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Pain-related synaptic plasticity in spinal dorsal horn neurons: role of CGRP
Gary C Bird, Jeong S Han, Yu Fu, Hita Adwanikar, William D Willis, Volker Neugebauer
Molecular Pain , 2006, DOI: 10.1186/1744-8069-2-31
Abstract: Whole-cell current- and voltage-clamp recordings were made from substantia gelatinosa (SG) neurons in spinal cord slices from control rats and arthritic rats (> 6 h postinjection of kaolin/carrageenan into the knee). Monosynaptic excitatory postsynaptic currents (EPSCs) were evoked by electrical stimulation of afferents in the dorsal root near the dorsal root entry zone. Neurons in slices from arthritic rats showed increased synaptic transmission and excitability compared to controls. A selective CGRP1 receptor antagonist (CGRP8-37) reversed synaptic plasticity in neurons from arthritic rats but had no significant effect on normal transmission. CGRP facilitated synaptic transmission in the arthritis pain model more strongly than under normal conditions where both facilitatory and inhibitory effects were observed. CGRP also increased neuronal excitability. Miniature EPSC analysis suggested a post- rather than pre-synaptic mechanism of CGRP action.This study is the first to show synaptic plasticity in the spinal dorsal horn in a model of arthritic pain that involves a postsynaptic action of CGRP on SG neurons.Inflammatory processes in peripheral tissues lead to central sensitization in the spinal cord, which contributes to hyperalgesia and allodynia typically associated with inflammatory pain. Although evidence suggests that plastic changes in the spinal dorsal horn account for central sensitization, the relative contribution of pre- and postsynaptic mechanisms and of peripheral and supraspinal factors are not entirely clear. The superficial dorsal horn of the spinal cord, particularly substantia gelatinosa (SG), is a major projection site of small-diameter afferent nerve fibers that predominantly transmit nociceptive signals [1,2]. SG neurons also receive descending inputs from the brainstem [1,3]. Therefore, in addition to intraspinal neuroplastic changes, peripheral as well as supraspinal factors may contribute to central sensitization.Pain-related neuroplastic cha
Ryanodine receptors contribute to the induction of nociceptive input-evoked long-term potentiation in the rat spinal cord slice
Long-Zhen Cheng, Ning Lü, Yu-Qiu Zhang, Zhi-Qi Zhao
Molecular Pain , 2010, DOI: 10.1186/1744-8069-6-1
Abstract: By means of field potential recordings in the adult male rat in vivo, we showed that RyR antagonist reduced LTP of C-fiber-evoked responses in the spinal dorsal horn by tetanic stimulation of the sciatic nerve. Using spinal cord slice preparations and field potential recordings from superficial dorsal horn, high frequency stimulation of Lissauer's tract (LT) stably induced LTP of field excitatory postsynaptic potentials (fEPSPs). Perfusion of RyR antagonists blocked the induction of LT stimulation-evoked spinal LTP, while Ins(1,4,5)P3 receptor (IP3R) antagonist had no significant effect on LTP induction. Moreover, activation of RyRs by caffeine without high frequency stimulation induced a long-term potentiation in the presence of bicuculline methiodide and strychnine. Further, in patch-clamp recordings from superficial dorsal horn neurons, activation of RyRs resulted in a large increase in the frequency of miniature EPSCs (mEPSCs). Immunohistochemical study showed that RyRs were expressed in the dorsal root ganglion (DRG) neurons. Likewise, calcium imaging in small DRG neurons illustrated that activation of RyRs elevated [Ca2+]i in small DRG neurons.These data indicate that activation of presynaptic RyRs play a crucial role in the induction of LTP in the spinal pain pathway, probably through enhancement of transmitter release.LTP is a long-lasting form of synaptic plasticity in many parts of the central nervous system, particularly in the hippocampus [1]. Likewise, compelling evidence reveals that tetanic stimulation of the peripheral nerve produces LTP of C-fiber-evoked responses in the spinal dorsal horn both in vivo [2-5] and in vitro [6,7], and prolonged behavioral pain hypersensitivity [8]. Therefore, it is conceivable that C-afferent-induced spinal LTP may be a substrate for central sensitization of the pain pathway, which amplifies nociceptive input resulting in hyperalgesia [4].Nitric oxide (NO) is a diffusible messenger throughout the central nervous system
Synaptically evoked glutamate transporter currents in Spinal Dorsal Horn Astrocytes
Haijun Zhang, Wenjun Xin, Patrick M Dougherty
Molecular Pain , 2009, DOI: 10.1186/1744-8069-5-36
