British journal of pharmacology
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1. A spinal ventral root response was measured following the activation of peripheral fibres by noxious (heat at 48 degrees C, capsaicin, bradykinin) and innocuous (brush) stimuli in a preparation of the neonatal rat spinal cord-tail maintained in vitro. 2. Following superfusion of the tail with 0.1-1.0 nM of the potent irritant, resiniferatoxin (RTX), brief, irregular depolarization and a selective loss of capsaicin sensitivity was produced. ⋯ Rather, RTX acts on nociceptors by a similar mechanism to capsaicin. These effects may be the basis for the irritant properties of RTX and may further relate to the antinociceptive actions observed in vivo. RTX is therefore a potent new tool with which to investigate the properties of nociceptive neurones and provides a prototype for further development of antinociceptive agents.
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1. The effects of a selective delta-opioid agonist Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr (DSTBULET) were examined on the C- and A beta-evoked responses of convergent dorsal horn neurones in the halothane anaesthetized, intact rat. 2. Intrathecal DSTBULET produced selective dose-dependent inhibitions of electrically-evoked C fibre responses of both superficial and deep neurones. ⋯ The same dose of kelatorphan inhibited the formalin response in the present study. 5. From this study it appears that the delta-opioid agonist DSTBULET can produce profound inhibitions of the responses of convergent neurones to nociceptive afferent inputs. Furthermore, activation of delta-opioid receptors either by DSTBULET, or by protection of endogenous enkephalins with kelatorphan, can inhibit a more prolonged chemically-evoked nociceptive input onto these dorsal horn neurones.
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1. Pithed rats were respired at a fixed rate of 54 cycles min-1 and with a ventilation volume of either 20 (control) or 10 ml kg-1. In these two preparations, the dose-response relationships for the systemic blood pressure responses to endothelin-1, administered i.v., were examined. ⋯ Endothelin-1 induced profound vasoconstriction in the mesenteric bed of the pithed rat both in vivo and in situ. The potency of endothelin-1 on this bed in situ was doubled by lowering the ventilation volume. An increase in cardiac contractility and severe gastrointestinal vasoconstriction may be the initial events leading to the eventual toxic effect of endothelin-1 in the hypoxic pithed rat.
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1. The relative spinal effectiveness of mu- and kappa-opioids has been assessed by their intravenous potencies on nociceptive responses (heat and/or pinch) of single motoneurones recorded in alpha-chloralose anaesthetized, spinalized rats. 2. The depressant actions of both mu- and kappa-opioids were reversed by low intravenous doses of naloxone (10 to 100 micrograms kg-1). ⋯ The agonist potency values obtained in this study contrast with those reported for local spinal administration. By this route, the potency of lipophilic opioids (e.g. fentanyl, U-50,488 and tifluadom) relative to hydrophilic opioids (e.g. morphine) is much reduced, implying that activity of intrathecally administered opioids is more dependent on the physico-chemical properties of the agonists used than on the relative abundance in the spinal cord of functional opioid receptors of the mu- and kappa-subtypes. This conclusion indicates that the results with locally applied opioids should not be used to assess spinal opioid receptor function.
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1. Flupirtine is a novel, centrally acting, non-opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. ⋯ Flupirtine-induced antinociception also remained unchanged after pretreatment with haloperidol. 9. Flupirtine has no pharmacologically relevant affinity for alpha 1-, alpha 2-adrenoceptors, 5-HT1- and 5-HT2-receptors as shown in direct binding studies. 10. The present results indicate that the antinociceptive action induced by flupirtine depends on the descending noradrenergic pain-modulating system.