Abstract
BACKGROUND AND PURPOSE: Clinical studies have demonstrated significant reductions in allergen-induced nasal symptoms of atopic rhinitis subjects by CysLT1 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 Ca2+ assays and whole-cell gramicidin-perforated patch-clamp studies. KEY RESULTS: Nasal C-fibre neurones express CysLT1 but not CysLT2 mRNA. LTD4 and LTC4 increased intracellular [Ca2+]free in a population of capsaicin-sensitive trigeminal nerves, an effect blocked by the CysLT1 antagonist ICI198615. In current clamp mode, LTD4 had no effect on resting membrane potential. However, LTD4 significantly increased electrical excitability (action potential discharge during current pulses) threefold in capsaicin-sensitive nasal neurones, which was inhibited by CysLT1 antagonists ICI198615 and montelukast. LTD4 had no effect on electrical excitability in capsaicin-insensitive neurones. Finally, LTD4 significantly augmented histamine-induced responses in capsaicin-sensitive neurones as measured by increased action potential discharge, peak frequency and membrane depolarization. CONCLUSIONS AND IMPLICATIONS: LTD4, likely through CysLT1 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 CysLT1 antagonists in treating nasal allergen-induced neuronal symptoms.