Abstract: Whole-cell patch clamp recordings were obtained from astrocytes in the spinal substantia gelatinosa (SG) area in spinal slices of young adult rats. Glutamate transporter currents were evoked in these cells by electrical stimulation at the spinal dorsal root entry zone in the presence of bicuculline, strychnine, DNQX and D-AP5. Transporter currents were abolished when synaptic transmission was blocked by TTX or Cd2+. Pharmacological studies identified two subtypes of glutamate transporters in spinal astrocytes, GLAST and GLT-1. Glutamate transporter currents were graded with stimulus intensity, reaching peak responses at 4 to 5 times activation threshold, but were reduced following low-frequency (0.1 – 1 Hz) repetitive stimulation.These results suggest that glutamate transporters of spinal astrocytes could be activated by synaptic activation, and recording glutamate transporter currents may provide a means of examining the real time physiological responses of glial cells in spinal sensory processing, sensitization, hyperalgesia and chronic pain.Spinal glial cells are now recognized as important participants in mechanisms of sensory encoding and the plasticity underlying the generation of spinal sensitization, hyperalgesia and chronic pain. Nevertheless, studies implicating glial cells in these processes have been confined to anatomical and behavioral approaches. An important facet of glial functions within the central nervous system (CNS) that may be fundamental to their contribution to sensory encoding in the spinal cord is the clearance of glutamate from the extracellular space via specific plasma membrane glutamate transporters [1-5]. Five cell membrane glutamate transporter proteins have been cloned, including EAAT1, EAAT2, EAAT3, EAAT4 and EAAT5 [5,6]. The rodent analogs of EAAT1 (GLAST) and EAAT2 (GLT-1) are expressed primarily in glial cells in the CNS [1,5]. Synaptic transmission in various brain structures such as the hippocampus has been shown to be potentl
Cortical Presynaptic Control of Dorsal Horn C–Afferents in the Rat  [PDF]
Yunuen Moreno-López, Jimena Pérez-Sánchez, Guadalupe Martínez-Lorenzana, Miguel Condés-Lara, Gerardo Rojas-Piloni
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069063
Abstract: Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C–fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C–fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C–fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C–fibers by means of GABAergic inhibitory interneurons.
Peripheral nerve injury increases glutamate-evoked calcium mobilization in adult spinal cord neurons  [cached]
Doolen Suzanne,Blake Camille B,Smith Bret N,Taylor Bradley K
Molecular Pain , 2012, DOI: 10.1186/1744-8069-8-56
Abstract: Background Central sensitization in the spinal cord requires glutamate receptor activation and intracellular Ca2+ mobilization. We used Fura-2 AM bulk loading of mouse slices together with wide-field Ca2+ imaging to measure glutamate-evoked increases in extracellular Ca2+ to test the hypotheses that: 1. Exogenous application of glutamate causes Ca2+ mobilization in a preponderance of dorsal horn neurons within spinal cord slices taken from adult mice; 2. Glutamate-evoked Ca2+ mobilization is associated with spontaneous and/or evoked action potentials; 3. Glutamate acts at glutamate receptor subtypes to evoked Ca2+ transients; and 4. The magnitude of glutamate-evoked Ca2+ responses increases in the setting of peripheral neuropathic pain. Results Bath-applied glutamate robustly increased [Ca2+]i in 14.4 ± 2.6 cells per dorsal horn within a 440 x 330 um field-of-view, with an average time-to-peak of 27 s and decay of 112 s. Repeated application produced sequential responses of similar magnitude, indicating the absence of sensitization, desensitization or tachyphylaxis. Ca2+ transients were glutamate concentration-dependent with a Kd = 0.64 mM. Ca2+ responses predominantly occurred on neurons since: 1) Over 95% of glutamate-responsive cells did not label with the astrocyte marker, SR-101; 2) 62% of fura-2 AM loaded cells exhibited spontaneous action potentials; 3) 75% of cells that responded to locally-applied glutamate with a rise in [Ca2+]i also showed a significant increase in AP frequency upon a subsequent glutamate exposure; 4) In experiments using simultaneous on-cell recordings and Ca2+ imaging, glutamate elicited a Ca2+ response and an increase in AP frequency. AMPA/kainate (CNQX)- and AMPA (GYKI 52466)-selective receptor antagonists significantly attenuated glutamate-evoked increases in [Ca2+]i, while NMDA (AP-5), kainate (UBP-301) and class I mGluRs (AIDA) did not. Compared to sham controls, peripheral nerve injury significantly decreased mechanical paw withdrawal threshold and increased glutamate-evoked Ca2+ signals. Conclusions Bulk-loading fura-2 AM into spinal cord slices is a successful means for determining glutamate-evoked Ca2+ mobilization in na ve adult dorsal horn neurons. AMPA receptors mediate the majority of these responses. Peripheral neuropathic injury potentiates Ca2+ signaling in dorsal horn.
