Local anesthetic properties of opioids and phencyclidines: Interaction with the voltage-dependent, batrachotoxin binding site in sodium channels

Abstract

[ 3H]Batrachotoxinin-A 20-α-benzoate ([ 3H]BTX-B) binds specifically and with high affinity (K d = 30 nM) to a site on voltage-dependent Na + channels. Compounds with local anesthetic activity inhibit the binding of [ 3H]BTX-B by a mutually exclusive, allosteric mechanism. The potential local anesthetic potency of a series of 23 opioids and phencyclidine-like compounds has been estimated by their inhibition of [ 3H]BTX-B binding to Na + channels in a preparation of synaptoneurosomes from guinea pig cerebral cortex. The potency of these compounds were also tested as inhibitors of the specific binding of [ 3H]phencyclidine ([ 3H]PCP) to a high affinity site on rat brain membranes. Opioids such as morphine and codeine show little affinity for the [ 3H]BTX-B binding site or for the [ 3H]PCP binding site. Other analgesics, many of the PCP-like compounds and dioxadrol derivatives are potent versus [ 3H]BTX-B binding and display both stereospecificity and high affinity towards the PCP-binding site. However, there was no correlation between local anesthetic potency assessed as antagonism of [ 3H]BTX-B binding and affinity towards the PCP site. Five classical local anesthetics had no affinity for the PCP-site, but did displace [ 3H]BTX-B from its binding site.