|Title||External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Hofmann ME, Largent-Milnes TM, Fawley JA, Andresen MC|
|Date Published||2014 Dec 01|
|Keywords||Anesthetics, 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 Journal||J. Neurophysiol.|
|PubMed Central ID||PMC4254884|
|Grant List||F32 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
External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1.
Faculty Member Reference:
Tally Largent-Milnes, Ph.D.