Biomedical subjects

Yuan-Xiang Tao

Publications and source records attributed to Yuan-Xiang Tao.

12 recordsLinked to original sources

PubMed2026

Nucleolin promotes neuropathic pain by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Nerve injury-induced transcriptional alterations in primary sensory neurons of the dorsal root ganglion (DRG) constitute a key molecular basis for the development of neuropathic pain. Nucleolin (NCL), a highly conserved multifunctional nucleolar protein, regulates gene transcription. Here, we identify that NCL is expressed exclusively in the nuclei of DRG neurons. Peripheral nerve injury time-dependently upregulates Ncl mRNA and NCL protein levels in injured DRG neurons. Blocking this upregulation through DRG microinjection of the adeno-associated virus 9 (AAV9) expressing an shRNA targeting Ncl attenuates nerve injury-induced increases of C-C motif chemokine ligand 2 (CCL2) mRNA and its protein in injured DRG and alleviates the development and maintenance of mechanical, heat and cold hypersensitivities. Conversely, mimicking DRG NCL upregulation through DRG microinjection of AAV9 carrying the full-length Ncl coding sequence increases Ccl2 mRNA and CCL2 protein levels in microinjected DRGs and produces neuropathic pain-like symptoms in the absence of nerve injury. Mechanistically, peripheral nerve injury increases NCL occupancy at the Ccl2 promoter and enhances chromatin accessibility at this locus, resulting in elevated CCL2 expression in injured DRG neurons, which is reversed by NCL knockdown. Given that Ncl mRNA is co-expressed with Ccl2 mRNA in individual DRG neurons, our findings suggest that NCL upregulation in the DRG contributes to neuropathic pain likely by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Animals↗

PubMed2005

Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain.

Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N(G)-nitro-arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2h) and maintenance (24h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24h after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain.

Animals↗

PubMed2005

Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states.

Glutamate is a neurotransmitter critical for spinal excitatory synaptic transmission and for generation and maintenance of spinal states of pain hypersensitivity via activation of glutamate receptors. Understanding the regulation of synaptically and non-synaptically released glutamate associated with pathological pain is important in exploring novel molecular mechanisms and developing therapeutic strategies of pathological pain. The glutamate transporter system is the primary mechanism for the inactivation of synaptically released glutamate and the maintenance of glutamate homeostasis. Recent studies demonstrated that spinal glutamate transporter inhibition relieved pathological pain, suggesting that the spinal glutamate transporter might serve as a therapeutic target for treatment of pathological pain. However, the exact function of glutamate transporter in pathological pain is not completely understood. This report will review the evidence for the role of the spinal glutamate transporter during normal sensory transmission and pathological pain conditions and discuss potential mechanisms by which spinal glutamate transporter is involved in pathological pain.

Amino Acid Transport System X-AG↗

PubMed2005

Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord.

Glutamate is a major excitatory neurotransmitter in primary afferent terminals and is critical for normal spinal excitatory synaptic transmission. However, little is known about the regulation of synaptically released glutamate in the spinal cord under physiologic conditions. The sodium-dependent, high-affinity glutamate transporters are the primary mechanism for the clearance of synaptically released glutamate. In the present study, we found that intrathecal injection of glutamate transporter blockers DL-threo-beta-benzyloxyaspartate (TBOA) and dihydrokainate produced significant and dose-dependent spontaneous nociceptive behaviors, such as licking, shaking, and caudally directed biting, phenomena similar to the behaviors caused by intrathecal glutamate receptor agonists. Intrathecal TBOA also led to remarkable hypersensitivity in response to thermal and mechanical stimuli. These behavioral responses could be significantly blocked by intrathecal injection of the NMDA receptor antagonists MK-801 and AP-5, the non-NMDA receptor antagonist CNQX or the nitric oxide synthase inhibitor L-NAME. In vivo microdialysis analysis showed short-term elevation of extracellular glutamate concentration in the spinal cord after intrathecal injection of TBOA. Furthermore, topical application of TBOA on the dorsal surface of the spinal cord resulted in a significant elevation of extracellular glutamate concentration demonstrated by in vivo glutamate voltametry. The present study indicates that defective spinal glutamate uptake caused by inhibition of glutamate transporters leads to excessive glutamate accumulation in the spinal cord. The latter results in persistent over-activation of synaptic glutamate receptors, producing spontaneous nociceptive behaviors and sensory hypersensitivity. Our results suggest that glutamate uptake through spinal glutamate transporters is critical for maintaining normal sensory transmission under physiologic conditions.

