ACUTE NOCICEPTION MEDIATED BY HINDPAW P2X RECEPTOR ACTIVATION IN THE RAT

1 The functional consequences of P2X receptor activation on peripheral sensory neurones have been investigated in vivo. Behavioural indices of acute nociception were monitored in the conscious rat following sub plantar injection of adenosine 5'-triphosphate (ATP), alpha,beta-methy lene ATP, adenosine 5'-diphosphate (ADP) and adenosine. 2 Signs of ove rt nociception, i.e. hindpaw lifting and licking, were apparent in ani mals injected subplantar with the P2X receptor agonist, alpha,beta-met hylene ATP. Nociceptive behaviours continued for 15 min following admi nistration of alpha,beta-methylene ATP (200 nmol) and were dose-relate d (0-5 min hindpaw lifting times after injection of alpha,beta-methyle ne ATP 100 nmol and 1000 nmol were 89 +/- 26 s and 232 +/- 11 s, respe ctively). Subplantar ATP evoked a modest response only at the highest dose tested (1000 nmol; 0-5 min hindpaw lifting time 66 +/- 19 s) whil st ADP or adenosine (both 600 nmol) elicited negligible spontaneous no ciceptive activity. 3 Morphine (3 mg kg(-1), i.v.) abolished hindpaw l icking behaviour induced by subplantar injection of either alpha,beta- methylene ATP (600 nmol) or bradykinin (1 nmol) and substantially redu ced (88 +/- 5%) paw licking in formalin (0.5%, 0.1 ml) injected animal s. In contrast, hindpaw lifting was only modestly inhibited (34 +/- 11 %) in morphine-pretreated animals that had received subplantar bradyki nin and was unaffected in rats in which the noxious stimulus was eithe r subplantar alpha,beta-methylene ATP or formalin. Pretreatment of hin dpaws with subplantar bupivacaine (1% w/v, 0.1 ml) abolished alpha,bet a-methylene ATP-evoked nociceptive behaviours. 4 Hindpaw lifting and l icking mediated by alpha,beta-methylene ATP (600 nmol, subplantar) wer e inhibited (72 +/- 15% and 95 +/- 5%, respectively) by 30 min local p retreatment with 600 nmol alpha,beta-methylene ATP. Subplantar alpha,b eta-methylene ATP pretreatment did not inhibit behaviour stimulated by subsequent bradykinin (1 nmol) or formalin (0.5%, 0.1 ml) injection i nto the hindpaw. 5 Desensitization of small diameter sensory neurones with a single subplantar injection of capsaicin (100 mu g) abolished a ll behaviours indicative of spontaneous nociceptive sensation in anima ls subsequently injected with alpha,beta-methylene ATP (600 nmol), bra dykinin (1 nmol) or formalin (0.5%, 0.1 ml). 6 We conclude that activa tion of P2X receptors present on small diameter (capsaicin-sensitive) primary afferent neurones in the rat hindpaw mediates behaviour indica tive of acute nociception.