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

1. ATP can elicit pain in humans and, together with other P2X channel agoni sts, can produce nocifensive responses in rodents. We used the rat in vitro skin-nerve preparation to quantify primary afferent responses to ATP and i ts stable analogue alpha,beta -methylene ATP in normal and carrageenan-infl amed skin. 2. Both ATP and alpha,beta -methylene ATP were found to specifically activa te the peripheral terminals of A delta and C-fibre, nociceptors in the skin . Thirty-nine per cent of the nociceptors tested responded to the maximal d ose of alpha,beta -methylene ATP (5 nam). In contrast, non-nociceptive, low -threshold mechano-sensitive fibres were never activated by the same agonis t concentrations. 3. Amongst the nociceptor population, C-mechanoheat fibres (C-MH or polymod al nociceptors) were markedly more responsive to P2X agonists than mechanon ociceptors (C-M nociceptors) with A delta- or C-fibre axons. Both C-mechano heat and C-mechanonociceptors were activated by alpha,beta -methylene ATP d oses as low as 50 muM. 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 obs erved in C-mechanoheat or polymodal nociceptors. After low doses of P2X ago nists C-MH fibres but not C-M fibres developed elevated ongoing activity an d 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 i n rats to the same agonist described in a previous study (Hamilton et al. 1 999). 5. We conclude that the rapid increase in the number of alpha,beta -methyle ne ATP responsive nociceptors and the increased magnitude of the neural res ponse following carrageenan inflammation explains why very low concentratio ns of such agonists can cause pain in inflammatory states.