RESUMO
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
RESUMO
We tested if E139, an anticonvulsant enaminone, interacts with norepinephrine [NE] to suppress population responses and chemically induced in vitro seizures in the rat hippocampus. Evoked field population spikes [PS] were recorded in the hippocampal CA1 area, and in vitro seizures were generated chemically using the zero Mg[2+]model. Low concentrations of E139 [/= 100 microM] enhanced them. For example, E139 [10 microM] depressed the PS amplitude by -23.9 +/- 2.3%, while 1 mM caused an enhancement. NE also depressed the PS by -34.5 +/- 6.0% and prevented E139 from subsequently depressing the PS amplitude. UK 14304, a selective alpha2-adrenoceptor agonist, also depressed the PS amplitude by -32.6 +/- 9.4% and occluded E139 suppression. NE suppression of PS was blocked by phentolamine and yohimbine which also blocked the effect of E139. Prazosin, a selective alpha1-adrenoceptor antagonist, did not block NE [-24.8 +/- 6.9%] or E139 [-29.7 +/- 6.1%] effects. Zero Mg[2+] buffer transformed a single PS to multiple spikes [MS; 3-8 spikes] and also induced spontaneous bursts [SB; 5-20/min]. NE suppressed the number of MS from 5.6 +/- 0.3 to 3.8 +/- 0.2. At its peak effect, E139 was able to further suppress the number of MS to 3.0 +/- 0.3. Yohimbine did not change the number of MS but blocked the NE- and E139-induced suppression of MS. SB frequency was suppressed by NE [-60.8 +/- 11.7%] which occluded E139 effects. Finally, SB were reversibly abolished by yohimbine [-94.5 +/- 11.7%]. E139 suppressed population responses and in vitro epileptiform activity by both adrenergic and non-adrenergic mechanisms