title: External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1.
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.
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon hofmannwfu@gmail.com.
authors.forename: Mackenzie E
authors.initials: ME
authors.lastname: Hofmann
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Tally M
authors.initials: TM
authors.lastname: Largent-Milnes
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Fawley
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Andresen
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D003391:Cranial Nerves / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C012647:QX-314; D008012:Lidocaine; C071423:capsazepine; D002211:Capsaicin
keywords: NTS; QX-314; TRPV1; solitary tract