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The regulation of substance P (SP) responsiveness in acutely isolated nodose neurones from adult guinea-pigs was investigated using standard intracellular recording techniques.
In control neurones, SP produced no measurable electrophysiological effects. However, following incubation with serotonin (5-HT, 10 µM), 64 % of neurones were depolarized by 10 ± 0·6 mV (n = 84 of 132 neurones) by SP (100 nM). 5-HT-induced SP responses were inhibited by SR48968 (100 nM, n = 6), a neurokinin 2 (NK-2) receptor antagonist, but were unaffected by CP99,994 and SR142801, NK-1 and NK-3 receptor antagonists (n = 3 each), respectively.
5-HT-induced unmasking of SP responses was maximal within 5 min. Increasing the 5-HT incubation time up to 120 min did not increase the mean response amplitude or the percentage of SP responsive neurones (P = 0·611 and 0·867, respectively).
5-HT-induced unmasking of SP responses was dose dependent (EC50 = 14 nM). A 5-HT3 receptor agonist CPBG (1 µM), mimicked the unmasking effects of 5-HT (n = 10 of 19 neurones), while 5-CT (10 µM), a non-selective 5-HT agonist devoid of action at 5-HT3 receptors, did not (n = 18). ICS205-930 (1 µM), a 5-HT3 receptor antagonist, completely blocked the 5-HT-induced unmasking of SP responses (n = 10 of 10 neurones).
In 68 % of the neurones tested, bath-applied 5-HT (10 µM) evoked a 178 ± 29·5 nM increase in [Ca2+]i (n = 16), which was blocked by nominally zero [Ca2+]o (n = 4) or by ICS205-930 (1 µM, n = 4). Nodose neurones incubated with 5-HT in the presence of nominally zero [Ca2+]o did not respond to SP (n = 12 of 13 neurones) in Locke solution containing normal [Ca2+]o, indicating that the 5-HT-mediated elevation of [Ca2+]i is required for unmasking of SP responses. Calmidazolium (100 nM), a calmodulin inhibitor, inhibited the unmasking effects of 5-HT (n = 5 of 5 neurones).
Incubating neurones with the nitric oxide (NO) donors papaNONOate (1 mM, 15-30 min) or SNAP (50 µM, 30-60 min) unmasked depolarizing SP responses in 71 % and 45 % of the neurones studied, respectively. L-NMMA (30 µM), a NO synthase inhibitor, blocked 5-HT-induced unmasking of SP responses (n = 10 of 10 neurones).
In sum, these results suggest that stimulation of 5-HT3 receptors activates an intracellular signalling cascade that couples calcium-calmodulin and NO activation to NK-2 receptor unmasking in sensory neurones.
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