Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models
| Autor: | Gianfranco Caselli, Albino Bonazzi, Emanuele Sala, Chiara Sabatini, Flora Ferrari, Miriam Borsi Franchini, Chiara Milia, Lucio C. Rovati, Eleonora Comi, Marco Lanza |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Sedation Analgesic Imidazoline receptor Physical dependence Rodentia Pharmacology Open field 03 medical and health sciences 0302 clinical medicine medicine Animals Morphine business.industry Imidazoles Drug Tolerance Research Papers Rats Analgesics Opioid 030104 developmental biology Opioid Hyperalgesia Quinazolines medicine.symptom business 030217 neurology & neurosurgery medicine.drug Research Paper |
| Zdroj: | British Journal of Pharmacology |
| ISSN: | 1476-5381 |
| Popis: | Background and purpose Prolonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I2 receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I2 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 (ED50 = 4.88 mg·kg-1 ) and morphine (ED50 = 2.07 mg·kg-1 ) synergized in reducing CFA-induced hyperalgesia (ED50 = 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. |
| Databáze: | OpenAIRE |
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