Neuropharmacology
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Recent studies have reported that estrogen has antidepressant-like effects in animal models. In this study we used the highly selective ER beta agonist, WAY-200070, to examine the role of ER beta activation on brain neurochemistry and activity in antidepressant and anxiolytic models in male mice. Within 15 min of administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ER beta receptors from the cytosol. ⋯ WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response). The effects of the selective ER beta agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ER beta function may provide a novel treatment for affective disorders.
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Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. ⋯ Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.
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Metabotropic glutamate receptors (mGluR) are classified into groups I (excitatory), II and III (inhibitory) mGluR. Activation of peripheral group III mGluR (mGluR4, mGluR6, mGluR7, mGluR8), particularly mGluR8, inhibits vagal afferent mechanosensitivity in vitro which translates into reduced triggering of transient lower oesophageal sphincter relaxations and gastroesophageal reflux in vivo. However, the expression and function of group III mGluR in central gastrointestinal vagal reflex pathways is not known. ⋯ The effects of DCPG were significantly reversed by the group III mGluR antagonist MAP4 (10 nmol, i.c.v.). In contrast, 4/4 NTS neurons inhibited by gastric distension were unaffected by DCPG. We conclude that group III mGluR are expressed in peripheral and central vagal pathways, and that mGluR8 within the NTS selectively reduce excitatory transmission along gastric vagal pathways.
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Review Comparative Study
Predictive validity of animal pain models? A comparison of the pharmacokinetic-pharmacodynamic relationship for pain drugs in rats and humans.
A number of previous reviews have very eloquently summarized pain models and endpoints in animals. Many of these reviews also discuss how animal models have enhanced our understanding of pain mechanisms and make forward-looking statements as to our proximity to the development of effective mechanism-based treatments. While a number of reports cite failures of animal pain models to predict efficacy in humans, few have actually analyzed where these models have been successful. ⋯ Key to prediction of clinical efficacy is a lack of side effects, which may incorrectly suggest efficacy in animals and an understanding of how pharmacokinetic parameters translate from animals to man. As such, this review focuses on a description of the pharmacokinetic-pharmacodynamic relationship for a number of pain treatments that are effective in both animals and humans. Finally we discuss where and why animal pain models have failed and summarize improvements to pain models that should expand and improve their predictive power.
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The sensory neuron-specific receptor (SNSR) is exclusively distributed in dorsal root ganglion (DRG) cells. We have demonstrated that intrathecal (i.t.) administration of SNSR agonists inhibits formalin-evoked responses and the development of morphine tolerance [Chen, T., Cai, Q., Hong, Y., 2006. Intrathecal sensory neuron-specific receptor agonists bovine adrenal medulla 8-22 and (tyr(6))-gamma2-msh-6-12 inhibit formalin-evoked nociception and neuronal fos-like immunoreactivity in the spinal cord of the rat. ⋯ Pretreatment with the SNSR agonist bovine adrenal medulla 8-22 (3, 10 and 30 nmol) dose-dependently diminished NMDA-evoked nocifensive behaviors and hyperalgesia. This agonist also reduced NMDA-evoked expression of FLI and NADPH reactivity in the spinal dorsal horn. Taken together, these data suggest that the activation of SNSR induces spinal analgesia by suppressing NMDA receptor-mediated activation of spinal dorsal horn neurons and an increase in NOS activity.