The hypothesis that antagonism of fentanyl analgesia by 2-chloroprocaine is mediated by direct action on opioid receptors

Background and Objectives. Although 2-chloroprocaine continues to be a useful drug for epidural anesthesia in obstetrics, it has the anomalous action of decreasing the analgesic effectiveness of subsequently administered epidural fentanyl. Some investigators have suggested that 2-chloroprocaine may act at an opioid receptor site to antagonize the effects of fentanyl. The purpose of our studies was to investigate this hypothesis. Methods. Radioligiand binding assays using the mu and kappa opioid receptor-selective radioligands [H-3]-DAMGO and [H-3]-U69,593, respectively, were performed to determine the potencies of lidocaine, 2-chloroprocaine, and 2-chloroprocaine metabolites at the mu and kappa opioid receptor sites. Electrophysiologic experiments in in vitro hippocampal slice preparations were then used to examine the effects of 2-chloroprocaine at these opioid receptor subtypes. Results. Lidocaine caused a partial reduction of [H-3]-DAMGO binding, which was dose-limited owing to the solubility of lidocaine. 2-Chloroprocaine caused complete displacement of [H-3]-DAMGO binding, with a median effective concentration of 1.44 +/- 0.36 mM. The EC(50) values for [H-3]-U69,593 displacement were 177 +/- 47 mu M for 2-chloroprocaine and 2.53 +/- 0.48 mM for lidocaine. Assuming a competitive interaction between anesthetic and opioid, the K-i value for 2-chloroprocaine was 435 mu M at mu receptors and 49 mu M at kappa receptors. In the mu activity bioassay, 2-chloroprocaine reversed the increased neuronal excitability caused by fentanyl, but this effect was further reduced by naloxone. In addition, 2-chloroprocaine did not reverse the afterdepolarization caused by fentanyl. In the kappa activity bioassay, 2-chloroprocaine produced effects similar to the kappa agonist U69,593, but these were not antagonized by naloxone. Conclusions. Although 2-chloroprocaine has binding affinity at mu and kappa opioid receptor sites, it does not appear to act through an opioid receptor to antagonize the physiologic effects of fentanyl.