Tumour necrosis factor-alpha, a pro-inflammatory cytokine, is expressed endoneurially following a variety of local and systemic pathophysiological insults which give rise to pain. We administered tumour necrosis factor-alpha to pentobarbital-anaesthetized rats, either topically along a restricted portion of the sciatic nerve or injected subcutaneously within the distribution of the sural nerve. Single nociceptive primary afferent fibres were assessed for ectopic discharge and receptor sensitization. Low concentrations (0.001-0.01 ng/ml) of tumour necrosis factor-alpha applied along the nerve elicited a dose-dependent, rapid onset (1-3 min) increase in discharge; higher concentrations led to reduced firing rates. C-fibres developed higher mean firing frequencies than A delta-fibres. Bursting frequency in both fibre types reached several (6) Hz. No change in mechanical threshold was observed. Intradermal injection (50 pg in 50 microliters) led to ectopic discharge and a decrease in mechanical threshold; these effects developed at different rates, suggesting multiple actions of the cytokine. Our data suggest that acute application of tumour necrosis factor-alpha to the axon can lead to aberrant electrophysiologic activity independent of peripheral receptor involvement. This low level of ectopic firing of nociceptive axons may produce wind-up in dorsal horn neurons or may, by itself, be interpreted as pain.