Peripheral nerve injury sensitizes neonatal dorsal horn neurons to tumor necrosis factor-α
Jie Li, Wenrui Xie, Jun-Ming Zhang, Mark L Baccei
Molecular Pain , 2009, DOI: 10.1186/1744-8069-5-10
Abstract: The spared nerve injury (SNI) model of peripheral neuropathy at postnatal day (P)6 failed to significantly alter miniature excitatory (mEPSCs) or inhibitory (mIPSCs) postsynaptic currents in SDH neurons at P9-11. However, SNI did alter the sensitivity of excitatory synapses in the immature SDH to TNFα. While TNFα failed to influence mEPSCs or mIPSCs in slices from sham-operated controls, it significantly increased mEPSC frequency and amplitude following SNI without modulating synaptic inhibition onto the same neurons. This was accompanied by a significant decrease in the paired-pulse ratio of evoked EPSCs, suggesting TNFα increases the probability of glutamate release in the SDH under neuropathic conditions. Similarly, while SNI alone did not alter action potential (AP) threshold or rheobase in SDH neurons at this age, TNFα significantly decreased AP threshold and rheobase in the SNI group but not in sham-operated littermates. However, unlike the adult, the expression of TNFα in the immature dorsal horn was not significantly elevated during the first week following the SNI.Developing SDH neurons become susceptible to regulation by TNFα following peripheral nerve injury in the neonate. This may include both a greater efficacy of glutamatergic synapses as well as an increase in the intrinsic excitability of immature dorsal horn neurons. However, neonatal sciatic nerve damage alone did not significantly modulate synaptic transmission or neuronal excitability in the SDH, which could reflect a relatively weak expression of TNFα in the injured spinal cord at early ages. The above data suggest that although the sensitivity of the SDH network to proinflammatory cytokines after nerve injury is present from the first days of life, the profile of spinal cytokine expression under neuropathic conditions may be highly age-dependent.Peripheral nerve injury in the adult evokes significant changes in both excitatory and inhibitory synaptic signaling within the superficial dorsal hor
Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn
Sandrine M Géranton, Vincenza Fratto, Keri K Tochiki, Stephen P Hunt
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-35
Abstract: Here, we describe how descending controls regulate MeCP2 phosphorylation (P-MeCP2), known to relieve transcriptional repression by MeCP2, and Zif268 and Fos expression in the rat superficial dorsal horn, after CFA injection into the hind paw. First, we report that CFA significantly increased P-MeCP2 in Lamina I and II, from 30 min post injection, with a maximum reached after 1 h. The increase in P-MeCP2 paralleled that of Zif268 and Fos, and P-MeCP2 was expressed in large sub-populations of Zif268 and Fos expressing neurones. Serotonergic depletion of the lumbar spinal cord with 5,7 di-hydroxytryptamine creatinine sulphate (5,7-DHT) reduced the inflammation evoked P-MeCP2 in the superficial dorsal horn by 57%, and that of Zif268 and Fos by 37.5% and 30% respectively. Although 5,7-DHT did not change primary thermal hyperalgesia, it significantly attenuated mechanical sensitivity seen in the first 24 h after CFA.We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state.The development and maintenance of pain states are dependant upon plastic changes in neurones of the superficial dorsal horn that are thought to be under the control of descending pathways originating in the brainstem [1,2]. The transcription factors Fos, Zif268 and Methyl-CpG-binding protein 2 (MeCP2) have been implicated in dorsal horn plasticity yet their dependence on descending controls for their full activation has not been explored.MeCP2 is a transcriptional repressor that regulates activity-dependent gene transcription and is critical for normal neurological function. Mutations in human MeCP2 result in the neurodevelopmental disorder Rett syndrome [3,4]. However, we know very little about the physiological role of MeCP2 in the central nervous system. MeCP2 regulates gene transcription by binding to methylated CpG dinucleotides and recruiting co-repressors such as his
Material basis for inhibition of Dragon’s Blood on evoked discharges of wide dynamic range neurons in spinal dorsal horn of rats
Min Guo,Su Chen,XiangMing Liu
Science China Life Sciences , 2008, DOI: 10.1007/s11427-008-0133-6
Abstract: In vivo experiments were designed to verify the analgesic effect of Dragon’s Blood and the material basis for this effect. Extracellular microelectrode recordings were used to observe the effects of Dragon’s Blood and various combinations of the three components (cochinchinenin A, cochinchinenin B, and loureirin B) extracted from Dragon’s Blood on the discharge activities of wide dynamic range (WDR) neurons in spinal dorsal horn (SDH) of intact male Wistar rats evoked by electric stimulation at sciatic nerve. When the Hill’s coefficients describing the dose-response relations of drugs were different, based on the concept of dose equivalence, the equations of additivity surfaces which can be applied to assess the interaction between three drugs were derived. Adopting the equations and Tallarida’s isobole equations used to assess the interaction between two drugs with dissimilar dose-response relations, the effects produced by various combinations of the three components in modulating the evoked discharge activities of WDR neurons were evaluated. Results showed that Dragon’s Blood and its three components could inhibit the evoked discharge frequencies of WDR neurons in a concentration-dependent way. The Hill’s coefficients describing dose-response relations of three components were different. Only the combined effect of cochinchinenin A, cochinchinenin B and loureirin B was similar to that of Dragons Blood. Furthermore, the combined effect was synergistic. This investigation demonstrated that through the synergistic interaction of the three components Dragon’s Blood could interfere with the transmission and processing of pain signals in spinal dorsal horn. All these further proved that the combination of cochinchinenin A, cochinchinenin B, and loureirin B was the material basis for the analgesic effect of Dragon’s Blood.
