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ABSTRACT: BACKGROUND: L5/6 spinal nerve ligation (SNL), one of the most widely used approaches rat models for neuropathic pain, results in the rapid development of mechanical allodynia within 24-72 h. However, the result of a single L6 SNL remains unclear. METHODS: The first series of experiments were performed to examine the pain behavior of rats with different nerve ligations. Thirty-six rats were randomly assigned to four groups as follows: group I, controls (n = 6); group II, L5/6 nerve ligation (n = 6); group III, single L6 nerve ligation (n = 18); and group IV, the sham operation group (n = 6). The mechanical allodynia of rats was assessed using a 50 % paw withdrawal threshold (PWT), and tail antinociception was determined using the percentage of the maximal possible antinociceptive effect (% MPE). The second series of experiments were performed using Western blots to evaluate dorsal horn GFAP expression in different groups at different time points (D1, D7, D14, and D28). For this series of experiments, fifty-four rats were randomly divided into three groups: group I, controls (n = 6); group II, L5/6 nerve ligation (n = 24); and group III, L6 nerve ligation (n = 24). RESULTS: In this study, a single L6 SNL induced prolonged development (1-14 days) of mechanical allodynia and gradually increased expression of glial fibrillary acidic protein (GFAP) in the ipsilateral dorsal horn. Notably, once mechanical allodynia developed, both the severity of mechanical allodynia and the alteration of GFAP expression were similar regardless of the identity of the ligated nerve (L5/6 or L6 only). CONCLUSIONS: Single L6 SNL might be used as an effective model for researching the development period of neuropathic pain and is thus worth further investigation.
Acta Neurochirurgica 01/2013; · 1.52 Impact Factor
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ABSTRACT: Activity of human ether-a-go-go-related gene (hERG) 1 voltage-gated K(+) channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ∼9 and ∼18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ∼10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.-Norring, S. A., Ednie, A. R., Schwetz, T. A., Du, D., Yang, H., Bennett, E. S. Channel sialic acids limit hERG channel activity during the ventricular action potential.
The FASEB Journal 11/2012; · 5.71 Impact Factor
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ABSTRACT: Recent studies have indicated that minocycline, a microglia inhibitor, could potentially be used as an antinociceptive agent in pain management, although the underlying mechanisms remain elusive. In this study, we investigated the extent to which minocycline could influence pain behavior in association with the expression of the N-methyl-D-aspartic acid receptor 1 (NMDAR1) in a rat L5 spinal nerve ligation (SNL) model. We observed that the intrathecal injection of minocycline significantly attenuated mechanical allodynia in a rat SNL model from day 1 postinjection and persisted for at least 18 days. We also observed that the expression of NMDAR1 was increased in the spinal dorsal horn at 8 days after SNL, which could be partly inhibited through the intrathecal injection of minocycline. These findings suggest that the attenuation of allodynia in the SNL model following minocycline administration might be associated with the inhibited expression of NMDAR1 and, therefore, might play an important role in the minocycline-mediated antinociception.
Journal of physiology and biochemistry 11/2012; · 1.71 Impact Factor
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Jun Li,
Yi Feng,
Jisheng Han,
Bifa Fan,
Dasheng Wu,
Daying Zhang, Dongping Du,
Hui Li,
Jian Lim,
Jiashuang Wang,
Yi Jin,
Zhijian Fu
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ABSTRACT: Neuropathic pain questionnaires are efficient diagnostic tools for neuropathic pain and play an important role in neuropathic pain epidemiologic studies in China. No comparison data was available in regards to the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Neuropathic Pain Questionnaire (NPQ) and ID Pain within and among the same population.
To achieve a linguistic adaptation, validation, and comparison of Chinese versions of the 3 neuropathic pain questionnaires (LANSS, NPQ and ID Pain).
A nonrandomized, controlled, prospective, multicenter trial.
Ten pain centers in China.
Two forward translations followed by comparison and reconciliation of the translations. Comparison of the 2 backward translations with the original version was made to establish consistency and accuracy of the translations. Pilot testing and pain specialists' evaluations were also required. A total of 140 patients were enrolled in 10 centers throughout China: 70 neuropathic pain patients and 70 nociceptive pain patients. Reliability (Cronbach's alpha coefficients and Guttman split-half coefficients) and validity (sensitivity, specificity, positive and negative predictive values, receiver operating characteristic [ROC] curves and the area under the ROC curves) of the 3 questionnaires were determined. ROC curves and the area under the ROC curves of the 3 questionnaires were also compared.
Chinese versions of LANSS, NPQ and ID Pain had a good reliability (Cronbach's alpha coefficients and Guttman split-half coefficients were greater than 0.7). Sensitivity, specificity, positive and negative predictive values of the Chinese versions of LANSS and ID Pain were considerably high ( > 80%). The area under the ROC curves of LANSS and ID Pain was significantly higher than that of NPQ (P < 0.05). There was no statistically significant difference between the area under the ROC curves of LANSS and ID Pain (P > 0.05).
The study was based on patients with a high school degree or above, which limited the application of the 3 neuropathic pain questionnaires to patients with lower educational levels.
