Physiological dependence to mitragynine indicated by a rapid cross-dependence procedure with heroin-dependent mice

The potential of mitragynine to produce physiological dependence (withdrawal) was assessed using a rapid assessment procedure with male ICR mice exposed to heroin-admixed food followed by naloxone (subcutaneously, s.c.) precipitation of withdrawal. Initial studies indicated that 3 days of exposure to 3.0 mg/g of heroin-admixed food followed by naloxone (0.6 mg/kg) reliably precipitated withdrawal jumping and weight loss. Lower concentrations of heroin-admixed food and lower doses of naloxone produced fewer withdrawal signs. A longer exposure to heroin-admixed food did not produce significantly greater amounts of jumping or weight loss. Further, these withdrawal signs were dose-dependently reversed by s.c. administration of heroin immediately following naloxone administration. Mitragynine (s.c.) also dose-dependently suppressed naloxone-precipitated withdrawal signs. Additionally, both jumping and weight loss were suppressed over a comparable range of mitragynine doses when administered by gavage with a noticeably, but not significantly, higher potency than with s.c. administration. The ED₅₀ values for mitragynine for the suppression of withdrawal by any route (354-911 μmol/kg) were greater than the minimally effective dose that decreased locomotor activity (251 μmol/kg) and from 40- to 104-fold greater than those for heroin. The results suggest inherent opioid dependence liability of mitragynine. The in vivo potency relations between mitragynine and heroin are consistent with a conclusion of dependence-producing effects, indicated by the suppression of withdrawal, comparable to standard opioid μ-receptor agonists, differing primarily in terms of potency. The present paper provides a method for the rapid assessment of physiological dependence liability applicable to other kratom plant constituents or any potential opioid dependence-producing agents.