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

• Published in: The Journal of physiology Vol. 534; no. 2; pp. 437 - 445
• Main Authors: Hamilton, Sara G., McMahon, Stephen B., Lewin, Gary R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.07.2001; Blackwell Science Ltd; Blackwell Science Inc
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Animals; Carrageenan; Dermatitis - physiopathology; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Male; Nociceptors - drug effects; Nociceptors - physiology; Original; Pain - physiopathology; Purinergic P2 Receptor Agonists; Rats; Rats, Wistar; Receptors, Purinergic P2 - physiology; Skin - innervation; Skin - physiopathology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.2001.00437.x

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. 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 m m ). In contrast, non-nociceptive, low-threshold mechano-sensitive fibres were never activated by the same agonist concentrations. 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 μ m . 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 ). 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.