Control of somatic membrane potential in nociceptive neurons and its implications for peripheral nociceptive transmission

Peripheral sensory ganglia contain somata of afferent fibres conveying somatosensory inputs to the central nervous system. Growing evidence suggests that the somatic/perisomatic region of sensory neurons can influence peripheral sensory transmission. Control of resting membrane potential (E(rest)) is an important mechanism regulating excitability, but surprisingly little is known about how E(rest) is regulated in sensory neuron somata or how changes in somatic/perisomatic E(rest) affect peripheral sensory transmission. We first evaluated the influence of several major ion channels on E(rest) in cultured small-diameter, mostly capsaicin-sensitive (presumed nociceptive) dorsal root ganglion (DRG) neurons. The strongest and most prevalent effect on E(rest) was achieved by modulating M channels, K2P and 4-aminopiridine-sensitive K(V) channels, while hyperpolarization-activated cyclic nucleotide-gated, voltage-gated Na(+), and T-type Ca(2+) channels to a lesser extent also contributed to E(rest). Second, we investigated how varying somatic/perisomatic membrane potential, by manipulating ion channels of sensory neurons within the DRG, affected peripheral nociceptive transmission in vivo. Acute focal application of M or K(ATP) channel enhancers or a hyperpolarization-activated cyclic nucleotide-gated channel blocker to L5 DRG in vivo significantly alleviated pain induced by hind paw injection of bradykinin. Finally, we show with computational modelling how somatic/perisomatic hyperpolarization, in concert with the low-pass filtering properties of the t-junction within the DRG, can interfere with action potential propagation. Our study deciphers a complement of ion channels that sets the somatic E(rest) of nociceptive neurons and provides strong evidence for a robust filtering role of the somatic and perisomatic compartments of peripheral nociceptive neuron.