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

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 alpha,beta-methylene ATP in normal and carrageenan-inflamed skin. 2. Both ATP and alpha,beta-methylene ATP were found to specifically activate the peripheral terminals of Adelta and C-fibre nociceptors in the skin. Thirty-nine per cent of the nociceptors tested responded to the maximal dose of alpha,beta-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 Adelta- or C-fibre axons. Both C-mechanoheat and C-mechanonociceptors were activated by alpha,beta-methylene ATP doses as low as 50 microM. 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 alpha,beta-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 alpha,beta-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.