Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents

Caroline M. Kopruszinski, Juliana Swiokla, Yeon Sun Lee, Edita Navratilova, Laurie VanderVeen, Miao Yang, Yi Liu, Takahiro Miyazaki, William K. Schmidt, Jonathan Zalevsky, Frank Porreca

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Objective: Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
JournalCellular and Molecular Neurobiology
StateAccepted/In press - 2020


  • Antinociception
  • Efficacy
  • Mice
  • NKTR-181
  • Opioid
  • Potency
  • Rats

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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