The Biased Kappa Opioid Receptor Agonist Nalfurafine Reduces the Reinforcing Properties of Oxycodone and Enhances Oxycodone‐Induced Spinal Anti‐Nociception

We recently described the effect of two G protein‐biased kappa opioid receptor agonists [1 mg ethoxymethyl ether (EOM)‐salvinorin B/kg and 15 μg nalfurafine/kg] on the reinforcing and anti‐nociceptive properties of co‐administered morphine (5 mg/kg) in mice (Kaski et al ., JPET , 2019). EOM‐salvinorin B and nalfurafine each reversed the reinforcing properties of co‐administered morphine in the conditioned place preference paradigm, and each potentiated morphine‐induced spinal anti‐nociception in the warm‐water tail withdrawal paradigm. EOM‐salvinorin B had no effect on morphine‐induced supraspinal anti‐nociception in the hot‐plate paradigm; however, nalfurafine potentiated supraspinal anti‐nociception. In the current study, we addressed whether nalfurafine co‐administration (15 μg/kg) had similar beneficial effects on the prescription opioid painkiller oxycodone (2 mg/kg) in mice. Nalfurafine markedly reduced the reinforcing properties of oxycodone in the conditioned place preference paradigm. In addition, nalfurafine potentiated oxycodone‐induced spinal anti‐nociception in the warm‐water tail withdrawal paradigm. Nalfurafine did not affect oxycodone‐induced supraspinal anti‐nociception in the hot‐plate paradigm. Because nalfurafine has a decade‐long record of safety, tolerability, and long‐lasting efficacy (as an anti‐pruritic agent) in Japan, it is an attractive anti‐addictive, dose‐sparing adjuvant to conventional opioid painkillers that have shown tremendous addiction liabilities. Support or Funding Information ANW acknowledges support from the WVU SOM BBS T32 (1 T32 GM132494).