Nalfurafine reverses fentanyl-induced muscle rigidity and respiratory depression without affecting sedation in rats: decoupling respiration from sedation.

This study examines whether nalfurafine, a κ-opioid receptor (κOR) agonist, reverses fentanyl-induced muscle rigidity and respiratory depression without impacting sedation. Adult, nonsedated Sprague-Dawley rats received intravenous fentanyl bolus injection (150 μg/kg), which induced immediate coma and muscle rigidity along with a transient central apnea, followed by sustained respiratory depression. Five minutes postfentanyl, rats were treated with saline, nalfurafine (0.1 or 1 mg/kg), or the κOR agonist U50488 (1 or 10 mg/kg). Muscle rigidity, sedation, and response to painful stimuli were assessed using blinded clinical scoring. Ventilation and pulmonary gas exchange were measured using open-flow body plethysmography. Nalfurafine at 1 mg/kg quickly and effectively reduced fentanyl-induced muscle rigidity, with a sustained effect throughout the 30-min observation period. Sedation scores remained consistent across all groups. In contrast to saline, nalfurafine (1 mg/kg) sharply increased minute ventilation V̇e, frequency (f), and tidal volume (Vt), which all plateaued at prefentanyl levels despite the animals remaining in a coma. V̇e/V̇o₂ and V̇e/V̇co₂ ratios also increased significantly compared with saline injection. U50488 at 1 mg/kg reversed muscle rigidity. Both nalfurafine (0.1 mg/kg) and U50488 at 1 mg/kg had a significantly weaker effect on ventilation than nalfurafine (1 mg/kg). At higher doses (10 mg/kg), U50488 after fentanyl was fatal. Nalfurafine is a promising therapeutic candidate able to reverse fentanyl-induced muscle rigidity and respiratory depression without affecting sedation or the response to painful stimuli, potentially improving the safety and efficacy of fentanyl in specific clinical settings. We could not, however, confirm that this effect was mediated via κOR.NEW & NOTEWORTHY Nalfurafine, a κ-opioid receptor (κOR) agonist, can reverse fentanyl-induced muscle rigidity and respiratory depression without affecting sedation. In nonanesthetized rats, nalfurafine (1 mg/kg) effectively reversed muscle rigidity and restored ventilation to prefentanyl levels even though the animals remained fully sedated. U50488, another κOR agonist, did not reproduce the results. These findings suggest that nalfurafine is a promising therapeutic to mitigate fentanyl's side effects while maintaining the benefits.