Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells.

Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.

Sciatic nerve block with resiniferatoxin: an electron microscopic study of unmyelinated fibers in the rat.

BACKGROUND: Perineural administration of the naturally occurring vanilloids (capsaicin, resiniferatoxin [RTX]) produces selective nociceptive blockade. Studies using perineural vanilloids in high concentrations suggest that they can cause a degeneration of unmyelinated fibers. However, electron microscopic studies of local vanilloid toxicity produced conflicting outcomes. In the present study, we sought to determine whether RTX-induced reversible sciatic nerve block results in the degenerative changes of unmyelinated fibers. METHODS: In rat experiments, RTX was administered percutaneously at the sciatic nerve. The effect of RTX was monitored by measuring the rat's response to noxious heat. The sciatic nerves were removed 48 h after the blockade initiation. Quantitative electron microscopic evaluation of the unmyelinated fibers was performed in three groups of animals: RTX 0.0001% (0.1 microg), RTX 0.001% (1 microg), and control (RTX vehicle, 0.1 mL). RESULTS: Cross-sections of the sciatic nerve 48 h after the initiation of RTX-induced reversible nerve blockade appeared essentially normal. One rarely observed finding was the irregularly compacted membranous deposits in the unmyelinated axons. The frequency of this finding was approximately one per thousand fibers with both concentrations of RTX. CONCLUSIONS: The results of the study suggest that a selective and long-lasting sciatic nerve block (up to 2 wk) can be provided by RTX without any significant damage to the unmyelinated nerve fibers.