Articles: analgesics.
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Flupirtine maleate is a centrally acting analgesic with a novel chemical structure and pharmacological profile. Because of its central mechanism(s) of action, flupirtine maleate was studied for physical dependence liability and abuse potential using the following four laboratory animal models: (1) mouse jumping test--jumping behaviour after narcotic antagonist challenge; (2) Hosoya test in rats--body weight reduction after drug withdrawal or narcotic antagonist challenge; (3) tolerance in mice--reduced analgesic activity after repeated dosing; and (4) self-administration in addicted Rhesus monkeys. Unlike the narcotic analgesic agents morphine and codeine, flupirtine maleate did not display evidence of physical dependence liability or abuse potential as measured by jumping behaviour in mice or body weight reduction in rats following repeated oral administration. ⋯ No tolerance developed to the analgesic activity of flupirtine maleate in mice or rats dosed for up to 19 consecutive days. Finally, in morphine-dependent Rhesus monkeys, there was no difference in the rate of self-administration of flupirtine maleate when compared to the saline vehicle. Therefore, these results clearly show that flupirtine maleate, in animals, is without abuse potential and physical dependence liability.
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The mechanisms of the antinociceptive action of flupirtine, a novel non-opioid analgesic, were investigated in animals. It was found that this effect could be abolished by pre-treatment with reserpine. Furthermore, it could be dose-dependently antagonized by yohimbine and changes in the EEG of the rat observed after administration of flupirtine were closely related to those obtained after giving clonidine. On these pharmacological results, it is likely that the antinociceptive activity of flupirtine is due to activation of descending noradrenergic pathways.
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Opioids were available in clinical practice since before the birth of modern anaesthesia--Setürner isolated morphine in 1806. They have a record of safety which is reflected in their high therapeutic ratios, especially the synthetic opioids introduced recently (table III). The most serious immediate adverse effect, respiratory depression, is a predictable effect related closely to analgesia. It is fortunate for anaesthetists who use opioids regularly, that recognition and treatment of respiratory problems are an integral part of their craft and that opioid antagonists are effective in reversing respiratory depression.
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After a brief review of the supraspinal and spinal effects of morphine, the reference substance for studies on analgesia, the authors expose a synthesis of the recent literature regarding neurotransmitter involvement in pain perception and transmission. From these data, some future prospects for pain treatment research are identified.
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Pharmacol. Biochem. Behav. · Jan 1987
Determination of cross tolerance in rat spinal cord using intrathecal infusion via sequential mini-osmotic pumps.
Continuous intrathecal (IT) infusion via ALZET mini-osmotic pumps was used to induced spinal tolerance to morphine in the rat. Naloxone (1 mg/kg IP), injected on day 3 of continuous IT morphine (10 micrograms/hr), produced mild withdrawal symptoms in all morphine-treated animals. In rats pretreated with continuous IT morphine (10 micrograms/hr) or saline, systemic morphine (2, 4, 8, 10 and 15 mg/kg IP) produced equivalent, dose-dependent antinociception using the tail-flick and paw pressure tests. ⋯ A sequential, double mini-osmotic pump technique for cross tolerance studies in rat spinal cord is described. In rats pretreated with continuous IT norepinephrine for 4 days, the antinociceptive actions of continuous IT morphine were reduced but not significantly different from saline-pretreated animals. These data suggest that morphine, injected into the spinal cord, does not produce behavioural analgesia by activation of local adrenergic systems.