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  • Guo, Wei  (7)
  • Linguistics  (7)
  • 1
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    Spinal 5-HT 3 Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade
    Society for Neuroscience ; 2011
    In:  The Journal of Neuroscience Vol. 31, No. 36 ( 2011-09-07), p. 12823-12836
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 36 ( 2011-09-07), p. 12823-12836
    Abstract: Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT 3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT 3 receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT 3 receptor by intrathecal injection of a selective 5-HT 3 receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via the cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous brain-derived neurotrophic factor-induced descending pain facilitation was accompanied by upregulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, and these events were significantly prevented by functional blockade of spinal 5-HT 3 receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.1564-11.2011
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2011
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  • 2
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    Group I Metabotropic Glutamate Receptor NMDA Receptor Coupling and Signaling Cascade Mediate Spinal Dorsal Horn NMDA Receptor 2B Tyrosine Phosphorylation Associated with Inflammatory Hyperalgesia
    Society for Neuroscience ; 2004
    In:  The Journal of Neuroscience Vol. 24, No. 41 ( 2004-10-13), p. 9161-9173
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 24, No. 41 ( 2004-10-13), p. 9161-9173
    Abstract: Hindpaw inflammation induces tyrosine phosphorylation (tyr-P) of the NMDA receptor (NMDAR) 2B (NR2B) subunit in the rat spinal dorsal horn that is closely related to the initiation and development of hyperalgesia. Here, we show that in rats with Freund's adjuvant-induced inflammation, the increased dorsal horn NR2B tyr-P is blocked by group I metabotropic glutamate receptor (mGluR) antagonists [7-(hydroxyimino)cyclopropa[b] chromen-1a-carboxylate ethyl ester (CPCCOEt) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP), by the Src inhibitor CGP 77675, but not by the MAP kinase inhibitor 2′-amino-3′-methoxyflavone. Analysis of the calcium pathways shows that the in vivo NR2B tyr-P is blocked by an IP 3 receptor antagonist 2-aminoethoxydiphenylborate (2APB) but not by antagonists of ionotropic glutamate receptors and voltage-dependent calcium channels, suggesting that the NR2B tyr-P is dependent on intracellular calcium release. In a dorsal horn slice preparation, the group I (dihydroxyphenylglycine), but not group II [(2 R ,4 R )-4-aminopyrrolidine-2,3-dicarboxylate] and III [ l -AP 4 ( l -(+)-2-amino-4-phosphonobutyric acid)], mGluR agonists, an IP 3 receptor ( d -IP 3 ) agonist, and a PKC (PMA) activator, induces NR2B tyr-P similar to that seen in vivo after inflammation. Coimmunoprecipitation indicates that Shank, a postsynaptic density protein associated with mGluRs, formed a complex involving PSD-95 (postsynaptic density-95), NR2B, and Src in the spinal dorsal horn. Double immunofluorescence studies indicated that NR1 is colocalized with mGluR5 in dorsal horn neurons. mGluR5 also coimmunoprecipitates with NR2B. Finally, intrathecal pretreatment of CPCCOEt, MPEP, and 2APB attenuates inflammatory hyperalgesia. Thus, inflammation and mGluR-induced NR2B tyr-P share similar mechanisms. The group ImGluR-NMDAR coupling cascade leads to phosphorylation of the NMDAR and appears necessary for the initiation of spinal dorsal horn sensitization and behavioral hyperalgesia after inflammation.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3422-04.2004
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2004
    detail.hit.zdb_id: 1475274-8
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  • 3
    Online Resource
    Online Resource
    Supraspinal Brain-Derived Neurotrophic Factor Signaling: A Novel Mechanism for Descending Pain Facilitation
    Society for Neuroscience ; 2006
    In:  The Journal of Neuroscience Vol. 26, No. 1 ( 2006-01-04), p. 126-137
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 26, No. 1 ( 2006-01-04), p. 126-137
    Abstract: In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10–100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs). In vitro studies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP 3 , PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3686-05.2006
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2006
    detail.hit.zdb_id: 1475274-8
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  • 4
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    Online Resource
