Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin

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Abstract
1 ATP can elicit pain in humans and, together with other P2X channel agonists, can produce nocifensive responses in rodents. We used the rat in vitro skin-nerve preparation to quantify primary afferent responses to ATP and its stable analogue α,β-methylene ATP in normal and carrageenan-inflamed skin. 2 Both ATP and α,β-methylene ATP were found to specifically activate the peripheral terminals of Aδ and C-fibre nociceptors in the skin. Thirty-nine per cent of the nociceptors tested responded to the maximal dose of α,β-methylene ATP (5 mm). In contrast, non-nociceptive, low-threshold mechano-sensitive fibres were never activated by the same agonist concentrations. 3 Amongst the nociceptor population, C-mechanoheat fibres (C-MH or polymodal nociceptors) were markedly more responsive to P2X agonists than mechanonociceptors (C-M nociceptors) with Aδ- or C-fibre axons. Both C-mechanoheat and C-mechanonociceptors were activated by α,β-methylene ATP doses as low as 50 μm. 4 In skin inflamed with carrageenan 3-4 h before recording both the number of responsive C-fibre nociceptors and their response magnitude increased. The increased neural response under inflammatory conditions was largely observed in C-mechanoheat or polymodal nociceptors. After low doses of P2X agonists C-MH fibres but not C-M fibres developed elevated ongoing activity and this effect was only seen after carrageenan inflammation. The time course of α,β-methylene ATP-evoked discharges in nociceptors was found to correlate well with the time course of behavioural nocifensive responses in rats to the same agonist described in a previous study ( Hamilton et al. 1999 ). 5 We conclude that the rapid increase in the number of α,β-methylene ATP responsive nociceptors and the increased magnitude of the neural response following carrageenan inflammation explains why very low concentrations of such agonists can cause pain in inflammatory states.