The Chinese versions of LANSS and ID Pain developed and validated by this study can be used as a diagnostic tool in differentiating neuropathic pain in patients whose native language is Chinese (Mandarin).
Pain physician 03/2012; 15(2):179-86. · 10.72 Impact Factor
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ABSTRACT: Recent studies have suggested that activated glia in the spinal cord may play a vital role at different times during spinal nerve ligation (SNL)-induced neuropathic pain; therefore, glial activation inhibitors have been used as effective painkillers. Brain-derived neurotrophic factor (BDNF) is also known to be a powerful pain modulator, but it remains unclear how it contributes to the glial activation inhibitor-based treatment. This study revealed the following results: (1) intrathecal administration of minocycline (a microglial activation inhibitor) could prevent mechanical allodynia during the initiation of SNL-induced neuropathic pain, and its action was associated with the elimination of BDNF overexpression in the dorsal horn; (2) the spinal injection of fluorocitrate (an astrocytic activation inhibitor) but not minocycline could reverse mechanical allodynia during the maintenance phase of SNL-induced pain, and its action was also related to a decrease in BDNF overexpression in the dorsal horn; and (3) treatment with TrkB/Fc (a BDNF-sequestering protein) had a similar effect during both the early development and maintenance periods. These results led to the following conclusions: (1) elevated BDNF expression in the dorsal horn was required to develop and maintain neuropathic pain; (2) minocycline could only prevent mechanical allodynia in the early stages, possibly by inhibiting BDNF release from microglia; and (3) fluorocitrate could reverse existing mechanical allodynia, and its action was associated with the inhibition of BDNF upregulation induced by astrocytic activation.
Acta Neurovegetativa 09/2011; 119(3):329-36. · 2.73 Impact Factor
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ABSTRACT: The cardiac action potential (AP) is produced by the orchestrated functions of ion channel dynamics. The coordinated functions can be simulated by computational cardiac cell models, which could not only overcome the practical and ethical limitations in physical experiments but also provide predictive insights on the underlying mechanisms. This investigation is aimed at modeling the variations of cardiac electrical signaling due to changes in glycosylation of a voltage-gated K+ channel, hERG, responsible for late phase 2 and phase 3 of the human ventricular AP. The voltage-dependence of hERG channels steady-state activation and inactivation under four glycosylation conditions, i.e., full glycosylation, reduced sialylation, mannose-rich and N-Glycanase treated, demonstrated that reduced glycosylation modulates hERG channel gating. Here, the proposed multi-scale computer model incorporates the measured changes in hERG channel gating observed under conditions of reduced glycosylation, and further predicts the electrical behaviors of cardiac cells and tissues (cable/ring). The multi-scale modeling results show that reduced glycosylation would act to shorten the repolarization period of cardiac APs, and distort the AP propagation in cardiac tissues. This multi-scale modeling investigation reveals novel mechanisms of hERG channel modulation by regulated glycosylation that also impact cardiac myocyte and tissue functions. It can potentially lead to new pharmaceutical treatments and drug designs for long QT syndrome and cardiac arrhythmia.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2011; 2011:104-7.
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ABSTRACT: Neuropathic pain is one of the most challenging clinical problems due to a lack of understanding the mechanisms. Recent studies have suggested that activated microglia in spinal cord may play a vital role in nerve injury-induced neuropathic pain, but the exact mechanisms have not been fully determined.
First, we investigated the changes of dorsal horn GABA(B) receptor 1 (R1) expression in spinal nerve ligation rats. Second, we explored whether activated microglia contributed to such neuron changes by intrathecal administration of the p38 inhibitor, SB203580.
In this study, we found a dynamic change of GABA(B)R1a protein expression after spinal nerve ligation, and the peripheral nerve injury-induced downregulation of GABA(B)R1a expression in the spinal dorsal horn could be prevented by intrathecal administration of a p38/MAPK inhibitor SB203580.
Our results provide valuable information for a better understanding of neuropathic pain and may contribute to developing effective treatments in future studies.
NeuroImmunoModulation 01/2011; 18(3):150-5. · 2.38 Impact Factor
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ABSTRACT: We evaluated the ability of spinally administered 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), and 2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, to modulate the antinociceptive action and tolerance of intrathecal (i.t.) morphine infusion in rats, and assessed the expression of spinal nitric oxide synthase (NOS). MPEP co-infused with morphine not only preserved the analgesia and retarded the development of antinociceptive tolerance, but also partially inhibited the up-regulation of spinal nNOS protein. However, the loss of morphine antinociceptive effect and tolerance were accelerated when CHPG and morphine were co-infused, while spinal nNOS activity was significantly up-regulated. We hypothesize that activation of mGluR5 and NMDA receptors occurs after the appearance of antinociceptive tolerance to morphine. The activation of these receptors might stimulate an increased concentration of intracellular calcium and activation of PKC, which both play a vital role in the development of morphine antinociceptive tolerance and expression of spinal NOS. The synergistic effect which seems to exist between mGluRs and iGluRs may also contribute to this phenomenon.
