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Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models
Author(s) -
Sala Emanuele,
Ferrari Flora,
Lanza Marco,
Milia Chiara,
Sabatini Chiara,
Bonazzi Albino,
Comi Eleonora,
Borsi Franchini Miriam,
Caselli Gianfranco,
Rovati Lucio Claudio
Publication year - 2020
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.15049
Subject(s) - morphine , opioid , pharmacology , physical dependence , medicine , hyperalgesia , conditioned place preference , (+) naloxone , anesthesia , nociception , receptor
Background and Purpose Prolonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I 2 receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I 2 receptor ligand CR4056 could improve efficacy and safety of morphine and explored the mechanisms of the CR4056–opioid interaction. Experimental Approach We used the complete Freund's adjuvant (CFA) model in rats to study the effects of treatments on hyperalgesia, morphine tolerance and microglia activation as measured by immunofluorescence. Opioid‐induced adverse effects were assessed in rodent models of morphine‐induced constipation, sedation (open field, sedation rating scale, and rotarod), physical dependence (naloxone‐induced withdrawal), and abuse (conditioned place preference‐associated reward). Chemiluminescence assays tested CR4056 as allosteric modulator of μ‐opioid receptors. Key Results CR4056 (ED 50 = 4.88 mg·kg −1 ) and morphine (ED 50 = 2.07 mg·kg −1 ) synergized in reducing CFA‐induced hyperalgesia (ED 50 = 0.52 mg·kg −1 ; 1:1 combination). Consistently, low doses of CR4056 (1 mg·kg −1 ) spared one third of the cumulative morphine dose administered during 4 days and prevented/reversed the development of tolerance to morphine anti‐hyperalgesia. These opioid‐sparing effects were associated with decreased activation of microglia, independent of CR4056 interactions on μ‐opioid receptors. Importantly, the low doses of CR4056 and morphine that synergize in analgesia did not induce constipation, sedation, physical dependence, or place preference. Conclusion and Implications We showed selective synergism between CR4056 and morphine as analgesics. Their combination showed an improved safety and abuse liability profile over morphine alone. CR4056 could be developed as an opioid‐sparing drug in multimodal analgesia.