Human sensory neurons: Membrane properties and sensitization by inflammatory mediators

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Abstract

Summary

Naïve hDRG neurons cultured from young adults without chronic pain are highly chemosensitive to algogens and pruritogens, and can be sensitized by inflammatory mediators. Small- to medium-size hDRG neurons exhibit AP waveforms similar to what has been described for rodent nociceptors. Cultured hDRG neurons represent a more direct way of studying analgesic translational efficacy and confirming target validation before initiating expensive and time-consuming clinical trials.

Biological differences in sensory processing between human and model organisms may present significant obstacles to translational approaches in treating chronic pain. To better understand the physiology of human sensory neurons, we performed whole-cell patch-clamp recordings from 141 human dorsal root ganglion (hDRG) neurons from 5 young adult donors without chronic pain. Nearly all small-diameter hDRG neurons (<50 μm) displayed an inflection on the descending slope of the action potential, a defining feature of rodent nociceptive neurons. A high proportion of hDRG neurons were responsive to the algogens allyl isothiocyanate (AITC) and ATP, as well as the pruritogens histamine and chloroquine. We show that a subset of hDRG neurons responded to the inflammatory compounds bradykinin and prostaglandin E2 with action potential discharge and show evidence of sensitization including lower rheobase. Compared to electrically evoked action potentials, chemically induced action potentials were triggered from less depolarized thresholds and showed distinct afterhyperpolarization kinetics. These data indicate that most small/medium hDRG neurons can be classified as nociceptors, that they respond directly to compounds that produce pain and itch, and that they can be activated and sensitized by inflammatory mediators. The use of hDRG neurons as preclinical vehicles for target validation is discussed.

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