Cannabidiol Modulates M-Type K(+) and Hyperpolarization-Activated Cation Currents

Cannabidiol (CBD) is a naturally occurring compound found in the Cannabis plant that is known for its potential therapeutic effects. However, its impact on membrane ionic currents remains a topic of debate. This study aimed to investigate how CBD modifies various types of ionic currents in pituitary GH(3) cells. Results showed that exposure to CBD led to a concentration-dependent decrease in M-type K(+) currents (I(K(M))), with an IC(50) of 3.6 μM, and caused the quasi-steady-state activation curve of the current to shift to a more depolarized potential with no changes in the curve’s steepness. The CBD-mediated block of I(K(M)) was not reversed by naloxone, suggesting that it was not mediated by opioid receptors. The I(K(M)) elicited by pulse-train stimulation was also decreased upon exposure to CBD. The magnitude of erg-mediated K(+) currents was slightly reduced by adding CBD (10 μM), while the density of voltage-gated Na(+) currents elicited by a short depolarizing pulse was not affected by it. Additionally, CBD decreased the magnitude of hyperpolarization-activated cation currents (I(h)) with an IC(50) of 3.3 μM, and the decrease was reversed by oxaliplatin. The quasi-steady-state activation curve of I(h) was shifted in the leftward direction with no changes in the slope factor of the curve. CBD also diminished the strength of voltage-dependent hysteresis on I(h) elicited by upright isosceles-triangular ramp voltage. Collectively, these findings suggest that CBD’s modification of ionic currents presented herein is independent of cannabinoid or opioid receptors and may exert a significant impact on the functional activities of excitable cells occurring in vitro or in vivo.