Leukotriene D 4 increases the excitability of capsaicin-sensitive nasal sensory nerves to electrical and chemical stimuli

T. E. Taylor-Clark, C. Nassenstein, Bradley J Undem

Research output: Contribution to journalArticle

Abstract

Background and purpose: Clinical studies have demonstrated significant reductions in allergen-induced nasal symptoms of atopic rhinitis subjects by CysLT 1 antagonists, including neuronally mediated symptoms such as sneeze, itch and reflex hypersecretion. Here, we test the hypothesis that cysteinyl leukotrienes activate and/or alter the activity of nasal nociceptive (capsaicin-sensitive) sensory neurones. Experimental approach: Using retrograde tracer (DiI), we labelled guinea-pig trigeminal sensory neurones that projected fibres to the nasal mucosa. Single-neurone reverse transcriptase (RT)-PCR was used to evaluate CysLT receptor gene expression. The effect of cysteinyl leukotrienes on individual nasal sensory nerve activity was assessed in Ca 2+ assays and whole-cell gramicidin-perforated patch-clamp studies. Key results: Nasal C-fibre neurones express CysLT 1 but not CysLT 2 mRNA. LTD 4 and LTC 4 increased intracellular [Ca 2+] free in a population of capsaicin-sensitive trigeminal nerves, an effect blocked by the CysLT 1 antagonist ICI198615. In current clamp mode, LTD 4 had no effect on resting membrane potential. However, LTD 4 significantly increased electrical excitability (action potential discharge during current pulses) threefold in capsaicin-sensitive nasal neurones, which was inhibited by CysLT 1 antagonists ICI198615 and montelukast. LTD 4 had no effect on electrical excitability in capsaicin-insensitive neurones. Finally, LTD 4 significantly augmented histamine-induced responses in capsaicin-sensitive neurones as measured by increased action potential discharge, peak frequency and membrane depolarization. Conclusions and implications: LTD 4, likely through CysLT 1 receptors, directly increases the excitability of capsaicin-sensitive guinea-pig nasal trigeminal neurones, demonstrating a novel mechanism for the actions of cysteinyl leukotrienes and potentially explains the effectiveness of CysLT 1 antagonists in treating nasal allergen-induced neuronal symptoms.

Original languageEnglish (US)
Pages (from-to)1359-1368
Number of pages10
JournalBritish Journal of Pharmacology
Volume154
Issue number6
DOIs
StatePublished - Jul 2008

Fingerprint

Leukotriene D4
Capsaicin
Nose
Neurons
montelukast
Sensory Receptor Cells
Allergens
Action Potentials
Guinea Pigs
Gramicidin
Unmyelinated Nerve Fibers
Trigeminal Nerve
Nasal Mucosa
Vulnerable Populations
Rhinitis
Reverse Transcriptase Polymerase Chain Reaction
Membrane Potentials
Histamine
Reflex
Gene Expression

Keywords

  • Allergic rhinitis
  • CysLT antagonist
  • Excitability
  • Histamine
  • Leukotriene
  • Nasal
  • Nerve
  • Single-cell RT-PCR
  • Trigeminal

ASJC Scopus subject areas

  • Pharmacology

Cite this

Leukotriene D 4 increases the excitability of capsaicin-sensitive nasal sensory nerves to electrical and chemical stimuli. / Taylor-Clark, T. E.; Nassenstein, C.; Undem, Bradley J.

In: British Journal of Pharmacology, Vol. 154, No. 6, 07.2008, p. 1359-1368.

Research output: Contribution to journalArticle

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title = "Leukotriene D 4 increases the excitability of capsaicin-sensitive nasal sensory nerves to electrical and chemical stimuli",
abstract = "Background and purpose: Clinical studies have demonstrated significant reductions in allergen-induced nasal symptoms of atopic rhinitis subjects by CysLT 1 antagonists, including neuronally mediated symptoms such as sneeze, itch and reflex hypersecretion. Here, we test the hypothesis that cysteinyl leukotrienes activate and/or alter the activity of nasal nociceptive (capsaicin-sensitive) sensory neurones. Experimental approach: Using retrograde tracer (DiI), we labelled guinea-pig trigeminal sensory neurones that projected fibres to the nasal mucosa. Single-neurone reverse transcriptase (RT)-PCR was used to evaluate CysLT receptor gene expression. The effect of cysteinyl leukotrienes on individual nasal sensory nerve activity was assessed in Ca 2+ assays and whole-cell gramicidin-perforated patch-clamp studies. Key results: Nasal C-fibre neurones express CysLT 1 but not CysLT 2 mRNA. LTD 4 and LTC 4 increased intracellular [Ca 2+] free in a population of capsaicin-sensitive trigeminal nerves, an effect blocked by the CysLT 1 antagonist ICI198615. In current clamp mode, LTD 4 had no effect on resting membrane potential. However, LTD 4 significantly increased electrical excitability (action potential discharge during current pulses) threefold in capsaicin-sensitive nasal neurones, which was inhibited by CysLT 1 antagonists ICI198615 and montelukast. LTD 4 had no effect on electrical excitability in capsaicin-insensitive neurones. Finally, LTD 4 significantly augmented histamine-induced responses in capsaicin-sensitive neurones as measured by increased action potential discharge, peak frequency and membrane depolarization. Conclusions and implications: LTD 4, likely through CysLT 1 receptors, directly increases the excitability of capsaicin-sensitive guinea-pig nasal trigeminal neurones, demonstrating a novel mechanism for the actions of cysteinyl leukotrienes and potentially explains the effectiveness of CysLT 1 antagonists in treating nasal allergen-induced neuronal symptoms.",
keywords = "Allergic rhinitis, CysLT antagonist, Excitability, Histamine, Leukotriene, Nasal, Nerve, Single-cell RT-PCR, Trigeminal",
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T1 - Leukotriene D 4 increases the excitability of capsaicin-sensitive nasal sensory nerves to electrical and chemical stimuli

