Pharmacological Characterization of Mitragynine: Antinociception, Respiratory Depression, Self‐Administration, Drug Discrimination, Tolerance, and withdrawal in Rats

Abstract

The primary kratom alkaloid mitragynine (MG) has low intrinsic activity at µ-opioid receptor (MOR). Here we characterized the MOR activity of MG using various in vivo assays in rats. Using a hotplate assay (52°C), MOR agonists fentanyl and morphine produced robust antinociception (i.v. cumulative ED50s: 0.015 and 8.1 mg/kg, respectively); MG (i.v.) was inactive up to 17.8 mg/kg and 32 mg/kg was lethal. The 32 mg/kg dose of MG (i.p.) did not significantly modify the dose-effect function (DEF) of morphine to produce antinociceptive effects. Using whole-body plethysmography under hypercapnic conditions (8% CO2), the maximum decreases of fentanyl, morphine, and MG in % control minute volume (mL/min./kg, normalized to ambient air) were 63% (i.v. cumulative ED25: 0.011 mg/kg), 46% (34 mg/kg), and 23%, respectively. In rats trained to self-administer remifentanil (RMF; 0.1-3.2 µg/kg/inj., fixed-ratio 5 schedule of reinforcement), the DEF of RMF self-administration was an inverted-U shaped curve and 1.0 µg/kg/inj. maintained maximum rates of responding (0.11 responses/sec. relative to 0.0071 responses/sec. without drug). When substituted for RMF, no dose of MG (0.1-3.2 mg/kg/inj.) maintained self-administration responding above control. A dose of 32 mg/kg MG (i.p.) decreased by 77% the maximum rates of responding maintained by RMF; 17.8 mg/kg MG was inactive. In contrast, the opioid antagonist naltrexone (3.2 mg/kg, i.p.) shifted the DEF of RMF to the right (i.e., appeared to produce surmountable antagonism). In rats discriminating morphine (3.2 mg/kg, i.p.; ED50=1.9 mg/kg) from vehicle, fentanyl and mitragynine produced 100% and 72% drug-lever responding (i.p. ED50s=0.022 and 30 mg/kg, respectively). The DEF of morphine was shifted 8.2-fold to the right (i.e., antagonized) by naltrexone (0.032 mg/kg, i.p.), and 3.9-fold to the left (i.e., potentiation) by MG (5.6 m/kg, i.p.). Tolerance to morphine antinociception (control ED50=14 mg/kg, i.p.) was assessed one day prior to (Day 1) and one day after (Day 6) escalating dosing of morphine (b.i.d. 10, 20, 30, and 40 mg/kg over 4 consecutive days, i.p.) or fixed dosing of MG (b.i.d. 32 mg/kg over 4 consecutive days, i.p.). The escalating dosing of morphine produced a 7.9-fold rightward shift of the morphine DEF (tolerance); in contrast, chronic MG treatment did not alter the potency of morphine (i.e., there was no cross-tolerance). One day after the tolerance test (Day 7), naltrexone (10 mg/kg, i.p.) produced diarrhea in 100% and 75% in morphine and MG groups (N=8 each), respectively. These data suggest that MG is a low efficacy MOR agonist in vivo that includes less respiratory and reinforcing effects as compared with other MOR agonists, as well as the capacity to reduce self-administration of those MOR agonists. Chronic MG does not appear to decrease the antinociceptive effectiveness of MOR agonists. Collectively, these data underscore the therapeutic potential of MG and novel chemical analogs of MG for opioid use disorder.