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

6 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)
Pages (from-to)949-960
Number of pages12
JournalCellular and Molecular Neurobiology
Issue number5
StatePublished - Jul 2021


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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


Dive into the research topics of 'Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents'. Together they form a unique fingerprint.

Cite this