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ANESTHETIC PHARMACOLOGY

The Inhibitory Effect of Bupivacaine on Prostaglandin E₂ (EP₁) Receptor Functioning: Mechanism of Action

Christian W. Hönemann, MD^*, Thomas J. Heyse^*, Thomas Möllhoff, MD, PhD^*, Klaus Hahnenkamp, MD^*, Sascha Berning^*, Frank Hinder, MD, PhD^*, Bettina Linck, Wilhelm Schmitz, MD, PhD, and Hugo van Aken, MD, PhD^*

*Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin and Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Münster, Germany

Address correspondence and reprint requests to Hugo Van Aken, Department of Anesthesiology and Critical Care, Universitätsklinikum Münster, Albert-Schweitzer-Straße 33, 48129 Münster, Germany. Address e-mail to HVA{at}anit.uni-muenster.de

Prostaglandin E₂ receptors, subtype EP₁ (PGE₂EP₁) have been linked to several physiologic responses, such as fever, inflammation, and mechanical hyperalgesia. Local anesthetics modulate these responses, which may be due to direct interaction of local anesthetics with PGE₂EP₁ receptor signaling. We sought to characterize the local anesthetic effects on PGE₂EP₁ signaling and elucidate mechanisms of anesthetic action. In Xenopus laevis oocytes, recombinant expressed PGE₂EP₁ receptors were functional (half maximal effect concentration, 2.09 ± 0.98 x 10^-6 M). Bupivacaine, after incubation for 10 min, inhibited concentration-dependent PGE₂EP₁ receptor functioning (half-maximal inhibitory effect concentration, 3.06 ± 1.26 x 10^-6 M). Prolonged incubation in bupivacaine (24 h) inhibited PGE₂-induced calcium-dependent chloride currrents (I_Cl(Ca)) even more. Intracellular pathways were not significantly inhibited after 10 min of incubation in bupivacaine. But I_Cl(Ca) activated by intracellular injection of GTPS (a nonhydrolyzable guanosine triphosphate [GTP] analog that activates G proteins, irreversible because it cannot be dephosphorylated by the intrinsic GTPase activity of the subunit of the G protein) was reduced after 24 h of incubation in bupivacaine, indicating a G protein-dependent effect. However, inositol 1,4,5-trisphosphate- and CaCl₂- induced I_Cl(Ca) were unaffected by bupivacaine at any time points tested. Therefore, bupivacaine’s effect is at phospholipase C or at the G protein or the PGE₂EP₁ receptor. All inhibitory effects were reversible. We conclude that bupivacaine inhibited PGE₂EP₁ receptor signaling at clinically relevant concentrations. These effects could, at least in part, explain how local anesthetics affect physiologic responses such as fever, inflammation, and hyperalgesia during the perioperative period.

IMPLICATIONS: Clinically relevant bupivacaine concentrations inhibit prostaglandin E₂ EP₁ subtype signaling. This may explain the effects of regional anesthesia on physiologic responses such as fever, inflammation, and hyperalgesia during the perioperative period.

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