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TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits

Cristian Acosta1, Laiche Djouhri, Roger Watkins

  • 1Institute of Histology and Embriology of Mendoza, Mendoza 5500, Argentina, Department of Biomedical Sciences, Faculty of Medicine, King Faisal University, Al-Hassa 11335, Kingdom of Saudi Arabia, and School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|January 24, 2014
PubMed

Insights

TREK2 potassium channels hyperpolarize C-fiber nociceptors, reducing spontaneous firing and limiting neuropathic pain. This discovery offers a new target for pain management strategies.

Area of Science:

  • Neuroscience
  • Pain Research
  • Molecular Biology

Background:

  • Spontaneous pain behavior in neuropathic pain models is linked to spontaneous firing (SF) in adult dorsal root ganglion (DRG) C-fiber nociceptors.
  • The underlying causes of this spontaneous firing are not fully understood, hindering the development of effective pain management strategies.
  • Resting membrane potential (Em) of C-nociceptors influences their firing rate, suggesting Em control is crucial for limiting pathological pain.

Purpose of the Study:

  • To investigate the role of the TREK2 potassium channel in controlling the resting membrane potential (Em) of DRG C-fiber nociceptors.
  • To determine the relationship between TREK2 expression, Em, spontaneous firing, and spontaneous pain behavior in neuropathic pain models.
  • To explore TREK2 as a potential therapeutic target for reducing pathological pain.

Main Methods:

  • Examined TREK2 expression in IB4-binding (IB4+) rat C-nociceptors, which exhibit more hyperpolarized Em compared to IB4- C-neurons.
  • Utilized small interfering RNA (siRNA) to knockdown TREK2 in cultured neurons and assessed the impact on Em.
  • Investigated the in vivo correlation between cytoplasmic edge-TREK2 expression (edge-TREK2) and Em in C-neurons following axotomy.
  • Assessed spontaneous foot lifting (a measure of spontaneous pain) in rats with varying natural TREK2 levels and after TREK2 knockdown.

Main Results:

  • TREK2 is selectively expressed in IB4+ C-nociceptors, contributing to their more hyperpolarized Em (approximately 10 mV difference).
  • TREK2 knockdown depolarized these neurons, and in vivo, decreased edge-TREK2 correlated with depolarized Em after axotomy.
  • Spontaneous pain behavior (foot lifting) was greater in rats with naturally lower TREK2 and increased following in vivo TREK2 knockdown.

Conclusions:

  • TREK2 functions to hyperpolarize IB4+ C-nociceptors, thereby limiting pathological spontaneous pain.
  • TREK2's role in controlling Em and reducing spontaneous firing suggests it is a key regulator of neuropathic pain.
  • The conserved expression of TREK2 in small DRG neurons across species indicates its potential as a widespread therapeutic target for pain management.
Keywords:
DRGK2PTREK2nociceptorsspontaneous firingspontaneous pain

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