MON-510 The Kratom-Derived Alkaloid Mitragynine Enhances Cortisol Secretion via Upregulation of Steroidogenic Enzymes in a Human Adrenocortical Cell Line

Abstract P.G. Kopf: None. W.C. Prozialeck: None. Kratom is a tropical evergreen tree indigenous to Southeast Asia whose leaves and decoctions have long been used in traditional folk medicine for the relief of pain and enhancement of vitality. In recent years kratom use has increased in the United States, where an estimated 10-15 million people use the herb for the self-management of pain and opioid withdrawal. Kratom leaves contain over 40 active alkaloids with complex receptor pharmacology that is still being elucidated. One of the best characterized kratom alkaloids, mitragynine, has partial biased activity at mu opioid receptors, mixed activities at delta opioid receptors, and a variety of effects on other neurotransmitters in the central nervous system. To explore the possible anti-inflammatory actions of kratom, we examined the effects of select kratom alkaloids on cortisol secretion in a human adrenocortical cell line. HAC15 cells were exposed to vehicle, mitragynine, 7-hydroxymitragynine, paynantheine, speciociliatine, or corynoxine (1 nM-10 μM) for 72 h. Following exposure, cortisol secretion was examined. Of these kratom alkaloids, mitragynine and speciociliatine exposure resulted in significant increases in basal cortisol secretion (in ng/mL: vehicle, 57.5±2.3; 10 μM mitragynine, 519.8±19.0; 10 μM speciociliatine, 277.8±5.2, n=8). To further investigate the molecular mechanism by which mitragynine enhances cortisol secretion, we examined the effect of mitragynine on the expression of the steroidogenic enzymes and cofactors involved in cortisol production. HAC15 cells were exposed to vehicle or mitragynine (10 μM). After 72 h, mRNA expression of the following steroidogenic enzymes, cofactors, and receptors was examined: CYP11A1, HSD3B2, CYP21A2, CYP11B1, CYP17A1, StAR, FDXR, FDX1, and MC2R. While mRNA expression was upregulated for all of these steroidogenic factors, CYP11B1 was induced to the greatest extent (fold change: vehicle, 1.0±0.2; 10 μM mitragynine, 18.4±1.5; n=6). To investigate the role of opioid receptors in mitragynine stimulation of cortisol secretion, HAC15 cells were exposed to vehicle or mitragynine in the presence of the opioid receptor antagonists naloxone and naltrexone. Both naloxone and naltrexone had a statistically significant, but minor attenuating effect of mitragynine-stimulated cortisol secretion (in ng/mL: vehicle, 76.1±2.2; 10 μM mitragynine, 472.8±9.2; 10 μM mitragynine/500 nM naloxone, 446.8±15.2; 10 μM mitragynine/10 μM naltrexone, 377.5±11.0, n=6-12). These data indicate that mitragynine enhances cortisol secretion in vitro via upregulation of the cortisol synthesis enzymatic pathway. Opioid receptors appear to play only a minor role in these effects. Enhanced cortisol secretion may contribute to anti-inflammatory and analgesic actions of kratom in vivo. Monday, June 3, 2024