(2007b, 2008) did not find any mechano-hyperalgesia (paw pressure test) or heat hyperalgesia after a single injection of oxaliplatin. 4.7 Abnormal spontaneous discharge There was a clearly abnormal incidence of A-fibers and C-fibers with spontaneous discharge of low frequency and irregular pattern in the oxaliplatin-treated rats. taxane agent, paclitaxel. The oxaliplatin model evokes mechano-allodynia, mechano-hyperalgesia, and cold-allodynia that have a delayed onset, gradually increasing severity, a distinct delay to peak severity, and duration of about 2.5 months. There is no effect on heat sensitivity. EM analyses found no evidence for axonal degeneration in peripheral nerve and there is no up-regulation of activating transcription factor-3 in the lumbar dorsal root ganglia. There is a statistically significant loss of intraepidermal nerve fibers in the plantar hind paw skin. Oxaliplatin treatment causes a significant increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons, but not in their Schwann cells. Nerve conduction studies found significant slowing of sensory axons, but no change in motor axons. Single fiber recordings found an abnormal incidence of A- and C-fibers with irregular, low-frequency spontaneous discharge. Prophylactic dosing with two drugs that are NCT-503 known to protect mitochondria, acetyl-L-carnitine and olesoxime, significantly reduced the development of pain hypersensitivity. Our results are very similar to those obtained previously with paclitaxel and support the hypothesis that NCT-503 these two agents, and perhaps other chemotherapeutics, produce very similar conditions because they have a mitotoxic effect on primary afferent neurons. 0.05 was considered significant. 3 Results 3.1 Oxaliplatin did not affect general health or kidney function There was a cessation of weight gain during oxaliplatin treatment (Fig. 1). The normal rate of weight gain resumed afterwards, but a small, statistically significant difference from the controls persisted for the duration of the experiment. There were no changes in the appearance of the animals and there were no deaths. Indices of kidney function (Table 1) were normal in animals assessed on D7 and D35. Open in a separate window Fig. 1 Body weights for vehicle-treated and oxaliplatin-treated rats used in the behavioral time-course assays for mechano-allodynia and mechano-hyperalgesia (see next figure). Mean SEM (error bars are smaller than the symbols); n = 12/group. BL: Baseline weight on the day of the first injection. The difference between groups is statistically significant from the day of the 4th injection onwards (two-way ANOVA followed by Bonferroni-corrected 0.05, 0.01 (repeated measures ANOVA with Dunnetts test for pair-wise comparisons to pre-injection baseline). There were no significant variations over time for the vehicle-treated groups in A, B, and D. However, the vehicle-treated group in C had a small NCT-503 but statistically significant increase in sensitivity to cold; the reason for this is not known. Nevertheless, the oxaliplatin-treated group was significantly more sensitive in comparison to the vehicle-treated group (Bonferroni-corrected 0.05 (and terminal receptor boutons. (D) Sections from the L5 DRG from a rat with an ipsilateral sciatic nerve transection (left) and from an oxaliplatin-treated rat (right). ATF-3-positive nuclei are stained red, Nissl substance is stained green. Scale bar = 30 m. No ATF-3-positive DRG cells were found in oxaliplatin-treated rats. 3.4 Oxaliplatin causes a partial loss of intraepidermal nerve fibers (IENFs) Vehicle-injected control animals had 338 24.1 (mean SEM) IENFs per cm of epidermal border. Oxaliplatin-treated rats had 273.6 26.1 IENFs per cm. This is a statistically significant decrease of 21% (Fig. NCT-503 3C). 3.5 Oxaliplatin did not induce ATF-3 in DRG neurons As expected, about 50% of the large and small neurons had ATF-3-positive nuclei in the DRG of the sciatic nerve transection rat (this is the percentage of L4CL5 cells cdc14 whose axons travel in the sciatic nerve). We did not find a single ATF-3-positive DRG cell nucleus in the L4CL5 DRGs of the oxaliplatin-treated rats (Fig. 3D). 3.6 Oxaliplatin treatment had no NCT-503 effect on motor nerve conduction velocity (MNCV) but slowed sensory nerve conduction velocity (SNCV) The MNCV in the vehicle-treated and oxaliplatin-treated rats were not significantly different (mean SEM): 49.8 2.3 m/s 0.05 relative to control ( 0.01 ( 0.001 ( 0.001 ( em t /em -test). 4 Discussion 4.1 Comparison to the clinic Our observations indicate that the oxaliplatin treatment protocol used here in the rat produces a chronic painful peripheral neuropathy like that seen in.