Comparison of the mu-opioid receptor antagonists methocinnamox (MCAM) and naloxone to reverse the ventilatory-depressant effects of fentanyl and heroin in male rats

Abstract

<b>Abstract ID 15541</b> <b>Poster Board 544</b> The number of opioid overdose deaths has increased significantly over the past decade. The life-threatening effect of opioids is ventilatory depression and the <i>mu</i>-opioid receptor (MOR) antagonist naloxone is the only medication approved by the United States Food and Drug Administration for treating opioid overdose. However, the short duration of action of naloxone limits its effectiveness to reverse and protect against opioid overdose. A longer-acting MOR antagonist could improve treatment of opioid overdose. The MOR antagonist methocinnamox (MCAM) antagonizes the ventilatory-depressant effects of the non-morphinan MOR agonist fentanyl in rats with an unusually long duration of action. The present study extended previous studies and compared the potency and effectiveness of MCAM to naloxone for reversing the ventilatory-depressant effects of fentanyl and the morphinan heroin in eight male Sprague-Dawley rats in a within-subjects design. Whole-body plethysmography was employed (normal air) to assess ventilatory parameters every minute continuously throughout sessions [ventilatory frequency (<i>f</i>, breaths/minute); tidal volume (V_T, mL/breath/kg); and minute volume (V_E, mL/minute/kg), the product of <i>f</i> and V_T)]. Chambers were equipped with towers and swivels that allowed automated i.v. infusions through a chronic indwelling catheter without breaking the seal of the chamber. Immediately after a 45-minute habituation period, saline or an acute dose of heroin or fentanyl was administered i.v. Five minutes later rats received a second infusion of MCAM, naloxone, or vehicle (10% β-cyclodextrin in water). Heroin (0.32-3.2 mg/kg) and fentanyl (0.0032-0.1 mg/kg) dose-dependently and significantly decreased ventilation (e.g., area under the curve, 1-10 minutes) of V_E up to 27.0% (One Way Repeated Measures Analysis of Variance followed by Bonferroni t-test, t=16.5, P&lt;0.001) and 29.4% (t=24.6, P&lt;0.001) of saline control, respectively. Heroin (ED₅₀ values: 4.81 micromol/kg, i.v.) was 36.2-fold less potent than fentanyl in decreasing V_E. Both MCAM and naloxone (0.0001-0.01 mg/kg) dose-dependently and significantly reversed ventilatory depression (V_E) by heroin (3.2 mg/kg) or fentanyl (0.1 mg/kg) compared with vehicle control (t values ≥ 15.1, P values &lt; 0.001). MCAM and naloxone reversed the ventilatory-depressant effects of heroin (3.2 mg/kg, i.v.) up to 67.7% and 94.0% of vehicle control (i.e. saline followed by vehicle), respectively. MCAM and naloxone reversed the ventilatory-depressant effects of fentanyl (0.1 mg/kg, i.v.) up to 58.9% and 129.2% of vehicle control, respectively. The potency of MCAM [ED₅₀ values: 0.0141 (95% confidence interval: 0.0121, 0.0166) and 0.0158 (0.0139, 0.0184) micromol/kg, i.v.] did not significantly differ from that of naloxone to reverse the ventilatory-depressant effects of heroin and fentanyl (potency ratios: 1.25 and 1.96), respectively. The present study demonstrates that MCAM is as potent and effective as naloxone to reverse the ventilatory-depressant effects of morphinan and non-morphinan MOR agonists. Supported by USPHS grant UG3DA048387-S1 and the Welch Foundation (Grant AQ-0039).