Although direct activation of mast cells by high concentrations (>10-6 M) of substance P is well established, the effect of sub-micromolar concentrations of the neuropeptide on mast cell activation has not been reported. We hence investigated if substance P would modulate immunologic activation of mast cells by studying the effect of the neuropeptide on anti-rat immunologlobulin E antibody (anti-IgE)-induced histamine release from purified rat peritoneal mast cells. We observed that substance P could dose-dependently potentiate anti-IgE-induced histamine release from rat peritoneal mast cells at concentrations (3x10-9 M to 3x10-7 M) which alone induced insignificant or low level of histamine release. While the potentiating effect of substance P was not suppressed by any of the non-peptide tachykinin receptor antagonists CP99994 ((2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), SR48968 ((S)-N-methyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl) butyl-benzamide) and SR142801 ((S)-(N)-(1-[3-(1-benzoyl-3(3,4-dichlorophenyl)piperidine-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-acetamide), it was mimicked by compound 48/80 and suppressed by benzalkonium chloride. Hence, substance P enhanced anti-IgE-induced histamine release through a similar receptor-independent mechanism as the direct mast cell activating action of polybasic compounds. Since high concentrations of substance P required for directly activating mast cells may not be achievable physiologically, the enhancing actions of the neuropeptide on the immunologic activation of mast cells may be more clinically relevant in the pathogenesis of various inflammatory conditions.
- Substance P
- Tachykinin receptor antagonist
- Mast cell
- Histamine release
- Benzalkonium chloride