Neuropharmacology
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The effects of intravenous administration of 2.5 mg/kg of GB 52, a highly potent derivative of the enkephalinase inhibitor, thiorphan, were studied on the threshold of both the nociceptive reflex (Tr) and sensation of pain (Tp) as well as on the thresholds of both recruitment of the maximal nociceptive reflex response (Tmr) and tolerable pain (Tip), elicited by electrical stimulation of the sural nerve in normal and relaxed volunteers. It was found that neither the nociceptive motor responses (Tr and Tmr) nor the subjective reports of pain (Tp and Tip), were significantly affected by GB 52. It is concluded that, in the experimental conditions used, the transmission of nociceptive messages at the spinal level is not tonically modulated by any enkephalinergic system.
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The neurophysiological mechanism for the depressant action of ketamine on nociceptive transmission in the spinal cord was examined in rabbits with an intact spinal cord and those with a transected or cold-blocked spinal cord. Ketamine depressed the nociceptive responses in both intact and transected spinal cord groups dose-dependently. The depressant effects of ketamine were significantly greater and longer in the intact group than in the transected group, particularly with 2 and 5 mg/kg of ketamine. ⋯ Compared to the reversible cold block of the upper part of the spinal cord, the depressant effects produced by both 2 and 5 mg/kg of ketamine on activity induced by bradykinin in the intact spinal cord were significantly greater, and 10 mg/kg of ketamine depressed the nociceptive responses to similar levels in both states. These results suggest that in small to moderate doses, the indirect depressant action of ketamine from the brain stem is more important than the direct action. On the other hand, at a large dose, the direct depressant action becomes predominant.
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The effect of cholecystokinin octapeptide (CCK-8) and its analogue, ceruletide on release of acetylcholine (ACh) from the cerebral cortex was investigated in urethane-anaesthetized and in unanaesthetized rats. Cholecystokinin octapeptide and ceruletide markedly stimulated output of ACh at doses of 1.5 and 5.0 micrograms/kg (i.p.), respectively. This effect was prevented by proglumide (160 mg/kg i.p.), a specific cholecystokinin receptor antagonist. ⋯ The decrease was prevented by naloxone (1 mg/kg, s.c.), and replaced by a short-lasting increase. Cholecystokinin octapeptide and ceruletide appear therefore to affect the activity of cortical cholinergic fibres by acting upon both specific and opiate receptors. The interaction between CCK-8 and ceruletide, and opiate receptors either direct or through the release of endogenous opiates, was also demonstrated by the antagonism between ceruletide (1, 5 and 10 micrograms/kg, i.p.) and analgesia induced by morphine (5 mg/kg, s.c.), evaluated by the tail-flick test in the rat.