Mitragynine Pretreatment Prevents Morphine-Induced Respiratory Depression

Abstract

<b>Abstract ID 26122</b> <b>Poster Board 264</b> <b>Objectives:</b> Kratom (Mitragynine speciosa), a natural product from southeast Asia, has become a popular self-treatment trend for pain and opioid use disorder (OUD) and users claim great success. Considering the current opioid epidemic, kratom is being studied as a potential OUD pharmacotherapy. Given that respiratory depression is a major cause of mortality due to opioid overdose, a great need exists to determine kratom-related respiratory effects alone and in the presence of opioids. For the current study we examined the effects of mitragynine, the most abundant alkaloid in kratom, in a rat model of intravenous (i.v.) administered morphine-induced respiratory depression. <b>Methods:</b> Adult male and female Sprague Dawley rats arrived pre-implanted with a jugular catheter. Experiments were conducted using a within-subjects experimental design over 8 weeks and each session lasted 3 hours. During a 3-hour session, respiratory parameters including respiratory frequency, tidal volume, and minute ventilation were measured using whole body plesmography in freely moving animals. A 3-hour session was comprised of a 1-hour acclimation, followed by a 20-minute baseline. The first i.v. infusion was delivered at the end of the baseline and the second i.v. infusion was delivered 5 minutes later. After the second infusion the above-mentioned respiratory parameters were continuously monitored for 110 minutes. A 7-day drug washout period between sessions was utilized, and session were counterbalanced with no more than 2 animals of the same sex receiving the same condition on the same day. In all experiments a solution consisting of 0.9% saline, tween, polyethylene, and propylene glycol served as vehicle for mitragynine, morphine was dissolved in 0.9% saline. <b>Results:</b> Saline + vehicle had no effect on the respiratory parameters measured. Morphine (32 mg/kg, i.v.) followed by vehicle injection produced robust respiratory depression as indicated by decreased frequency, tidal volume, and minute ventilation for the duration of the study. Mitragynine (10 mg/kg, i.v.) followed by vehicle injection significantly increased respiratory frequency and minute ventilation but did not alter tidal volume. When morphine (32 mg/kg, i.v.) was delivered before mitragynine (10 mg/kg, i.v.) no significant differences were observed in respiratory frequency, tidal volume, or minute ventilation compared to the morphine + vehicle administration results. However, when mitragynine (10 mg/kg, i.v.) was delivered first, 5 minutes prior to morphine (32 mg/kg, i.v.) mitragynine prevented opioid induced respiratory depression, as indicated by decreased frequency, tidal volume, and minute ventilation. <b>Conclusions:</b> Intravenously administered morphine produced robust respiratory depression symptoms, whereas at the dose studied here, mitragynine did not. When given after morphine, mitragynine failed to alter morphine-induced respiratory depression symptoms. However, when given before morphine, mitragynine prevented morphine-induced respiratory depression. These findings have important implications in opioid use disorder and opioid overdose medication development. Supported by National Institute on Drug Abuse grants DA25267 and DA048353.