A novel long-latency response of locus coeruleus neurons to noxious stimuli: mediation by peripheral C-fibers.

1. Extracellular recordings were obtained from single presumed noradrenergic neurons in the nucleus locus coeruleus (LC) in response to percutaneous electrical foot shock (FS) stimulation in the rat. We employed long-duration stimulus pulses to examine the possible contribution of peripheral C-fibers to evoked activity in LC. 2. As in previous studies, 0.5-ms FS stimuli produced a short-latency excitatory response (onset 20.8 ms) followed by a prolonged postactivation inhibition. However, 2.0- or 5.0-ms FS stimuli yielded an additional late excitatory response. 3. The onset and termination latency of this late excitatory response were approximately 200 and 400 ms, respectively, after the FS. The conduction velocity for this late response (peripheral plus central pathway) was estimated to be < 1.2 m/s. 4. The percentages of LC neurons that exhibited a significant late response was 4% (3/85) with 0.5-ms stimuli, 53% (31/59) with 2.0-ms stimuli, and 73% (47/64) with 5.0-ms FS stimuli. 5. The average number of spikes evoked per FS stimulus (presented at 0.5 Hz) increased from the 1st to the 21st FS stimulus. This increased response occurred selectively in the late, not in the early, response. This result was interpreted to represent a "windup" phenomenon reflected at the level of LC. 6. Direct application of capsaicin onto the sciatic nerve reduced the average magnitude of the late response of LC neurons to 17% of control 42.5 min after application. The magnitude of the short-latency response components showed little or no change. 7. Averaged compound action potential (cAP) recordings from the sciatic nerve revealed that C-fiber responses were more consistently observed and much larger with 5.0-ms compared with 0.5-ms FS stimuli. 8. C-fiber cAPs were reduced or eliminated after application of capsaicin distal to the recording site with a time course similar to that of the late response of LC neurons, with little or no effect on A-fiber cAPs. 9. These data show that a previously undescribed long-latency response of LC neurons to noxious FS stimulation in rat results from C-fiber activation in the sciatic nerve. This late response may be involved in generating descending noradrenergic analgesia induced by electrical stimulation of the foot pad or other body regions. Future studies of the pharmacology of this late response to noxious stimuli in LC may aid in developing new therapies for the treatment of acute or chronic pain.