Animals↗

PubMed2004

Involvement of the NMDA receptor/nitric oxide signal pathway in platelet-activating factor-induced neurotoxicity.

Platelet-activating factor (PAF), a bioactive phospholipid implicated in neuronal excitotoxic death, augments the presynaptic release of glutamate. Excessive activation of postsynaptic glutamate receptors and subsequent downstream signals leads to excitotoxicity. The present study proposed that the NMDA receptor/nitric oxide (NO) signal pathway might be involved in PAF-induced neurotoxicity. After the cultured neurons were exposed to PAF for 24 h the percentage of neuronal death increased in a dose-dependent manner. The PAF effects were significantly prevented not only by BN52021, a PAF antagonist, but also by MK-801, an NMDA antagonist, and L-NAME, an NO synthase (NOS) inhibitor. Moreover, the increases in NOS activity and neuronal NOS expression induced by chronic exposure of the cultured neurons to PAF were dramatically blocked by BN52021 and MK-801, respectively. Our findings suggest that the NMDA receptor/NO signaling pathway might contribute to the pathological mechanism of cell death triggered via PAF receptor activation.

Animals↗

PubMed2004

Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons.

PSD-93, a molecular adaptive protein, binds to and clusters the N-methyl-D-aspartate (NMDA) receptor and assembles a specific set of signaling proteins (for example neuronal nitric oxide synthase, nNOS) around the NMDA receptor at synapses in the central nervous system. This suggests that PSD-93 might mediate many NMDA receptor-dependent physiological and pathophysiological functions. We report here that PSD-93 colocalizes and interacts with the NMDA receptor and neuronal nitric oxide synthase in cultured cortical neurons. Targeted disruption of PSD-93 gene significantly prevented NMDA receptor-nitric oxide signaling-dependent neurotoxicity triggered via platelet-activating factor (PAF) receptor activation. In addition, the deficiency of PSD-93 markedly attenuated platelet-activating factor-induced increase in cyclic guanosine 3',5'-monophosphate (cGMP) and prevented platelet-activating factor-promoted formation of NMDA receptor-neuronal nitric oxide synthase complex. These findings indicate that PSD-93 is involved in the NMDA receptor--nitric oxide-mediated pathological processing of neuronal damage triggered via platelet--activating factor receptor activation. Since platelet-activating factor is a potent neuronal injury mediator during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal damage in these brain disorders.

Animals↗

PubMed2004

Are synaptic MAGUK proteins involved in chronic pain?

Chronic pain, particularly neuropathic pain, is notoriously difficult to treat. NMDA receptor antagonists are effective in reducing pain hypersensitivity in animal models and clinical settings but are associated with an unacceptable level of side-effects. Recent studies of the role of a family of synaptic membrane-associated guanylate kinase proteins in chronic pain provide new insights into central mechanisms of chronic pain that could result in new biochemical targets for its treatment.

Animals↗

PubMed2004

Neuronal PDZ domains: a promising new molecular target for inhaled anesthetics?

Despite widespread use of volatile general anesthetics in millions of patients each year, the mechanisms by which they exert multiple effects on the behavior of central neurons are poorly understood. PDZ [postsynaptic density 95 (PSD-95), discs large (Dlg), and zonula occludens-1 (ZO-1)] domains are ubiquitous protein interaction modules that participate in neuronal signaling. Recent studies have indicated that clinically relevant concentrations of inhaled anesthetics dose-dependently and specifically inhibit the PDZ domain-mediated protein interactions among multiprotein signaling complexes. These inhibitory effects are immediate, potent, reversible, and occur at a hydrophobic peptidebinding groove on the surface of the PDZ domain. Thus, the PDZ domain might be a new molecular target for inhalational anesthetics.

Anesthetics, Inhalation↗

PubMed2003

Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein.

Modification of synaptic NMDA receptor (NMDAR) expression influences NMDAR-mediated synaptic function and associated persistent pain. NMDARs directly bind to a family of membrane-associated guanylate kinases (MAGUKs) that regulate surface and synaptic NMDAR trafficking in the CNS. We report here that postsynaptic density-93 protein (PSD-93), a postsynaptic neuronal MAGUK, is expressed abundantly in spinal dorsal horn and forebrain, where it colocalizes and interacts with NMDAR subunits NR2A and NR2B. Targeted disruption of the PSD-93 gene reduces not only surface NR2A and NR2B expression but also NMDAR-mediated excitatory postsynaptic currents and potentials, without affecting surface AMPA receptor expression or its synaptic function, in the regions mentioned above. Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain. PSD-93 appears to be important for NMDAR synaptic targeting and function and to be a potential biochemical target for the treatment of persistent pain.

