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LETTERS TO THE EDITOR

Muscle Relaxants and 5-HT₃ Receptors

Department of Anesthesiology Harbor-University of California Los Angeles Medical Center Torrance, CA 90509

To the Editor:

The recent article of Min et al. (1) delineated differences in affinity of several nondepolarizing neuromuscular blocking drugs to 5-HT₃ receptors and concluded that d-tubocurarine (d-TC) was the most potent among them as a 5-HT₃ receptor antagonist. Based on a previous clinical study (2) and on their own experimental data, the authors proposed that some neuromuscular blocking drugs, under certain conditions may beneficially affect postoperative nausea and vomiting (PONV). This is exactly what we have proposed earlier (3), based on the known blocking effect of dTC on 5-HT₃ receptors (4). We also have proposed that "with pharmacologic reversal of the neuromuscular blocking effect of dTC, its antiemetic effect may be unmasked and thus become detectable postoperatively." Min et al. (1) suggested that the clinically observed anti-PONV properties of alcuronium and dTC are explainable by their structural similarities. This assumption is incorrect. Alcuronium is a semisynthetic alkaloid and contains two tricyclic carboline ring systems, unlike dTC, which contains two bicyclic isoquinoline rings. Furthermore, these ring systems are connected in alcuronium and in dTC by entirely different connecting linkages. Likeness in structure between dTC and other tetrahydroisoquinoline type synthetic agents, e.g., atracurium and mivacurium, is more apparent. Yet there seems to be no direct relationship between the neuromuscular blocking potency and 5-HT₃ receptor-blocking potencies of these drugs. [Fig. 3C in the article of Min et al. (1)].

Furthermore, we have obtained data in functional preparations using "typical" 5-HT₃ receptor agonists and have found no overlap between 5-HT₃ and nicotinic receptors-mediated responses (5). Despite several common structural features of these two ion channel-type receptors, the ligand binding intricacies within these receptors still rank them in functionally very distinct categories. Yet it remains possible that some molecules, belonging to the same structural group (e.g., tetrahydroisoquinolines), may function as "double agents" serving two receptor types, whereas others may remain very selective to only one of them. Thus, the structures of alcuronium and dTC both might be considered "lead" compounds for the development of new 5-HT₃ type anti-PONV drugs.

References

1. Min KT, Wu CL, Yang J. Nondepolarizing neuromuscular blockers inhibit the Serotonin-type 3A receptor expressed in xenopus oocytes. Anesth Analg 2000; 90: 476–81.[Abstract/Free Full Text]
2. Haigh CG, Kaplan LA, Durham JM, et al. Nausea and vomiting after gynecological surgery: a meta analysis of factors affecting their incidence. Br J Anaesth 1993; 71: 517–22.[Abstract/Free Full Text]
3. Gyermek L. Is d-tubocurarine an antiemetic? Acta Anesthesiol Sin 1996;34:53.
4. Yakel JL, Jackson MB. 5-HT3 receptors mediate rapid responses in cultured hippocampus and clonal cell line. Neuron 1988; 1: 615–21.[Web of Science][Medline]
5. Gyermek L, Sun X, Nguyen N, Dukat M. Is there a functional-overlap between 5-HT3 and nicotinic ion channel receptors? Ann NY Acad Sci 1998; 861: 255–7.[Web of Science][Medline]

Response

Department of Anesthesiology and Pharmacology/Physiology University of Rochester Medical Center Rochester, NY 14642

In Response:

I thank Dr. Gyermek for pointing out his earlier work suggesting neuromuscular blockers may possess antiemetic properties (1) and clarification on the structure of alcuronium. In fact, receptors that mediate pharmacological actions are far more complex and rarely compartmentalized according to the traditional pharmacological classifications. Cross-talk between different receptors are not limited to promiscuous drugs acting at multiple receptors as suggested by our work. For example, the 5HT₃a subunit forms heteroligomeric complex with the 4 subunit of the nicotinic acetylcholine receptor (2). This results in a receptor with hybrid-properties opened by serotonin but with enhanced permeability to Ca⁺⁺. An interaction between the dopamine D2 and somatostatin SST5 receptors, both members of the seven-transmembrane G protein receptor coupled receptor (GPCR) family, has been demonstrated as well (3). Recent evidence indicates that direct protein-protein interactions between receptors are not restricted to closely related members of the same gene family. Direct GABA_A receptor (a four-transmembrane ligand gated ion channel) interaction with dopamine D5 receptor (a GPCR) results in dynamic modulation of synaptic strength in the hippocampus (4). Understanding pharmacological cross-talk both at the drug-binding site and at the receptor protein levels will be a necessary first step in our efforts to optimize the actions of drugs given to our patients.

References

1. Gyermek L. Is d-tubocurarine an antiemetic? Acta Anesthesiol Sin 1996; 34: 53.[Medline]
2. Van Hooft JA, Spier AD, Yakel JL, et al. Promiscuous coassembly of serotonin 5-HT3 and nicotinic 4 receptor subunits into Ca⁺⁺ permeable ion channel. Proc Natl Acad Sci USA 1998; 95: 11456–61.[Abstract/Free Full Text]
3. Rochville M, Lange DC, Kumar U, et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 2000; 288: 154–7.[Abstract/Free Full Text]
4. Liu F, Wan Q, Pristupa ZB, et al. Direct protein-protein coupling enables cross-talk between dopamine D5 and -aminobutyric acid A receptors. Nature 2000; 403: 274–80.[Medline]

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