• Loren J Martin, Marjo H Piltonen, Josee Gauthier, Marino Convertino, Erinn L Acland, Nikolay V Dokholyan, Jeffrey S Mogil, Luda Diatchenko, and William Maixner.
• Department of Psychology, McGill University, Montreal, Quebec, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec, Canada; Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario, Canada. Electronic address: lj.martin@utoronto.ca.
• J Pain. 2015 Dec 1; 16 (12): 1321-1333.

UnlabelledRecent efforts have suggested that the β-adrenergic receptor (β-AR) system may be a novel and viable therapeutic target for pain reduction; however, most of the work to date has focused on the β(2)-adrenergic receptor (AR). Here, we compared the antinociceptive effects of enantiomeric configurations of propranolol and bupranolol, two structurally similar nonselective β-blocking drugs, against mouse models of inflammatory and chronic pain. In addition, we calculated in silico docking and measured the binding properties of propranolol and bupranolol for all 3 β-ARs. Of the agents examined, S-bupranolol is superior in terms of its antinociceptive effect and exhibited fewer side effects than propranolol or its associated enantiomers. In contrast to propranolol, S-bupranolol exhibited negligible β-AR intrinsic agonist activity and displayed a full competitive antagonist profile at β(1)/β(2)/β(3)-ARs, producing a unique blockade of β(3)-ARs. We have shown that S-bupranolol is an effective antinociceptive agent in mice without negative side effects. The distinctive profile of S-bupranolol is most likely mediated by its negligible β-AR intrinsic agonist activity and unique blockade of β(3)-AR. These findings suggest that S-bupranolol instead of propranolol may represent a new and effective treatment for a variety of painful conditions.PerspectiveThe S enantiomer of bupranolol, a β-receptor antagonist, shows greater antinociceptive efficacy and a superior preclinical safety profile and it should be considered as a unique β-adrenergic receptor compound to advance future clinical pain studies.Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

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