External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1

Mackenzie E. Hofmann, Tally M. Largent-Milnes, Jessica A. Fawley, Michael Andresen

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The cell-impermeant lidocaine derivative QX-314 blocks sodium channels via intracellular mechanisms. In somatosensory nociceptive neurons, open transient receptor potential vanilloid type 1 (TRPV1) receptors provide a transmembrane passageway for QX-314 to produce long-lasting analgesia. Many cranial primary afferents express TRPV1 at synapses on neurons in the nucleus of the solitary tract and caudal trigeminal nucleus (Vc). Here, we investigated whether QX-314 interrupts neurotransmission from primary afferents in rat brain-stem slices. Shocks to the solitary tract (ST) activated highly synchronous evoked excitatory postsynaptic currents (ST-EPSCs). Application of 300 μM QX-314 increased the ST-EPSC latency from TRPV1+ ST afferents, but, surprisingly, it had similar actions at TRPV1− ST afferents. Continued exposure to QX-314 blocked evoked ST-EPSCs at both afferent types. Neither the time to onset of latency changes nor the time to ST-EPSC failure differed between responses for TRPV1+ and TRPV1− inputs. Likewise, the TRPV1 antagonist capsazepine failed to prevent the actions of QX-314. Whereas QX-314 blocked ST-evoked release, the frequency and amplitude of spontaneous EPSCs remained unaltered. In neurons exposed to QX-314, intracellular current injection evoked action potentials suggesting a presynaptic site of action. QX-314 acted similarly at Vc neurons to increase latency and block EPSCs evoked from trigeminal tract afferents. Our results demonstrate that QX-314 blocked nerve conduction in cranial primary afferents without interrupting the glutamate release mechanism or generation of postsynaptic action potentials. The TRPV1 independence suggests that QX-314 either acted extracellularly or more likely entered these axons through an undetermined pathway common to all cranial primary afferents.

Original languageEnglish (US)
Pages (from-to)2697-2706
Number of pages10
JournalJournal of Neurophysiology
Volume112
Issue number11
DOIs
StatePublished - Dec 1 2014

Fingerprint

Synaptic Transmission
Neurons
Action Potentials
Trigeminal Caudal Nucleus
QX-314
vanilloid receptor subtype 1
Synaptic Potentials
Nociceptors
Solitary Nucleus
Sodium Channels
Excitatory Postsynaptic Potentials
Neural Conduction
Lidocaine
Evoked Potentials
Synapses
Analgesia
Brain Stem
Axons
Glutamic Acid
Shock

Keywords

  • NTS
  • QX-314
  • Solitary tract
  • TRPV1

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1. / Hofmann, Mackenzie E.; Largent-Milnes, Tally M.; Fawley, Jessica A.; Andresen, Michael.

In: Journal of Neurophysiology, Vol. 112, No. 11, 01.12.2014, p. 2697-2706.

Research output: Contribution to journalArticle

Hofmann, Mackenzie E. ; Largent-Milnes, Tally M. ; Fawley, Jessica A. ; Andresen, Michael. / External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1. In: Journal of Neurophysiology. 2014 ; Vol. 112, No. 11. pp. 2697-2706.
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