Abstract
In earlier work, amitriptyline was found to be a more potent local anesthetic than bupivacaine for rat sciatic nerve blockade, probably because of its greater potency to block Na+channels. 1,2 In that rat model, amitriptyline displayed some differential blocking properties, i.e. , selective block of specific (pain-transmitting) nerve fiber groups, 3 whereas no differential blockade was found with bupivacaine. This is in contradiction to the clinical impression that bupivacaine is the drug of choice when a more sensory-selective action over motor blockade is desired. We hypothesize that species differences account for the different amounts of differential blockade seen previously. We therefore investigated the differential block phenomenon via two different routes of administration in two different species (peripheral sciatic nerve block in rats and intrathecal block in rats and sheep). In addition, because adding a methyl group to amitriptyline has been shown to increase blocking properties for K+channels in isolated rat sympathetic neurons, 4 we investigated whether this held true for Na+channels in GH3cells. We also investigated whether the addition of the methyl group to amitriptyline increased the amount of differential blockade. We studied this N -methyl derivative of amitriptyline because it has interesting physicochemical properties, i.e. , it is more soluble than amitriptyline and N -phenylethyl amitriptyline. 5 Preliminary electrophysiologic studies revealed that this drug is trapped within the cell and its block of sodium channels remains even after prolonged washoff.