Expression and properties of hyperpolarization-activated current in rat dorsal root ganglion neurons with known sensory function

Key point I h is a hyperpolarisation-activated current that influences neuronal excitability and is present in some sensory neurons. The magnitude and properties of Ih in different groups of sensory neurons that respond to painful stimuli (nociceptors) or to non-painful stimuli, such as low threshold mechanoreceptors (LTMs), were unknown. We found that neurons with the greatest Ih were the nociceptors and LTMs with the fastest conducting fibres. The highest Ih of all was present in LTM neurons that sense muscle stretch and length (muscle spindle afferents). The high levels of Ih could fundamentally influence excitability of fast conducting sensory neurons which detect muscle stretch/length, touch and pressure, and painful stimuli. Ih could thus influence sensations associated with all these. The properties of Ih are similar to those of HCN1- and HCN2-related Ih, suggesting that these channels underlie the current. Abstract The hyperpolarization-activated current (Ih) has been implicated in nociception/pain, but its expression levels in nociceptors remained unknown. We recorded Ih magnitude and properties by voltage clamp from dorsal root ganglion (DRG) neurons in vivo, after classifying them as nociceptive or low-threshold-mechanoreceptors (LTMs) and as having C-, Ad- or Aa/beta-conduction velocities (CVs). For both nociceptors and LTMs, Ih amplitude and Ih density (at -100 mV) were significantly positively correlated with CV. Median Ih magnitudes and Ih density in neuronal subgroups were respectively: muscle spindle afferents (MSAs): -4.6 nA, -33 pA pF-1; cutaneous Aa/beta LTMs: -2.2 nA, -20 pA pF-1; A beta-nociceptors: -2.6 nA, -21 pA pF-1; both Ad-LTMs and nociceptors: -1.3 nA, similar to-14 pA pF-1; C-LTMs: -0.4 nA, -7.6 pA pF-1; and C-nociceptors: -0.26 nA, -5 pA pF-1. Ih activation slow time constants (slow t values) were strongly correlated with fast t values; both were shortest in MSAs. Most neurons had t values consistent with HCN1-related Ih; others had t values closer to HCN1+HCN2 channels, or HCN2 in the presence of cAMP. In contrast, median half-activation voltages (V0.5) of -80 to -86 mV for neuronal subgroups suggest contributions of HCN2 to Ih. t values were unrelated to CV but were inversely correlated with Ih and Ih density for all non-MSA LTMs, and for Ad-nociceptors. From activation curves similar to 27% of Ih would be activated at normal membrane potentials. The high Ih may be important for excitability of A-nociceptors (responsible for sharp/pricking-type pain) and Aa/beta-LTMs (tactile sensations and proprioception). Underlying HCN expression in these subgroups therefore needs to be determined. Altered Ih expression and/or properties (e.g. in chronic/pathological pain states) may influence both nociceptor and LTM excitability.