ABSTRACT
Objective: The aim of this study was to elucidate any electrophysiological changes that may contribute to the development of neuropathic pain during treatment with the anticancer drug paclitaxel, particularly in the micro-aminobutyric acid [GABA] system
Materials and Methods: One hundred and eight Sprague-Dawley rats were used [untreated control: 43; vehicle-treated: 21, and paclitaxel-treated: 44]. Paclitaxel [8 mg/kg] was administered intraperitoneally on 2 alternate days to induce mechanical allodynia. The rats were sacrificed 7 days after treatment to obtain slices of the anterior cingulate cortex [ACC], a brain region involved in the central processing of pain. Field excitatory postsynaptic potentials [fEPSPs] were recorded in layer II/III of ACC slices, and stimulus-response curves were constructed. The observed effects were pharmacologically characterized by bath application of GABA and appropriate drugs to the slices
Results: The paclitaxel-treated rats developed mechanical allodynia [i.e. reduced withdrawal threshold to mechanical stimuli]. Slices from paclitaxel-treated rats produced a significantly higher maximal response [Emax] than those from untreated rats [p < 0.001]. Bath application of GABA [0.4 microM] reversed this effect and returned the excitability to a level similar to control. Pretreatment of the slices with the GABAB receptor blocker CGP 55845 [50 microM] increased Emax in slices from untreated rats [p < 0.01] but not from paclitaxel-treated rats
Conclusion: In this study, there was a GABA deficit in paclitaxel-treated rats compared to untreated ones. Such a deficit could contribute to the pathophysiology of paclitaxel-induced neuropathic pain [PINP]. Thus, the GABAergic system might be a potential therapeutic target for managing PINP
ABSTRACT
To study the potential of chemically modified tetracycline-3 [COL-3], a potent matrix metalloproteinase [MMP] inhibitor, to protect against the development of paclitaxel-induced painful neuropathy and its immunomodulatory effects. The reaction latency to thermal stimuli [hot plate test] of female BALB/c mice was recorded before and after treatment with paclitaxel [2 mg/kg i.p.], paclitaxel plus COL-3 [4, 20 or 40 mg/kg p.o.] or their vehicles for 5 consecutive days. Gene transcripts of CD11b [marker for microglia], 5 cytokines [IFN-gamma, IL-1 beta, IL-6, IL-10 and TNF- alpha] and 3 chemokines [CCL2, CXCL10 and CX3CL1] were quantified by real-time PCR in the brains, spinal cords and spleens of mice sacrificed on day 7 after treatment. Treatment with paclitaxel reduced the reaction latency time to thermal stimuli [thermal hyperalgesia] for 4 weeks, with maximum effect on days 7 and 10. The coadministration of paclitaxel with COL-3 40 mg/kg, but not lower doses, prevented the development of paclitaxel-induced thermal hyperalgesia. Treatment with paclitaxel alone or coadministration with COL-3 increased CD11b transcript levels in the brain but not in the spinal cord. Treatment with paclitaxel reduced IL-6 transcript levels in the spinal cord but did not alter the transcript levels of other cytokines or chemokines in the brain, spinal cord or spleen. The coadministration of COL-3 with paclitaxel significantly increased the transcript levels of IL-6 in the spleen and decreased CX3CL1 transcripts in the brain in comparison to treatment with paclitaxel alone. Our results indicate that the MMP inhibitor COL-3 protected against paclitaxel-induced thermal hyperalgesia and, thus, could be useful in the prevention of chemotherapy-induced painful neuropathy