Abstract

Voltage-gated sodium channels (Navs) play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion (hDRG) tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Nav1.7 (~50% of total Nav expression) and lower expression of Nav1.8 (~12%), whereas the mouse DRG has higher expression of Nav1.8 (~45%) and lower expression of Nav1.7 (~18%). To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel (0.1–1 μmol/L) for 24 h. Paclitaxel increased the Nav1.7 but not Nav1.8 expression and also increased the transient Na+ currents and action potential firing frequency in small-diameter (<50 μm) hDRG neurons. Thus, the hDRG provides a translational model in which to study “human pain in a dish” and test new pain therapeutics.

Highlights

  • Over the last 20 years, great progress has been made in identifying novel pain targets and illustrating the neuronal, immune, and glial mechanisms of pathological pain in animal models [1,2,3,4]

  • HDRG neurons were much larger than rodent DRG neurons, and small human dorsal root ganglion (hDRG) neurons were identified with diameters of \50 lm [7, 11]

  • There have been many failures in developing new analgesics, because (1) molecular mechanisms identified in rodents may not apply to humans and (2) animal models of pain may not represent human pains [5, 6]

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Summary

Introduction

Over the last 20 years, great progress has been made in identifying novel pain targets and illustrating the neuronal, immune, and glial mechanisms of pathological pain in animal models [1,2,3,4]. A translational gap from rodents to humans has been blamed for the failure in developing pain medications [5, 6]. To address this issue, several groups including our own have begun to investigate pain mechanisms in native primary sensory neurons in human dorsal root ganglia (hDRGs) obtained from donors [7,8,9,10,11]. HDRG neurons respond to the inflammatory mediators bradykinin and prostaglandin E2, showing evidence of peripheral sensitization [7]

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