CHARACTERISTICS OF THE ANALGESIC EFFECTS AND DRUG-INTERACTIONS OF INTERACTIONS OF INTRATHECAL CARBACHOL IN RATS

Background: Intrathecal carbachol produces consistent analgesia in animals without appreciable adverse effects. Little is known about the ability of this drug to provide analgesia as stimulus intensity is increased. Likewise, there are few data regarding interactions between carbachol and other intrathecal analgesics. Methods: Using two different noxious radiant heat intensities, one applied to each hind limb, analgesic effects of 1, 3, 10, and 30 mu g intrathecal carbachol on paw withdrawal latencies were measured, Similar testing was done for intrathecal morphine and clonidine. ED(50) fractions (1/2, 1/4, 1/8, 1/16) of drug combinations of carbachol-morphine and carbachol-clonidine were administered, responses to the low intensity stimulus were recorded, and the ED(50) of each combination was established and isobolographic analysis of the drug interactions was carried out. Results: The 30-mu g dose of carbachol was associated with transient agitation, salivation, and hind limb weakness. No other adverse effects were noted. The ED(50) (95% confidence interval) of intrathecal carbachol was 2.34 mu g (1.34-4.04) for low intensity stimulation and 12.64 mu g (4.18-38.25) for high intensity. There was no significant difference between high- and low-intensity ED(50) values for intrathecal morphine and clonidine. The analgesic effect of the carbachol-morphine and carbachol-clonidine combinations were significantly greater than the calculated additive effects. The ED(50) for the carbachol-morphine combination was 12% of the expected additive value and the ED(50) for the carbachol-clonidine combination was 30% of the expected additive value. Conclusions: Intrathecal carbachol provides analgesia to noxious thermal stimulation of the hind paw in rats. It is relatively less effective at providing analgesia than intrathecal morphine or clonidine when stimulus intensity is raised. Intrathecal carbachol is synergistic when combined with intrathecal morphine or clonidine.