Neuroscience Letters 06/2008; 436(2):214-8. · 2.11 Impact Factor
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ABSTRACT: Prolonged intrathecal (i.t.) administration of morphine results in tolerance to morphine-induced antinociception. We found that co-administration of selective metabotropic glutamate receptor subtype 5 antagonist MPEP with morphine could suppress the loss of morphine-induced antinociception and inhibit the development of tolerance to morphine-induced antinociceptive effect. Whereas, the specific metabotropic glutamate receptor subtype 5 agonist CHPG does the opposite. As the activation of NMDA receptor after chronic morphine administration has been verified, we suppose there is an enhanced activation of mGluR5 during the development of tolerance to morphine-induced antinociception. Activation of mGluR5 may mobilize the release of intracellular Ca(2+) and activate PKC, leading to morphine-induced antinociception suppression. We conclude that mGluR5 contributes to the development of tolerance to morphine-induced antinociception after chronic morphine exposure.
Neuroscience Letters 07/2007; 420(2):155-9. · 2.11 Impact Factor
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ABSTRACT: Estrogen sensitizes responses to painful stimuli, but its contribution to acute and chronic pain from the uterine cervix is unknown. Previous studies link the excitatory transient receptor potiential-1 channel (TRPV-1) to sensitization in viscera, and show that estrogen increases TRPV-1 expression in afferents from the uterine cervix. Here, we tested whether estrogen enhanced responses to uterine cervical distension in rats, and whether this involved TRPV-1 channels.
Ovariectomized rats, with or without estrogen replacement, were anesthetized and hypogastric nerve and abdominal muscle contraction reflex responses to graded uterine cervical distension were recorded. Single unit hypogastric nerve fiber firing was measured before and after acute treatment with the TRPV-1 antagonist, capsaizepine, or vehicle.
Abdominal muscle contraction reflex responses to uterine cervical distension were enhanced in estrogen-treated rats. Hypogastric afferent responses to cervical distension were reduced by capsaizepine in estrogen-treated animals, but were unaffected in ovariectomized animals without estrogen replacement.
These data suggest that the TRPV-1 channel is unimportant for normal mechanosensation in the cervix in the absence of estrogen, since capsaizepine failed to reduce responses to uterine cervical distension in rats without estrogen replacement. In contrast, TRPV-1 function is important for estrogen-induced sensitization. These data raise the possibility that acute and chronic pain coming from the cervix, such as labor or cancer, may be enhanced by estrogen and might be reduced by antagonists of TRPV-1.
Anesthesia and analgesia 06/2007; 104(5):1246-50, tables of contents. · 3.08 Impact Factor
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ABSTRACT: To test the effect of mild hypothermia in reducing pancreatic damage and improving the survival of acute hemorrhagic and necrotic pancreatitis (AHNP) in rats.
Thirty-six male Sprague-Dawley rats were studied. Sham animals (n = 12) received laparotomy and normothermia; for AHNP with normothermia (n = 12), the core temperature was maintained at 37 degrees C to 37.5 degrees C after AHNP for 2 to 5 hours; for AHNP with hypothermia (n = 12), the core temperature was maintained at 32 degrees C to 33 degrees C afterward. Serum amylase and lipase, interleukin (IL)-1beta, and tumor necrosis factor (TNF-alpha) were measured. The pancreas was examined histologically. In a separate experiment, the core temperature was kept either in normothermia (n = 20) or mild hypothermia (n = 20) for 12 hours after the induction of AHNP; the animals were then returned to their cage. The survival rate was monitored up to 72 hours.
Mild hypothermia significantly decreased the release of serum amylase and lipase compared with AHNP normothermia at 2 and 5 hours. Histology examination revealed significantly less tissue damage in AHNP hypothermia. There was a further increase in TNF-alpha and IL-1beta in AHNP in animals with hypothermia compared with normothermia animals. The application of mild hypothermia significantly improved the survival in animals induced with AHNP.
Mild hypothermia decreases amylase and lipase release and improves a survival of AHNP in rats.
Pancreas 06/2005; 30(4):e80-6. · 2.39 Impact Factor
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ABSTRACT: Pain during labor is common and severe, as is menstrual pain, and this pain originates from the uterine cervix and is transmitted via the hypogastric nerve to the spinal cord. Prostaglandins play an important role in nociceptive transmission in the spinal cord. Pharmacologically, targeting a specific cyclooxygenase (COX) enzyme isoform has as its goal to effectively treat pain while avoiding side effects. Both COX-1 and COX-2 inhibitors have been shown to effectively treat a variety of pain conditions in animals and in humans; however, their efficacy in treatment of acute visceral pain has not been explored. The purpose of this study is to evaluate the pharmacologic effects of specific spinal COX inhibitors on uterine cervical distention induced nociception. The results indicate that intrathecal (i.t.) administration of the COX-2 inhibitor, SC58238, and the nonspecific COX inhibitor, indomethacin, effectively inhibited the electromyographic activity induced by UCD. None of the inhibitors altered hemodynamic response to uterine cervical distension. The study suggests that targeting spinal COX-2 could be useful to treat transient and acute visceral pain from the uterine cervix.
Brain Research 11/2004; 1024(1-2):130-6. · 2.73 Impact Factor
