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Modulation of imidazoline I 2 binding sites by CR 4056 relieves postoperative hyperalgesia in male and female rats
Author(s) -
Lanza Marco,
Ferrari Flora,
Menghetti Ilaria,
Tremolada Dario,
Caselli Gianfranco
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12728
Subject(s) - pharmacology , antagonist , morphine , imidazoline receptor , analgesic , yohimbine , hyperalgesia , opioid , (+) naloxone , opioid antagonist , nociception , idazoxan , medicine , chemistry , receptor , prazosin
Background and Purpose CR 4056 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 CR 4056 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 CR 4056, potential sex differences in pain perception and response to treatment, and the pharmacodynamic interaction of CR 4056 with morphine. Key Results Oral CR 4056 and subcutaneous morphine dose‐dependently reversed the hyperalgesic response. Analgesic effects of CR 4056 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 CR 4056 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 CR 4056 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 CR 4056 and morphine. Conclusions and Implications CR 4056 is a novel pharmacological agent under development for postoperative pain both as stand‐alone treatment and in association with morphine. CR 4056 has successfully completed P hase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof‐of‐concept study in patients.