title: Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.
abstract: While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Matson
authors.affiliation: Department of Diagnostics and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
authors.forename: Darryl T
authors.initials: DT
authors.lastname: Hamamoto
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.affiliation: Department of Pharmaceutics Research & Development, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Melanie
authors.initials: M
authors.lastname: Cooke
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.affiliation: Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Liyue
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Xingwen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Jeff
authors.initials: J
authors.lastname: McDermott
authors.affiliation: Department of Pharmaceutics Research & Development, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Carrie
authors.initials: C
authors.lastname: Morgan
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Wilenkin
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Annika B
authors.initials: AB
authors.lastname: Malmberg
authors.affiliation: Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Stefan I
authors.initials: SI
authors.lastname: McDonough
authors.affiliation: Department of Diagnostics and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Simone
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000698:Analgesia / Q000379:methods; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D005557:Formaldehyde / Q000494:pharmacology; D005620:Freund's Adjuvant / Q000494:pharmacology; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D059408:Pain Management; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; C503480:Scn9a protein, rat; D026941:Sodium Channel Blockers; D005557:Formaldehyde; D013779:Tetrodotoxin; D005620:Freund's Adjuvant