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

TitleExternal QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1.
Publication TypeJournal Article
Year of Publication2014
AuthorsHofmann ME, Largent-Milnes TM, Fawley JA, Andresen MC
JournalJ Neurophysiol
Date Published2014 Dec 01
KeywordsAnesthetics, Local, Animals, Capsaicin, Cranial Nerves, Excitatory Postsynaptic Potentials, Lidocaine, Male, Neurons, Afferent, Rats, Rats, Sprague-Dawley, Reaction Time, TRPV Cation Channels

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.

Alternate JournalJ. Neurophysiol.
PubMed ID25185814
PubMed Central IDPMC4254884
Grant ListF32 DE022499 / DE / NIDCR NIH HHS / United States
F32 HL112419 / HL / NHLBI NIH HHS / United States
F32-HL-112419 / HL / NHLBI NIH HHS / United States
R01-HL-105703 / HL / NHLBI NIH HHS / United States
R01 HL105703 / HL / NHLBI NIH HHS / United States
F32-DE-022499 / DE / NIDCR NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD