European journal of pharmacology
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The effects of glutamate and other more selective excitatory amino acid (EAA) analogs on intracellular free calcium concentration ( [Ca2+]i) were examined in Fura 2-loaded cultured chick embryo cortical cells (90% neuronal). Four EAA receptors were evident in these studies: an N-methyl-D-aspartate (NMDA) receptor, a kainate receptor, and two quisqualate receptors. The [Ca2+]i response to NMDA was blocked or reversed by selective antagonists such as 2-amino-5-phosphonovalerate (APV), MK801 and ketamine, as well as by desmethylimipramine and dextromethorphan. ⋯ Quisqualate and glutamate, but not the other EAA agonists, also increased [Ca2+]i after chelation of extracellular calcium with EGTA. This effect appears to be mediated by the metabotropic quisqualate receptor. These cells should provide a useful system for studying regulation and interactions of EAA receptors, and for screening drugs which might act at these receptors.
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Clinical Trial Controlled Clinical Trial
Diffuse noxious inhibitory controls in man: involvement of an opioidergic link.
In man, heterotopic painful thermal conditioning stimuli induce parallel decreases in the spinal nociceptive flexion (RIII) reflex and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve at the ankle. Such phenomena may be related to the diffuse noxious inhibitory controls (DNIC) which were initially described in the rat and subsequently documented in humans. In nine subjects in the present study, a 2-min application of a moderately noxious temperature (46 degrees C) to the contralateral hand strongly depressed the RIII reflex elicited in the biceps femoris muscle by electrical stimulation of the sural nerve at 1.2 times the reflex threshold. ⋯ During all the experimental sessions, heart and respiratory rates remained stable at their control levels. It is concluded that the loop subserving DNIC which ascends from--and redescends to--the spinal cord involves an opioidergic link in man as in experimental animals. Possible implications for hypoalgesia based on the principles of counter-irritation or elicited by naloxone are discussed.
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The effects of dantrolene on the sarcoplasmic reticulum and contractile machinery were examined in skinned skeletal muscles of guinea pigs. Dantrolene inhibited Ca-induced Ca2+ release at 38 degrees C. The inhibitory effect of dantrolene on Ca2+ release was greater in the presence of caffeine or adenine nucleotide than in their absence at low Ca2+ concentrations. ⋯ At 20 degrees C, however, dantrolene did not inhibit Ca2+ release induced by any Ca2+ concentration, regardless of the presence and absence of caffeine, adenine nucleotide or Mg2+. Ca2+ uptake into the sarcoplasmic reticulum and the Ca2+ sensitivity of the contractile machinery were not affected by dantrolene at 38 degrees C and 20 degrees C. These results suggest that dantrolene is a selective inhibitor of the Ca-induced Ca2+ release mechanism at physiological temperatures without having an effect on the Ca2+ pump of the sarcoplasmic reticulum or on the contractile machinery of skeletal muscle.
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The present study examined the actions of the putative 5-HT1A antagonist BMY 7378 on central pre- and postsynaptic 5-HT1A function in the rat in vivo. Unlike the direct acting 5-HT1A agonist 8-hydroxy-2-(di-n-pro-pylamino)tetralin (8-OH-DPAT), BMY 7378 (0.25-5 mg/kg s.c.) did not induce the full postsynaptically mediated 5-HT behavioural syndrome (forepaw treading, head weaving, flat body posture hindlimb abduction). Indeed, the maximal 5-HT behavioural syndrome scores of BMY 7378 were about 10% of those for 8-OH-DPAT. ⋯ As with 8-OH-DPAT, the inhibitory effect of BMY 7378 on 5-HT release was attenuated by pretreatment with the 5-HT1 receptor/beta-adrenoceptor antagonist pindolol (8 mg/kg s.c.) but not its counterpart propranolol (20 mg/kg s.c.). Pretreatment with a combination of the beta 1- and beta 2-adrenoceptor antagonists metoprolol (4 mg/kg s.c.) and ICI 118 551 (4 mg/kg s.c.), respectively, did not alter the 5-HT response to BMY 7378. From these data we conclude that BMY 7378 is a mixed agonist/antagonist at central 5-HT1A receptors.
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Although bradykinin (BK) antagonists have antinociceptive effects, they have not been evaluated for anti-inflammatory activity. When administered with carrageenan into the rat hindpaw, NPC567 significantly blocked carrageenan-induced hyperalgesia, hyperthermia and edema. In addition, NPC567 did not alter the in vitro release of immunoreactive BK by plasma kallikrein. These results indicate that the antinociceptive activity of NPC567, a BK antagonist, may be related to its overall anti-inflammatory activity and that is mechanism of action does not include inhibition of plasma kallikrein.