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

David J. Matson, Darryl T. Hamamoto, Howard Bregman, Melanie Cooke, Erin F. DiMauro, Liyue Huang, Danielle Johnson, Xingwen Li, Jeff McDermott, Carrie Morgan, Ben Wilenkin, Annika B. Malmberg, Stefan I. McDonough, Donald A. Simone

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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.

Original languageEnglish (US)
Article numbere0138140
JournalPloS one
Volume10
Issue number9
DOIs
StatePublished - Sep 17 2015

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tetrodotoxin
Unmyelinated Nerve Fibers
Nociceptors
sodium channels
Freund's Adjuvant
Sodium Channels
Tetrodotoxin
analgesia
formalin
Analgesia
Formaldehyde
adjuvants
pain
Pain
Fibers
Touch
heat
NAV1.7 Voltage-Gated Sodium Channel
Hot Temperature
Myelinated Nerve Fibers

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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. / Matson, David J.; Hamamoto, Darryl T.; Bregman, Howard; Cooke, Melanie; DiMauro, Erin F.; Huang, Liyue; Johnson, Danielle; Li, Xingwen; McDermott, Jeff; Morgan, Carrie; Wilenkin, Ben; Malmberg, Annika B.; McDonough, Stefan I.; Simone, Donald A.

In: PloS one, Vol. 10, No. 9, e0138140, 17.09.2015.

Research output: Contribution to journalArticle

Matson, DJ, Hamamoto, DT, Bregman, H, Cooke, M, DiMauro, EF, Huang, L, Johnson, D, Li, X, McDermott, J, Morgan, C, Wilenkin, B, Malmberg, AB, McDonough, SI & Simone, DA 2015, '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', PloS one, vol. 10, no. 9, e0138140. https://doi.org/10.1371/journal.pone.0138140
Matson, David J. ; Hamamoto, Darryl T. ; Bregman, Howard ; Cooke, Melanie ; DiMauro, Erin F. ; Huang, Liyue ; Johnson, Danielle ; Li, Xingwen ; McDermott, Jeff ; Morgan, Carrie ; Wilenkin, Ben ; Malmberg, Annika B. ; McDonough, Stefan I. ; Simone, Donald A. / 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. In: PloS one. 2015 ; Vol. 10, No. 9.
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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.",
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AU - Hamamoto, Darryl T.

AU - Bregman, Howard

AU - Cooke, Melanie

AU - DiMauro, Erin F.

AU - Huang, Liyue

AU - Johnson, Danielle

AU - Li, Xingwen

AU - McDermott, Jeff

AU - Morgan, Carrie

AU - Wilenkin, Ben

AU - Malmberg, Annika B.

AU - McDonough, Stefan I.

AU - Simone, Donald A.

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AB - 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.

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