Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents
| Autor: | Laurie VanderVeen, Yi Liu, Frank Porreca, Caroline M. Kopruszinski, William K. Schmidt, Juliana Swiokla, Takahiro Miyazaki, Edita Navratilova, Miao Yang, Yeon Sun Lee, Jonathan Zalevsky |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Agonist Male medicine.drug_class Drug Evaluation Preclinical Receptors Opioid mu Physical dependence Rodentia Pharmacology Fentanyl Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Noxious stimulus medicine Potency Animals Pain Measurement Dose-Response Relationship Drug Morphine business.industry Cell Biology General Medicine Rats Analgesics Opioid 030104 developmental biology Opioid Morphinans Female medicine.symptom business Oxycodone 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Cellular and molecular neurobiology. 41(5) |
| ISSN: | 1573-6830 |
| Popis: | Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared. NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine. NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids. |
| Databáze: | OpenAIRE |
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