Blood pressure changes after intrathecal co-administration of calcium channel blockers with morphine or clonidine at the spinal level.

Opioids, alpha(2)-adrenoceptor agonists and blockers of voltage-gated calcium channels have been attributed antinociceptive activity, but only few studies have investigated their influence on the haemodynamic parameters. This study was performed to examine the changes in the mean arterial blood pressure (MAP) after intrathecal (i.t.) co-administration of morphine or clonidine with drugs blocking L- or N-type voltage gated calcium channels (verapamil and omega-conotoxin MVIIA, respectively) in anaesthetized rats. Lower doses of clonidine (0.01-5 microg i.t.) produced dose-dependent decreases in MAP, while the highest dose of clonidine (20 microg i.t.) produced a pressor response. The administration of morphine (0.01-20 microg i.t.) caused only minor decreases of blood pressure and these appeared not to be dose dependent. Both omega-conotoxin MVIIA (1 ng-10 microg i.t.) and verapamil (1-100 microg i.t.) at higher doses decreased blood pressure significantly. Omega-conotoxin MVIIA caused a sustained decrease in MAP, while the effect of verapamil was short-lasting. Co-administration of morphine with verapamil or omega-conotoxin MVIIA led to dose-dependent and sustained decreases in blood pressure. The co-administration of omega-conotoxin MVIIA with clonidine did not influence the effect of clonidine significantly. In contrast, the combination of higher doses of verapamil with clonidine caused far greater blood pressure decreases than saline, verapamil or clonidine treatments alone. These data suggest that the calcium channel blockers differentially influence the cardiovascular effect of the well-known antinociceptive drugs morphine and clonidine after intrathecal co-administration.

Role of calcium channels in the spinal transmission of nociceptive information from the mesentery.

Opioids, alpha(2)-adrenoceptor agonists and blockers of voltage-gated calcium channels (VGCCs) have been attributed antinociceptive activity in various experimental set-ups. The present study tested the ability of morphine, clonidine and drugs acting at various VGCCs to inhibit the transmission of noxious stimuli from the mesentery at the level of the spinal cord. In rats under barbiturate anaesthesia traction of 20 g was applied to a bundle of mesenteric blood vessels. This caused immediate transient changes of mean arterial pressure that were taken as indication of nociception. Similar reflexes were elicited by applying 0.6% acetic acid to the same bundle of vessels. The reflexes were dose-dependently reduced by intrathecal administration of morphine or clonidine, but were left unaltered by intrathecal administration of verapamil, Bay-K 8644 or omega-conotoxin MVIIA. Neither verapamil nor Bay-K 8644 influenced clonidine-induced analgesia. Conotoxin markedly enhanced the effectiveness of all doses of clonidine against both types of mesenteric stimuli. Verapamil, Bay-K 8644, as well as conotoxin reduced the ability of morphine to inhibit mechanically evoked reflexes, while there was no statistically significant effect in chemonociception. These data suggest that, at the spinal level, both morphine and clonidine are effective drugs to decrease the cardiovascular changes caused by acute mesenteric pain. In the dorsal spinal cord neither L-type nor N-type VGCCs are responsible on their own for the transmission of noxious stimuli from the mesentery. Inhibition of N-type channels markedly augments the action of clonidine, whereas blocking either VGCC seems to inhibit antinociceptive mechanisms induced by morphine. It is suggested that in patients the combined administration of clonidine with omega-conotoxin MVIIA might lead to effective pain control with reduced side effects.