European journal of pharmacology
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The present study was designed to investigate the modulatory effects of blockade of spinal GABAA and GABAB receptors on antinociception induced by supraspinally administered mu- and epsilon-opioid receptor agonists. The effects of intrathecal (i.t.) injections with GABAA and GABAB receptor antagonists, SR 95531 [2-(3-carboxypropyl)-3-amino-6-(4-mehylphenyl)pyridazinium bromide] and 5-aminovaleric acid, respectively, on the antinociception induced by morphine (a mu-opioid receptor agonist) and beta-endorphin (an epsilon-opioid receptor agonist) injected intracerebroventricularly (i.c.v.) were studied. ⋯ The i.t. injection of SR 95531 attenuated dose-dependently the inhibition of the tail-flick response induced by i.c.v. administered morphine, without affecting the i.c.v. administered beta-endorphin-induced response. 5-Aminovaleric acid attenuated dose-dependently the inhibition of the tail-flick response induced by beta-endorphin, without affecting the response to i.c.v. administered morphine. Our results indicate that GABAA but not GABAB receptors located at the spinal cord appears to be involved in the antinociception induced by morphine administered supraspinally whereas GABAB but not GABAA receptors located at the spinal cord may be involved in the antinociception induced by supraspinally administered beta-endorphin, supporting further the hypothesis that morphine and beta-endorphin administered supraspinally produce their antinociception via the activation of different descending pain inhibitory systems.
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The effects of 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) on blood pressure, total peripheral resistance, cardiac index, heart rate and arterial conductance in different vascular beds in the presence and absence of hexamethonium (ganglionic blocker) and phenylephrine (alpha 1-adrenoceptor agonist) were investigated in pentobarbitone-anaesthetized rats using a radioactive microsphere technique. CGS 21680 (0.1, 0.3 and 1.0 microgram/kg/min) significantly decreased blood pressure and total peripheral resistance, and increased heart rate and cardiac index. In addition, after infusion with CGS 21680 (0.1, 0.3 and 1.0 microgram/kg/min) arterial conductance in coronary bed significantly increased. ⋯ Our present findings suggest that CGS 21680 decreased blood pressure by decreasing total peripheral resistance, and increased cardiac index possibly through a reflex-mediated increase in heart rate. Moreover the coronary arterial bed is the most sensitive and cerebral arterial bed is the least sensitive to the effects of CGS 21680. In addition, the autonomic nervous system did not appear to play a major role in the actions of CGS 21680 on arterial conductance, and there was no difference in the action of this compound in the states of normal and raised vascular tone.
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The relative contribution(s) of different Ca2+ channel subtypes to synaptic transmission between Schaffer collaterals of hippocampal CA3 pyramidal cells and CA1 pyramidal cell dendrites has been assessed using the synthetic invertebrate peptide toxins omega-conotoxin GVIA to block N-type Ca2+ channels, omega-agatoxin-IVA to block P-type Ca2+ channels and omega-conotoxin MVIIC to block N-, P- and Q-type Ca2+ channels. Omega-Agatoxin-IVA, omega-conotoxin GVIA and omega-conotoxin MVIIC all produced dose-dependent inhibitions of the excitatory post-synaptic field potential (fEPSP) recorded from the CA1 region of transverse hippocampal slices. Application of 300 nM omega-conotoxin GVIA generally produced no further inhibition to that observed with 100 nM, resulting in a maximal 50% inhibition of the fEPSP. ⋯ Application of 30 nM omega-agatoxin-IVA together with omega-conotoxin GVIA (300 nM) produced no greater inhibition of the fEPSP than that observed with omega-conotoxin GVIA alone, suggesting that the omega-agatoxin-IVA-sensitive and omega-conotoxin MVIIC-sensitive component presents a pharmacology similar to the reported Q-type Ca2+ channel. The inhibition produced by omega-conotoxin GVIA and omega-conotoxin MVIIC showed no recovery with prolonged washing (1-2 h) whereas that produced by omega-agatoxin-IVA was slowly reversible. The observation that omega-agatoxin-IVA, which does not effect N-type Ca2+ channels (Mintz et al. (1992a) Neuron 9, 85), is capable of completely suppressing the fEPSP suggests that, whilst N-type Ca2+ channels may contribute to normal synaptic transmission at Schaffer collateral-CA1 synapses, they are not capable of supporting transmission when Q-type channels are blocked.