    Transition to Persistent Orofacial Pain after Nerve Injury Involves Supraspinal Serotonin Mechanisms
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 12 ( 2013-03-20), p. 5152-5161
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 12 ( 2013-03-20), p. 5152-5161
    Abstract: The orofacial region is a major focus of chronic neuropathic pain conditions characterized by primary hyperalgesia at the site of injury and secondary hyperalgesia outside the injured zone. We have used a rat model of injury to the maxillary branch (V2) of the trigeminal nerve to produce constant and long-lasting primary hyperalgesia in the V2 territory and secondary hyperalgesia in territories innervated by the mandibular branch (V3). Our findings indicate that the induction of primary and secondary hyperalgesia depended on peripheral input from the injured nerve. In contrast, the maintenance of secondary hyperalgesia depended on central mechanisms. The centralization of the secondary hyperalgesia involved descending 5-HT drive from the rostral ventromedial medulla and the contribution of 5-HT3 receptors in the trigeminal nucleus caudalis (Vc), the homolog of the spinal dorsal horn. Electrophysiological studies further indicate that after nerve injury spontaneous responses and enhanced poststimulus discharges in Vc nociresponsive neurons were time-dependent on descending 5-HT drive and peripheral input. The induction phase of secondary hyperalgesia involved central sensitization mechanisms in Vc neurons that were dependent on peripheral input, whereas the maintenance phase of secondary hyperalgesia involved central sensitization in Vc neurons conducted by a delayed descending 5-HT drive and a persistence of peripheral inputs. Our results are the first to show that the maintenance of secondary hyperalgesia and underlying central sensitization associated with persistent pain depend on a transition to supraspinal mechanisms involving the serotonin system in rostral ventromedial medulla-dorsal horn circuits.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3390-12.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
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  • 5
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    Supraspinal Glial–Neuronal Interactions Contribute to Descending Pain Facilitation
    Society for Neuroscience ; 2008
    In:  The Journal of Neuroscience Vol. 28, No. 42 ( 2008-10-15), p. 10482-10495
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 42 ( 2008-10-15), p. 10482-10495
    Abstract: Spinal glial reaction and proinflammatory cytokine induction play an important role in the development of chronic pain states after tissue and nerve injury. The present study investigated the cellular and molecular mechanisms underlying descending facilitation of neuropathic pain with an emphasis on supraspinal glial–neuronal relationships. An early and transient reaction of microglia and prolonged reaction of astrocytes were found after chronic constriction injury (CCI) of the rat infraorbital nerve in the rostral ventromedial medulla (RVM), a major component of brainstem descending pain modulatory circuitry. There were prolonged elevations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after CCI, and they were expressed in RVM astrocytes at 14 d after injury. Intra-RVM injection of microglial and astrocytic inhibitors attenuated mechanical hyperalgesia and allodynia at 3 and 14 d after CCI, respectively. Moreover, TNFR1 and IL-1R, receptors for TNF-α and IL-1β, respectively, were expressed primarily in RVM neurons exhibiting immunoreactivity to the NMDA receptor (NMDAR) subunit NR1. CCI increased TNFR1 and IL-1R levels and NR1 phosphorylation in the RVM. Neutralization of endogenous TNF-α and IL-1β in the RVM significantly reduced CCI-induced behavioral hypersensitivity and attenuated NR1 phosphorylation. Finally, intra-RVM administration of recombinant TNF-α or IL-1β upregulated NR1 phosphorylation and caused a reversible and NMDAR-dependent allodynia in normal rats, further suggesting that TNF-α and IL-1β couple glial hyperactivation with NMDAR function. These studies have addressed a novel contribution of supraspinal astrocytes and associated cytokines as well as central glial–neuronal interactions to the enhancement of descending facilitation of neuropathic pain.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3593-08.2008
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2008
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  • 6
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    Tyrosine Phosphorylation of the NR2B Subunit of the NMDA Receptor in the Spinal Cord during the Development and Maintenance of Inflammatory Hyperalgesia