Animals↗

PubMed2003

Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics.

Anesthetics exert multiple effects on the central nervous system through altering synaptic transmission, but the mechanisms for this process are poorly understood. PDZ domain-mediated protein interactions play a central role in organizing signaling complexes around synaptic receptors for efficient signal transduction. We report here that clinically relevant concentrations of inhalational anesthetics dose-dependently and specifically inhibit the PDZ domain-mediated protein interaction between PSD-95 or PSD-93 and the N-methyl-d-aspartate receptor or neuronal nitric-oxide synthase. These inhibitory effects are immediate, potent, and reversible and occur at a hydrophobic peptide-binding groove on the surface of the second PDZ domain of PSD-95 in a manner relevant to anesthetic action. These findings reveal the PDZ domain as a new molecular target for inhalational anesthetics.

Anesthetics, Inhalation↗

PubMed2003

Effect of knock down of spinal cord PSD-93/chapsin-110 on persistent pain induced by complete Freund's adjuvant and peripheral nerve injury.

PSD-93/chapsin-110 is a neuronal PDZ domain-containing protein that binds to and clusters the N-methyl-D-aspartate receptor (NMDAR) at synapses in the central nervous system. It also assembles a specific set of signaling proteins around the NMDAR and mediates downstream signaling by the NMDAR. Thus, PSD-93/chapsin-110 might be involved in many physiological and pathophysiological actions triggered via the activation of the NMDAR. In the current study, we report that abundant PSD-93/chapsin-110 protein was detected in rat spinal cord, particularly in the superficial dorsal horn. The rats injected intrathecally with PSD-93/chapsin-110 antisense oligodeoxynucleotide every 24 h for 4 days displayed not only a remarkable decrease in spinal cord PSD-93/chapsin-110 expression but also a significant reduction in the paw withdrawal responses to thermal and mechanical stimuli during complete Freund's adjuvant-induced inflammatory pain and peripheral nerve injury-induced neuropathic pain. In contrast, the rats injected intrathecally with PSD-93/chapsin-110 missense oligodeoxynucleotide did not exhibit these changes. We also found that pretreatment with PSD-93/chapsin-110 antisense oligodeoxynucleotide did not change the locomotor activity or the responses to acute noxious thermal and mechanical stimuli in intact rats. The present results indicate that the deficiency of spinal cord PSD-93/chapsin-110 protein significantly attenuates thermal and mechanical hyperalgesia in complete Freund's adjuvant- or peripheral nerve injury-induced chronic pain. This suggests that spinal cord PSD-93/chapsin-110 might be involved in the central mechanism of chronic pain. Our work might provide a new target for the therapy of chronic pain.

Acute Disease↗

PubMed2003

Role of micro-opioid receptors in formalin-induced pain behavior in mice.

Intraplantar formalin injection is widely used as an experimental model of tonic pain. We investigated the role of endogenous micro-opioid receptor mechanisms in formalin-induced nocifensive behavior in mice. The flinching response induced by formalin (2%, 20 microl) was studied in mice with normal (wild type, n = 8) and absent (homozygous micro-opioid receptor knockout, n = 8) micro-opioid receptor levels. The flinch responses were counted every 5 min for 60 min post-formalin injection. Lumbar spinal cord (L4, 5) was harvested 2 h post-formalin injection to examine c-Fos expression using immunohistochemistry. The effects of naloxone (5 mg/kg, sc) administered 30 min before the intraplantar formalin injection on the flinching response of wild-type mice (n = 7) were also recorded. The second-phase formalin response (10-60 min after formalin) was higher in homozygous micro-opioid receptor knockout mice compared to the wild-type mice (P < 0.01). Naloxone administration in wild-type mice before formalin injection resulted in pain behavior similar to that observed in homozygous micro-opioid receptor knockout mice (P > 0.05). The c-Fos expression induced by formalin injection in the knockout mice was not different from that observed in wild-type mice. Our results suggest that the endogenous micro-opioid system is activated by intraplantar formalin injection and exerts a tonic inhibitory effect on the pain behavior. These results suggest an important modulatory role of endogenous micro-opioid receptor mechanisms in tonic pain states.

Animals↗