNA-seq), we uncovered more than 13,000 genes. Differential gene expression analysis revealed more than 900 genes with at least 2-fold enrichment. In addition to many known dorsal horn genes, we identified and validated several novel transcripts from pharmacologically tractable functional classes: Carbonic Anhydrase 12 (Car12), Phosphodiesterase 11A (Pde11a), Protease-Activated Receptor 3 (F2rl2) and G-protein Coupled Receptor 26 (Gpr26). In situ hybridization of these novel genes revealed differential expression patterns in the SDH, demonstrating the presence of transcriptionally distinct subpopulations within the SST population. Pathway analysis revealed several enriched signaling pathways including cyclic AMP-mediated signaling, Nitric Oxide Synthase signaling, and voltage-gated calcium channels, highlighting the importance of these pathways to SST neuron function. Overall, our findings provide new insights into the gene repertoire of SST dorsal horn neurons and reveal several candidate targets for pharmacological modulation of this pain-mediating population.Significance StatementSomatostatin(SST)-expressing interneurons in the spinal dorsal horn (SDH) are required for the perception of mechanical pain. Identifying the distinctive genes expressed by SST neurons could facilitate the development of novel, circuit-targeting analgesics. Thus, we applied cell type-specific RNA-sequencing (RNA-seq) to provide the first transcriptional profile of SST neurons in the SDH. Bioinformatic analysis revealed hundreds of genes enriched in SST neurons, including several previously undescribed genes from druggable classes (Car12, Pde11a, F2rl2 and Gpr26). Taken together, our study unveils a comprehensive transcriptional signature for SST neurons, highlights promising candidate genes for future analgesic development, and establishes a flexible method for transcriptional profiling of any spinal cord cell type.

scholarly journals Sanguinarine Attenuates Neuropathic Pain in a Rat Model of Chronic Constriction Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Ping Li ◽  
Yan-Xiu Wang ◽  
Guang Yang ◽  
Zun-Cheng Zheng ◽  
Chao Yu
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
P38 Mapk ◽  
Spinal Dorsal Horn ◽  
Chronic Constriction Injury ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Withdrawal Threshold ◽  
Spinal Dorsal ◽  
Plant Medicine

Objective. There is still no effective treatment of neuropathic pain. Sanguinarine is a natural plant medicine with anti-inflammatory effects, but its effect on neuropathic pain remains unclear. This study was aimed at investigating the potential of sanguinarine to attenuate neuropathic pain. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Rats were randomly divided into several groups: sham, CCI, CCI+SG (1.00 mg/kg), CCI+SG (2.50 mg/kg), and CCI+SG (6.25 mg/kg). SG was injected intraperitoneally from the day of surgery every three days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded before surgery and on days 1, 3, 7, and 14 after surgery. The microglia in the spinal dorsal horn were examined by immunofluorescence. p38 MAPK expression in the spinal dorsal horn was detected by PCR and Western blot analysis. Cytokine levels in the spinal dorsal horn were measured by ELISA. Results. MWT and TWL were significantly reduced in the CCI group, but sanguinarine recovered MWT and TWL in the CCI group. In addition, sanguinarine inhibited the activation of microglia and decreased the expression of p-p38 and TNF-α, IL-1β, and IL-6 in the spinal dorsal horn of the CCI group in a dose-dependent manner. Conclusions. Our results suggest that sanguinarine can attenuate neuropathic pain via inhibiting the activation of microglia and the activation of the p38 MAPK signaling pathway.

scholarly journals Responses of spinal dorsal horn neurons to foot movements in rats with a sprained ankle

2011 ◽  
Vol 105 (5) ◽  
pp. 2043-2049 ◽  
Author(s):  
Jae Hyo Kim ◽  
Hee Young Kim ◽  
Kyungsoon Chung ◽  
Jin Mo Chung
Keyword(s):  
Dorsal Horn ◽  
Ankle Sprain ◽  
Spinal Dorsal Horn ◽  
Underlying Mechanism ◽  
Ankle Injuries ◽  
Dependent Manner ◽  
Dorsal Horn Neurons ◽  
Spinal Dorsal ◽  
Spinal Dorsal Horn Neurons ◽  
And Inversion

Acute ankle injuries are common problems and often lead to persistent pain. To investigate the underlying mechanism of ankle sprain pain, the response properties of spinal dorsal horn neurons were examined after ankle sprain. Acute ankle sprain was induced manually by overextending the ankle of a rat hindlimb in a direction of plantarflexion and inversion. The weight-bearing ratio (WBR) of the affected foot was used as an indicator of pain. Single unit activities of dorsal horn neurons in response to plantarflexion and inversion of the foot or ankle compression were recorded from the medial part of the deep dorsal horn, laminae IV-VI, in normal and ankle-sprained rats. One day after ankle sprain, rats showed significantly reduced WBRs on the affected foot, and this reduction was partially restored by systemic morphine. The majority of deep dorsal horn neurons responded to a single ankle stimulus modality. After ankle sprain, the mean evoked response rates were significantly increased, and afterdischarges were developed in recorded dorsal horn neurons. The ankle sprain-induced enhanced evoked responses were significantly reduced by morphine, which was reversed by naltrexone. The data indicate that movement-specific dorsal horn neuron responses were enhanced after ankle sprain in a morphine-dependent manner, thus suggesting that hyperactivity of dorsal horn neurons is an underlying mechanism of pain after ankle sprain.

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