AU - Taylor-Clark, T. E.

AU - Nassenstein, C.

AU - Undem, Bradley J

PY - 2008/7

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N2 - Background and purpose: Clinical studies have demonstrated significant reductions in allergen-induced nasal symptoms of atopic rhinitis subjects by CysLT 1 antagonists, including neuronally mediated symptoms such as sneeze, itch and reflex hypersecretion. Here, we test the hypothesis that cysteinyl leukotrienes activate and/or alter the activity of nasal nociceptive (capsaicin-sensitive) sensory neurones. Experimental approach: Using retrograde tracer (DiI), we labelled guinea-pig trigeminal sensory neurones that projected fibres to the nasal mucosa. Single-neurone reverse transcriptase (RT)-PCR was used to evaluate CysLT receptor gene expression. The effect of cysteinyl leukotrienes on individual nasal sensory nerve activity was assessed in Ca 2+ assays and whole-cell gramicidin-perforated patch-clamp studies. Key results: Nasal C-fibre neurones express CysLT 1 but not CysLT 2 mRNA. LTD 4 and LTC 4 increased intracellular [Ca 2+] free in a population of capsaicin-sensitive trigeminal nerves, an effect blocked by the CysLT 1 antagonist ICI198615. In current clamp mode, LTD 4 had no effect on resting membrane potential. However, LTD 4 significantly increased electrical excitability (action potential discharge during current pulses) threefold in capsaicin-sensitive nasal neurones, which was inhibited by CysLT 1 antagonists ICI198615 and montelukast. LTD 4 had no effect on electrical excitability in capsaicin-insensitive neurones. Finally, LTD 4 significantly augmented histamine-induced responses in capsaicin-sensitive neurones as measured by increased action potential discharge, peak frequency and membrane depolarization. Conclusions and implications: LTD 4, likely through CysLT 1 receptors, directly increases the excitability of capsaicin-sensitive guinea-pig nasal trigeminal neurones, demonstrating a novel mechanism for the actions of cysteinyl leukotrienes and potentially explains the effectiveness of CysLT 1 antagonists in treating nasal allergen-induced neuronal symptoms.

AB - Background and purpose: Clinical studies have demonstrated significant reductions in allergen-induced nasal symptoms of atopic rhinitis subjects by CysLT 1 antagonists, including neuronally mediated symptoms such as sneeze, itch and reflex hypersecretion. Here, we test the hypothesis that cysteinyl leukotrienes activate and/or alter the activity of nasal nociceptive (capsaicin-sensitive) sensory neurones. Experimental approach: Using retrograde tracer (DiI), we labelled guinea-pig trigeminal sensory neurones that projected fibres to the nasal mucosa. Single-neurone reverse transcriptase (RT)-PCR was used to evaluate CysLT receptor gene expression. The effect of cysteinyl leukotrienes on individual nasal sensory nerve activity was assessed in Ca 2+ assays and whole-cell gramicidin-perforated patch-clamp studies. Key results: Nasal C-fibre neurones express CysLT 1 but not CysLT 2 mRNA. LTD 4 and LTC 4 increased intracellular [Ca 2+] free in a population of capsaicin-sensitive trigeminal nerves, an effect blocked by the CysLT 1 antagonist ICI198615. In current clamp mode, LTD 4 had no effect on resting membrane potential. However, LTD 4 significantly increased electrical excitability (action potential discharge during current pulses) threefold in capsaicin-sensitive nasal neurones, which was inhibited by CysLT 1 antagonists ICI198615 and montelukast. LTD 4 had no effect on electrical excitability in capsaicin-insensitive neurones. Finally, LTD 4 significantly augmented histamine-induced responses in capsaicin-sensitive neurones as measured by increased action potential discharge, peak frequency and membrane depolarization. Conclusions and implications: LTD 4, likely through CysLT 1 receptors, directly increases the excitability of capsaicin-sensitive guinea-pig nasal trigeminal neurones, demonstrating a novel mechanism for the actions of cysteinyl leukotrienes and potentially explains the effectiveness of CysLT 1 antagonists in treating nasal allergen-induced neuronal symptoms.

KW - Allergic rhinitis

KW - CysLT antagonist

KW - Excitability

KW - Histamine

KW - Leukotriene

KW - Nasal

KW - Nerve

KW - Single-cell RT-PCR

KW - Trigeminal

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