Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels and Pain

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the pacemaker currents in neurons and cardiac cells designated as I-h and I-f, respectively. HCN channels are activated at negative membrane potentials and specifically upon repolarization following action potential firing resulting in a depolarizing current influencing the threshold for subsequent action potential generation. Consequently, HCN channels and I-h/I-f play a critical role in regulating excitability and rhythmic activity in excitable cells. The distribution of the four HCN channel subtypes has been studied in some detail in sensory neurons demonstrating a diverse and widespread distribution and raising the question as to their potential involvement in pain pathophysiology, frequently ascribed to aberrant neuronal hyperexcitability. This review discusses the evidence implicating a role for HCN channels in pain.