Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are responsible for the functional hyperpolarization-activated current (Ih) in dorsal root ganglion (DRG) neurons, playing an important role in pain processing. We found that the known analgesic loperamide inhibited Ih channels in rat DRG neurons. Loperamide blocked Ih in a concentration-dependent manner, with an IC50 = 4.9 ± 0.6 and 11.0 ± 0.5 μM for large- and small-diameter neurons, respectively. Loperamide-induced Ih inhibition was unrelated to the activation of opioid receptors and was reversible, voltage-dependent, use-independent, and was associated with a negative shift of V1/2 for Ih steady-state activation. Loperamide block of Ih was voltage-dependent, gradually decreasing at more hyperpolarized membrane voltages from 89% at –60 mV to 4% at –120 mV in the presence of 3.7 μM loperamide. The voltage sensitivity of block can be explained by a loperamide-induced shift in the steady-state activation of Ih. Inclusion of 10 μM loperamid...