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ANESTHETIC PHARMACOLOGY

Molecular Properties Important for Inhaled Anesthetic Action on Human 5-HT_3A Receptors

Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts

Address correspondence and reprint requests to Douglas E. Raines, MD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Clinics Building 3, Boston, MA 02114. Address e-mail to draines{at}partners.org.

Although inhaled anesthetics have diverse effects on 5-hydroxytryptamine type 3 (5-HT_3A) receptors, the mechanism accounting for this diversity is not understood. Studies have shown that modulation of 5-HT_3A receptor currents by n-alcohols depends on molecular volume, suggesting that steric interactions between n-alcohols and their binding sites define their action on this receptor. Electrostatic interactions also play an important role in anesthetic action on other ligand-gated receptors. We aimed to determine the contribution of molecular volume and electrostatics in defining volatile anesthetic actions on 5-HT_3A receptors. Human 5-HT_3A receptors were expressed in, and recorded from, Xenopus oocytes using the two-electrode voltage-clamp technique. The effects of a range of volatile anesthetics, n-alcohols, and nonhalogenated alkanes on submaximal serotonin-evoked peak currents, and full serotonin concentration-response curves were defined. Volatile anesthetics and n-alcohols, but not alkanes, smaller than 0.120 nm³ enhanced submaximal serotonin-evoked peak currents whereas all larger agents reduced currents. Most compounds tested inhibited maximal serotonin-evoked peak currents to varying degrees. However, only agents smaller than 0.120 nm³ shifted the 5-HT_3A receptor’s serotonin concentration-response curve to the left, whereas larger anesthetics shifted them to the right. Modulation of human 5-HT_3A-mediated currents by volatile anesthetics exhibits a dependence on molecular volume consistent with the n-alcohols, suggesting that both classes of agents may enhance 5-HT_3A receptor function via the same mechanism. Furthermore, the enhancing but not inhibiting effects of anesthetic compounds on 5-HT_3A receptor currents are modulated by electrostatic interactions.

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