Prostaglandins (PGs), products of cyclooxygenase (COX) enzymes, activate and sensitise articular mechanonociceptors to nociceptive stimuli (Birrell et al. 1991). Evidence suggests that there is basal release of PGs in the rat knee joint (Egan et al. 2000). The analgesic dipyrone inhibits PG production in peripheral tissues and is anti-nociceptive when administered peripherally. However, the site of action of dipyrone remains controversial. We investigated the effects of peripheral administration of dipyrone on noxious mechanically evoked responses of knee joint afferents in non-inflamed rats and rats with Freund′s Complete Adjuvant (FCA)-induced monoarthritis (100μg/100μl injected intra-articularly under brief halothane (3% in O₂) anaesthesia; n=7 each group). FCA-injected rats exhibited a significant reduction in weight bearing on ipsilateral hind-limbs (p<0.01, 1-way ANOVA), and ipsilateral knee joints were significantly swollen (p<0.01 vs contralateral, paired t test). For electrophysiological studies, rats were anaesthetised (60mg/kg pentobarbital i.p.) and the external jugular vein and trachea cannulated. Mechanically evoked responses (~170 g mechanical indent, 5 s duration every 5 min) of teased filaments of the medial articular nerve were recorded ipsilateral to either a non-inflamed joint or a FCA-inflamed joint. Once stable control evoked responses were obtained, 100μl of saline or dipyrone (50 and 100μM = 1.5 and 3μg/100μl) was injected intra-articularly, and effects on mechanically evoked responses of primary afferent C-fibres (conduction velocities = 0.7-2.4 m/s) were followed for 50-60 min. The frequency of evoked response was quantified and expressed as % of control response. Data are means ± S.E.M. Saline had no significant effect on mechanically evoked responses in non-inflamed (81 ± 13%) and inflamed (80 ± 6%) rats. However, dipyrone inhibited mechanically evoked responses in non-inflamed (50μM: 54 ± 10%; 100μM: 42 ± 12%, p<0.05 vs control, paired t test) and inflamed (50μM: 60 ± 11%; 100μM: 37 ± 10%, p<0.05 vs control, paired t test) rats. Inhibitory effects of dipyrone were similar in the two groups and were dose related. These data suggest that PGs released into the rat knee joint under basal conditions and during inflammation are involved in determining the mechanical sensitivity of C-fibre afferents. This study provides support for a peripheral site of action for dipyrone. As low concentrations of dipyrone were used, we postulate that dipyrone may inhibit mechanically evoked activity by inhibition of COX1 or an as yet unidentified COX isoform.