Background: Clinically, differential block Is manifested by the loss of small fiber mediated sensation (e.g., temperature) two or more dermatomes beyond the sensory limit for large fiber mediated sensations. These observations support the belief that sensitivity to local anesthetics is inversely proportional to axon diameter, This study reports the first measurements of differential sensitivity to lidocaine in individual myelinated and unmyelinated mammalian dorsal root axons. Methods: Lumbar dorsal roots and vagus nerves were isolated from anesthetized adult rats and maintained in vitro in a perfusion/recording chamber at 37 +/- 0.3 degrees C, Using single fiber techniques, evoked action potentials in individual myelinated and unmyelinated axons were digitized and recorded for subsequent analysis, Axons were exposed to lidocaine at 150, 260, or 520 mu M. Sensitivity to local anesthetic was assessed by measuring the incidence of conduction block and the magnitude of conduction velocity slowing under steady-state conditions. Results: Data were obtained from 77 dorsal root axons and 41 vagal axons. The estimated steady-state EC(50) lidocaine concentration for myelinated dorsal root axons (232 mu M) was comparable to that for unmyelinated axons (228 mu M). Similarly, the incidence of conduction block was not significantly different among dorsal root axon groups. However, unmyelinated dorsal root axons were significantly less sensitive to the conduction velocity slowing effect of lidocaine than their myelinated counterparts (P < 0.01). The incidence of conduction block in short (mean length 13.5 mm) dorsal root axons was not significantly different from that in long (mean length 22.4 mm) axons. Compared with dorsal root axons, the estimated EC(50)s for vagal myelinated and unmyelinated axons (345 and 285 mu M, respectively), while lower were not significantly different, However, the incidence of conduction block at 260 mu M lidocaine was significantly lower (16.7% vs. 56.7%; P < 0.05) In vagal myelinated axons. Conclusions: Although no difference in sensitivity to the conduction blocking effects of lidocaine could be demonstrated among dorsal root axons, myelinated axons were more sensitive to the conduction velocity slowing effects of lidocaine, This differential effect cannot explain clinical observations of differential nerve block, Differential sensory block with lidocaine may depend on factors (e,g., physiologic function) related only indirectly to individual axon conduction velocity (diameter).