    Society for Neuroscience ; 2002
    In:  The Journal of Neuroscience Vol. 22, No. 14 ( 2002-07-15), p. 6208-6217
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 22, No. 14 ( 2002-07-15), p. 6208-6217
    Abstract: The present study examined the levels of NMDA receptor NR2 subunit tyrosine phosphorylation in a rat model of inflammation and correlated it with the development of inflammation and hyperalgesia. Hindpaw inflammation and hyperalgesia were induced by intraplantar injection of complete Freund's adjuvant. Proteins from the spinal cord (L4–L5) were immunoprecipitated with anti-NR2A or anti-NR2B antibodies and used for subsequent analysis using 4G-10, a specific anti-phosphotyrosine antibody. Compared with naive rats, there was a rapid and prolonged increase in tyrosine phosphorylation of the NR2B, but not NR2A, subunit after inflammation. The increase in NR2B tyrosine phosphorylation was dependent on primary afferent drive because (1) the phosphorylation correlated with the temporal profile of inflammation and hyperalgesia, (2) shorter-duration noxious stimulation produced a rapid and shorter-lasting increase in phosphorylation, and (3) local anesthetic block of the injected paw reversibly blocked inflammation-induced NR2B tyrosine phosphorylation and delayed hyperalgesia. The increase in NR2B tyrosine phosphorylation was abolished by intrathecal pretreatment with genistein, a tyrosine kinase inhibitor; PP2, an Src family tyrosine kinase inhibitor; AIDA, a group I metabotropic glutamate receptor antagonist; L733,060, an NK1 tachykinin receptor antagonist, and chelerythrine, a protein kinase C inhibitor. In addition, intrathecal PP2 delayed the onset of mechanical hyperalgesia and allodynia. These findings correlate in vivo NMDA receptor tyrosine phosphorylation with the development and maintenance of inflammatory hyperalgesia and suggest that signal transduction upstream to NR2B tyrosine phosphorylation involves G-protein-coupled receptors and PKC and Src family protein tyrosine kinases.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.22-14-06208.2002
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2002
    detail.hit.zdb_id: 1475274-8
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  • 7
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    Glial–Cytokine–Neuronal Interactions Underlying the Mechanisms of Persistent Pain
    Society for Neuroscience ; 2007
    In:  The Journal of Neuroscience Vol. 27, No. 22 ( 2007-05-30), p. 6006-6018
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 22 ( 2007-05-30), p. 6006-6018
    Abstract: The emerging literature implicates a role for glia/cytokines in persistent pain. However, the mechanisms by which these non-neural elements contribute to CNS activity-dependent plasticity and pain are unclear. Using a trigeminal model of inflammatory hyperalgesia, here we provide evidence that demonstrates a mechanism by which glia interact with neurons, leading to activity-dependent plasticity and hyperalgesia. In response to masseter inflammation, there was an upregulation of glial fibrillary acidic proteins (GFAPs), a marker of astroglia, and interleukin-1β (IL-1β), a prototype proinflammatory cytokine, in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input. The activated astroglia exhibited hypertrophy and an increased level of connexin 43, an astroglial gap junction protein. The upregulated IL-1β was selectively localized to astrocytes but not to microglia and neurons. Local anesthesia of the masseter nerve prevented the increase in GFAP and IL-1β after inflammation, and substance P, a prototype neurotransmitter of primary afferents, induced similar increases in GFAP and IL-1β, which was blocked by a nitric oxide synthase inhibitor N G -nitro- l -arginine methyl ester. Injection of IL-1 receptor antagonist and fluorocitrate, a glial inhibitor, attenuated hyperalgesia and NMDA receptor phosphorylation after inflammation. In vitro application of IL-1β induced NR1 phosphorylation, which was blocked by an IL-1 receptor antagonist, a PKC inhibitor (chelerythrine), an IP 3 receptor inhibitor (2-aminoethoxydiphenylborate), and inhibitors of phospholipase C [1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1 H -pyrrole-2,5-dione] and phospholipase A 2 (arachidonyltrifluoromethyl ketone). These findings provide evidence of astroglial activation by tissue injury, concomitant IL-1β induction, and the coupling of NMDA receptor phosphorylation through IL-1 receptor signaling.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.0176-07.2007
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2007
    detail.hit.zdb_id: 1475274-8
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