Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.

AIMS: Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored.

MAIN METHODS: Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS.

KEY FINDINGS: The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure.

SIGNIFICANCE: Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids.