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Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats

BACKGROUND AND PURPOSE: CR4056 is a novel imidazoline-2 (I(2)) ligand exhibiting potent analgesic activity in animal models of pain. In this study, we investigated the effects of CR4056 in a well-established model of postoperative pain where rats develop hyperalgesia in the injured hind paw. EXPERIM...

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Autores principales: Lanza, Marco, Ferrari, Flora, Menghetti, Ilaria, Tremolada, Dario, Caselli, Gianfranco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128066/
https://www.ncbi.nlm.nih.gov/pubmed/24758515
http://dx.doi.org/10.1111/bph.12728
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author Lanza, Marco
Ferrari, Flora
Menghetti, Ilaria
Tremolada, Dario
Caselli, Gianfranco
author_facet Lanza, Marco
Ferrari, Flora
Menghetti, Ilaria
Tremolada, Dario
Caselli, Gianfranco
author_sort Lanza, Marco
collection PubMed
description BACKGROUND AND PURPOSE: CR4056 is a novel imidazoline-2 (I(2)) ligand exhibiting potent analgesic activity in animal models of pain. In this study, we investigated the effects of CR4056 in a well-established model of postoperative pain where rats develop hyperalgesia in the injured hind paw. EXPERIMENTAL APPROACH: By measuring paw withdrawal threshold to mechanical pressure, we studied the pharmacology of CR4056, potential sex differences in pain perception and response to treatment, and the pharmacodynamic interaction of CR4056 with morphine. KEY RESULTS: Oral CR4056 and subcutaneous morphine dose-dependently reversed the hyperalgesic response. Analgesic effects of CR4056 were completely suppressed by the non-selective imidazoline I(2)/α(2)-adrenoceptor antagonist idazoxan, were partially reduced (∼30%; P < 0.05) by the selective α(2)-adrenoceptor antagonist yohimbine, but were not influenced by the non-selective I(1)/α(2)-adrenoceptor antagonist efaroxan or by the μ opioid receptor antagonist naloxone. We found no differences in responses to CR4056 or morphine between male and female rats. However, females had a lower pain threshold than males, and needed lower doses of drugs to reach a significant analgesia. When CR4056 and morphine were combined, their median effective doses were lower than expected for additive effects, both in males and in females. Isobolographic analysis confirmed a synergism between CR4056 and morphine. CONCLUSIONS AND IMPLICATIONS: CR4056 is a novel pharmacological agent under development for postoperative pain both as stand-alone treatment and in association with morphine. CR4056 has successfully completed Phase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof-of-concept study in patients.
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spelling pubmed-41280662015-01-15 Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats Lanza, Marco Ferrari, Flora Menghetti, Ilaria Tremolada, Dario Caselli, Gianfranco Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: CR4056 is a novel imidazoline-2 (I(2)) ligand exhibiting potent analgesic activity in animal models of pain. In this study, we investigated the effects of CR4056 in a well-established model of postoperative pain where rats develop hyperalgesia in the injured hind paw. EXPERIMENTAL APPROACH: By measuring paw withdrawal threshold to mechanical pressure, we studied the pharmacology of CR4056, potential sex differences in pain perception and response to treatment, and the pharmacodynamic interaction of CR4056 with morphine. KEY RESULTS: Oral CR4056 and subcutaneous morphine dose-dependently reversed the hyperalgesic response. Analgesic effects of CR4056 were completely suppressed by the non-selective imidazoline I(2)/α(2)-adrenoceptor antagonist idazoxan, were partially reduced (∼30%; P < 0.05) by the selective α(2)-adrenoceptor antagonist yohimbine, but were not influenced by the non-selective I(1)/α(2)-adrenoceptor antagonist efaroxan or by the μ opioid receptor antagonist naloxone. We found no differences in responses to CR4056 or morphine between male and female rats. However, females had a lower pain threshold than males, and needed lower doses of drugs to reach a significant analgesia. When CR4056 and morphine were combined, their median effective doses were lower than expected for additive effects, both in males and in females. Isobolographic analysis confirmed a synergism between CR4056 and morphine. CONCLUSIONS AND IMPLICATIONS: CR4056 is a novel pharmacological agent under development for postoperative pain both as stand-alone treatment and in association with morphine. CR4056 has successfully completed Phase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof-of-concept study in patients. Blackwell Publishing Ltd 2014-08 2014-07-17 /pmc/articles/PMC4128066/ /pubmed/24758515 http://dx.doi.org/10.1111/bph.12728 Text en © 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Research Papers
Lanza, Marco
Ferrari, Flora
Menghetti, Ilaria
Tremolada, Dario
Caselli, Gianfranco
Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats
title Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats
title_full Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats
title_fullStr Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats
title_full_unstemmed Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats
title_short Modulation of imidazoline I(2) binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats
title_sort modulation of imidazoline i(2) binding sites by cr4056 relieves postoperative hyperalgesia in male and female rats
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128066/
https://www.ncbi.nlm.nih.gov/pubmed/24758515
http://dx.doi.org/10.1111/bph.12728
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