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Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

¹Discovery Neuroscience and ²Chemical and Screening Sciences, Wyeth Research, Princeton, New Jersey

Submitted 10 August 2006; accepted in final form 18 March 2007

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are responsible for the functional hyperpolarization-activated current (I_h) in dorsal root ganglion (DRG) neurons, playing an important role in pain processing. We found that the known analgesic loperamide inhibited I_h channels in rat DRG neurons. Loperamide blocked I_h 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 I_h inhibition was unrelated to the activation of opioid receptors and was reversible, voltage-dependent, use-independent, and was associated with a negative shift of V_1/2 for I_h steady-state activation. Loperamide block of I_h 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 I_h. Inclusion of 10 µM loperamide into the recording pipette did not affect I_h voltage for half-maximal activation, activation kinetics, and the peak current amplitude, whereas concurrent application of equimolar external loperamide produced a rapid, reversible I_h inhibition. The observed loperamide-induced I_h inhibition was not caused by the activation of peripheral opioid receptors because the broad-spectrum opioid receptor antagonist naloxone did not reverse I_h inhibition. Therefore we suggest that loperamide inhibits I_h by direct binding to the extracellular region of the channel. Because I_h channels are involved in pain processing, loperamide-induced inhibition of I_h channels could provide an additional molecular mechanism for its analgesic action.