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 Ih and If, 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 Ih/If 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.