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. © 2008 Nature Publishing Group All rights reserved.