The hypothesis that antagonism of fentanyl analgesia by 2-chloroprocaine is mediated by direct action on opioid receptors.
OBJECTIVE
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
Radioligand binding assays using the mu and kappa opioid receptor-selective radioligands [3H]-DAMGO and [3H]-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 [3H]-DAMGO binding, which was dose-limited owing to the solubility of lidocaine. 2-Chloroprocaine caused complete displacement of [3H]-DAMGO binding, with a median effective concentration of 1.44 +/- 0.36 mM. The EC50 values for [3H]-U69,593 displacement were 177 +/- 47 microM for 2-chloroprocaine and 2.53 +/- 0.48 mM for lidocaine. Assuming a competitive interaction between anesthetic and opioid, the Ki value for 2-chloroprocaine was 435 microM at mu receptors and 49 microM 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 after depolarization 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.
Coda
B
B
Department of Anesthesiology and Pharmacology, University of Washington, Seattle 98195, USA.
Bausch
S
S
Haas
M
M
Chavkin
C
C
D000700:Analgesics / Q000378:metabolism / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D001667:Binding, Competitive; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology; D005283:Fentanyl / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D007700:Kinetics; D008012:Lidocaine / Q000378:metabolism; D011343:Procaine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D000700:Analgesics; D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D044482:Benzeneacetamides; D004745:Enkephalins; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014316:Tritium; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D011343:Procaine; C004616:chloroprocaine; D008012:Lidocaine; C045444:U 69593; D005283:Fentanyl