Dorsal horn-enriched genes identified by DNA microarray, in situ hybridization and immunohistochemistry
Hong Sun, Jian Xu, Kimberly B Della Penna, Robert J Benz, Fumi Kinose, Daniel J Holder, Kenneth S Koblan, David L Gerhold, Hao Wang
BMC Neuroscience , 2002, DOI: 10.1186/1471-2202-3-11
Abstract: A large scale screening was conducted for genes with enriched expression in the dorsal spinal cord using DNA microarray and quantitative real-time PCR. In addition to genes known to be specifically expressed in the dorsal spinal cord, other neuropeptides, receptors, ion channels, and signaling molecules were also found enriched in the dorsal spinal cord. In situ hybridization and immunohistochemistry revealed the cellular expression of a subset of these genes. The regulation of a subset of the genes was also studied in the spinal nerve ligation (SNL) neuropathic pain model. In general, we found that the genes that are enriched in the dorsal spinal cord were not among those found to be up-regulated in the spinal nerve ligation model of neuropathic pain. This study also provides a level of validation of the use of DNA microarrays in conjunction with our novel analysis algorithm (SAFER) for the identification of differences in gene expression.This study identified molecules that are enriched in the dorsal horn of the spinal cord and provided a molecular neuroanatomy in the spinal cord, which will aid in the understanding of the molecular mechanisms important in nociception and pain.The dorsal horn of the spinal cord plays important roles in sensory information processing. The dorsal horn contains the neural circuitry conveying nociceptive information, including pain and temperature, from the periphery by the primary afferents [1-3]. Nociceptive afferent fibers terminate predominately in the dorsal horn of the spinal cord. Activation of the nociceptors transmits afferent messages to the spinal cord dorsal horn through neurotransmitters such as glutamate. Initial processing of nociceptive information occurs in the spinal cord dorsal horn by excitatory and inhibitory interneurons. The projecting neurons, spinalthalamic tract cells, then convey primary nociceptive information to higher centers, signaling localization and encoding the character of the nociceptive input. Oth
Material basis for inhibition of Dragon’s Blood on evoked discharges of wide dynamic range neurons in spinal dorsal horn of rats

Min Guo,Su Chen,XiangMing Liu,

中国科学C辑(英文版) , 2008,
Abstract: In vivo experiments were designed to verify the analgesic effect of Dragon’s Blood and the material basis for this effect. Extracellular microelectrode recordings were used to observe the effects of Dragon’s Blood and various combinations of the three components (cochinchinenin A, cochinchinenin B, and loureirin B) extracted from Dragon’s Blood on the discharge activities of wide dynamic range (WDR) neurons in spinal dorsal horn (SDH) of intact male Wistar rats evoked by electric stimulation at sciatic nerve. When the Hill’s coefficients describing the dose-response relations of drugs were different, based on the concept of dose equivalence, the equations of additivity surfaces which can be applied to assess the interaction between three drugs were derived. Adopting the equations and Tallarida’s isobole equations used to assess the interaction between two drugs with dissimilar dose-response relations, the effects produced by various combinations of the three components in modulating the evoked discharge activities of WDR neurons were evaluated. Results showed that Dragon’s Blood and its three components could inhibit the evoked discharge frequencies of WDR neurons in a concentration-dependent way. The Hill’s coefficients describing dose-response relations of three components were different. Only the combined effect of cochinchinenin A, cochinchinenin B and loureirin B was similar to that of Dragons Blood. Furthermore, the combined effect was synergistic. This investigation demonstrated that through the synergistic interaction of the three components Dragon’s Blood could interfere with the transmission and processing of pain signals in spinal dorsal horn. All these further proved that the combination of cochinchinenin A, cochinchinenin B, and loureirin B was the material basis for the analgesic effect of Dragon’s Blood. Supported by the Nature Science Foundation of State Ethnic Affairs Commission, China (Grant No. MZY06002)
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