Mitragynine Attenuates the Development of Tolerance to and Withdrawal from Morphine in Rats

Abstract

Mitragyna speciosa (kratom) has been used for centuries in Southeast Asia as a self-treatment for opioid dependence. However, scientific evidence to support the medical use of kratom has not been established. Kratom products contain numerous alkaloids, the most abundant of which is mitragynine (MG). This study assessed the potential for MG to attenuate the development and expression of opioid tolerance and dependence. In Sprague-Dawley rats, morphine (MOR) antinociception was measured prior to and following four days of escalating doses of morphine (10-40 mg/kg, every 12 hours). Chronic dosing tests were conducted with both morphine alone and co-treatment of morphine with mitragynine or other test compounds. Naltrexone-induced diarrhea was measured as a sign of opioid withdrawal. Chronic MG treatment alone (10, 32, and 56 mg/kg, every 12 hours) was assessed for the capacity to alter sensitivity to MOR and to result in naltrexone-induced withdrawal. Repeated MOR treatment conferred tolerance, as evidenced by a 7.9-fold rightward shift in the MOR antinociception dose-response function. Naltrexone produced diarrhea in the chronic MOR group and not the chronic saline group. Chronic administration of MG (10, 32, and 56 mg/kg) with MOR dose-dependently attenuated the development of MOR tolerance. Chronic MG alone produced up to a 2.4-fold rightward shift in the MOR antinociception dose-response function; chronic treatment with 32 mg/kg of mitragynine resulted in naltrexone-induced diarrhea. The effects of acutely administered MG on the expression of tolerance to and withdrawal from MOR were further compared to those of two FDA-approved medications for opioid use disorder: the μ-opioid receptor partial agonist buprenorphine and the α2-adrenergic receptor agonist lofexidine. In MOR-tolerant rats, lofexidine (1.0 mg/kg) significantly increased the potency of MOR to produce antinociception, buprenorphine (1.0 mg/kg) significantly antagonized morphine, and MG (32 and 56 mg/kg) did not modify the potency of MOR. Naltrexone-induced diarrhea was fully attenuated by lofexidine (1.0 mg/kg) and partially attenuated by MG (32 and 56 mg/kg) and buprenorphine (1.0 mg/kg). Collectively, these results support the potential of MG as a medication to attenuate the development of opioid tolerance and dependence. More studies are needed to assess the safety profile of mitragynine when administered in combination with opioids or other compounds.