Life sciences
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The excitatory effect of bradykinin (BK) and of low pH on nociceptors appears to partly depend on secondary release of prostaglandins from the surrounding tissue. Rat skin, in vitro, is introduced as a novel model to measure basal and stimulated release of PGE2 and, in future, other substances relevant to nociception, such as neuropeptides. Flaps of hairy skin (n=57) from the rat saphenous region of the hindpaw were subcutaneously excised and fixed on acrylic rods, the corium side exposed. ⋯ Solutions of high proton concentration are known to stimulate and sensitize nociceptors. However, phosphate buffered SIF at pH 6.1 and 6.4 caused a substantial and significant decrease of the PGE2 release, probably due to low-pH block of phospholipases. Thus, algogenic potency of mediators does not necessarily match their pro-inflammatory action.
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Hydromorphone-3-glucuronide (H3G) was synthesized biochemically using rat liver microsomes, uridine-5'-diphosphoglucuronic acid (UDPGA) and the substrate, hydromorphone. Initially, the crude putative H3G product was purified by ethyl acetate precipitation and washing with acetonitrile. Final purification was achieved using semi-preparative high-performance-liquid-chromatography (HPLC) with ultraviolet (UV) detection. ⋯ Using HPLC with tandem mass spectrometry (HPLC-MS-MS) in the positive ionization mode, the molecular mass (M+1) was found to be 462 g/mol, in agreement with H3G's expected molecular weight of 461 g/mol. Importantly, proton-NMR indicated that the glucuronide moiety was attached at the 3-phenolic position of hydromorphone. A preliminary evaluation of H3G's intrinsic pharmacological effects revealed that following i.c.v. administration to adult male Sprague-Dawley rats in a dose of 5 microg, H3G evoked a range of excitatory behavioural effects including chewing, rearing, myoclonus, ataxia and tonic-clonic convulsions, in a manner similar to that reported previously for the glucuronide metabolites of morphine, morphine-3-glucuronide and normorphine-3-glucuronide.
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A mouse model for binge drinking has been developed in this laboratory, and several aspects of this model have been characterized. Many of the immunosuppressive effects of ethanol (EtOH) in this model seem to be mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis and consequent increases in the concentration of glucocorticoids, catecholamines, and perhaps other immunosuppressive mediators. The purpose of the work described here is to examine three important issues regarding the EtOH-induced neuroendocrine response in this model: 1) Are Ro15-4513-sensitive gamma aminobutyric acid type A (GABA-A) receptors involved in activation of the HPA axis by EtOH? 2) Does daily administration of EtOH produce tolerance with regard to activation of the HPA axis or with regard to suppression of natural killer cell activity? 3) Is the HPA axis activated by similar blood EtOH concentrations in humans and in the mouse model? Ro15-4513, a partial inverse agonist of GABA-A receptors, did not affect EtOH-induced increases in blood corticosterone levels. ⋯ To compare the HPA axis response of mice and humans, lower EtOH dosages than generally used in our model were administered to mice, and the corticosterone response was compared to published data for humans who had similar ranges of blood EtOH levels. The results suggest that humans and mice exhibit activation of the HPA axis only when blood EtOH levels exceed approximately 0.14%. Together these results further characterize a mouse model for binge drinking that seems to provide a reasonable representation of many aspects of binge drinking in humans.
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Neurotropin is commonly used in Japan for the treatment of chronic pain. Using a rat model, we evaluated the effect of neurotropin on a unilateral peripheral mononeuropathy produced by placing loose ligatures around the sciatic nerve. ⋯ No significant reduction in mechanical allodynia, however, was noted under the tested condition. A possibility of differential drug sensitivity for thermal hyperalgesia and mechanical allodynia was indicated in this model, although the reason still remain elusive.
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Neurotropin, a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug in Japan. Its analgesic effect has been demonstrated by reduced mechano-nociception in hyperalgesic rats exposed to SART-stress (a repeated cold stress) for 5 days. In order to clarify the mechanism of the analgesic effect of neurotropin at the spinal cord level, we examined the effects of several neurotransmitter receptor antagonists given by intrathecal (i.t.) injection on the antinociceptive effect of intraperitoneally (i.p.) injected neurotropin [100 and 200 Neurotropin Unit (NU)/kg]. ⋯ However, the analgesic effect of neurotropin (100 and 200 NU/kg, i.p.) was not influenced by naloxone (30 nmol/rat, i.t.), an opioid antagonist. These results suggest that the mechanism of the antinociceptive effect of neurotropin is via enhancement of endogenous descending pain inhibitory pathways of the serotonergic and noradrenergic systems, especially involving 5-HT3 and noradrenergic alpha2 receptors in spinal dorsal horn in which these neurons terminate. No influence of opioid receptors at the spinal cord level is indicated.