Tramadol-induced block of hyperpolarization-activated cation current in rat pituitary lactotrophs

The hyperpolarization-activated cation current ( I h ) in rat pituitary lactotrophs (GH 3 cells) was characterized. Tramadol-induced block of this current was investigated. Effects of various related compounds on I h in GH 3 cells were also compared. Tramadol caused a time- and concentration-dependent reduction in the amplitude of I h with an IC 50 value of 13.6 μM. ZD7288 (30 μM), CsCl (2 mM), and propofol (30 μM) were effective in suppressing the amplitude of I h . 2′,5′-dideoxyadenosine (100 μM) suppressed I h , while sp-cAMPS (100 μM) had no effect on it. Tramadol (10 μM) shifted the activation curve of I h to a more negative potential by approximately −20 mV, although no change in the slope factor was observed. Under current-clamp configuration, tramadol (10 μM) could reduce the firing frequency of action potentials. Intracellular Ca 2+ measurements revealed its ability to reduce spontaneous Ca 2+ oscillations in GH 3 cells. The results suggests that during cell exposure to tramadol used at clinically relevant concentration, the tramadol-mediated inhibition of I h could be direct and mediated via a non-opioid mechanism and would be one of the ionic mechanisms underlying reduced cell excitability.