Kratom Alkaloid Mitragynine: Inhibition of Chemotherapy-Induced
Peripheral Neuropathy in Mice is Dependent on Sex and Adrenergic and
Opioid Receptors
Abstract
Background and Purpose: Mitragynine (MG) is an alkaloid found in
Mitragyna speciosa (kratom) that is used as an herbal remedy for pain
relief and opioid withdrawal. MG acts at μ-opioid and α-adrenergic
receptors in vitro, but the physiological relevance of this activity in
the context of neuropathic pain remains unknown. The purpose of the
present study was to characterize the effects of MG in a mouse model of
CIPN, and to investigate the potential impact of sex on MG’s therapeutic
efficacy. Experimental Approach: Inhibition of oxaliplatin-induced
mechanical hypersensitivity was measured following intraperitoneal
administration of MG. Both male and female C57BL/6J mice were used to
characterize potential sex-differences in MG’s therapeutic efficacy.
Pharmacological mechanisms of MG were characterized through pretreatment
with the opioid and adrenergic antagonists naltrexone, prazosin,
yohimbine, and propranolol (1, 2.5, 5 mg/kg). Key Results: Oxaliplatin
produced significant mechanical allodynia of equal magnitude in both
male and females, which was dose-dependently attenuated by repeated MG
exposure. MG was more potent in males vs females, and the highest dose
of MG (10 mg/kg) exhibited greater anti-allodynic efficacy in males.
Mechanistically, activity at µ-opioid, α1- and α2-adrenergic receptors,
but not β-adrenergic receptors contributed to the effects of MG against
oxaliplatin-induced mechanical hypersensitivity. Conclusions and
Implications: Repeated MG exposure significantly attenuated
oxaliplatin-induced mechanical hypersensitivity with greater potency and
efficacy in males, which has crucial implications in the context of
individualized pain management. The opioid and adrenergic components of
MG indicate that it shares pharmacological properties with clinical
neuropathic pain treatments.