| As a common clinical symptom, pain is involved in complex of physiological and psychological activities. As a warning signal, pain can help our body keep away from harm stimuli. However, excessive or persistent pain exert a vicious impact to patients. The pain signal transmitted from body skin and related tissue nociceptors can be converted into electrical nerve impulses. Subsequently, these impulses are transmitted through afferent nerve fibers, dorsal root ganglia, t he spinal cord or trigeminal nucleus neurons to the thalamus, and finally reach the cerebral cortex and other brain areas. The gate control theory of pain indicates that certain neurons act as pain controlling gate, and these neurons themselves are controlled by afferent fibers and the central nervous system in SG of spinal dorsal horn. Gate opening and closing is subject to different types of afferent fibers, which inhibitory SG neurons would lost the inhibition of uplink cells, leading to the “gate open”. The others excite SG neurons, so that the gate is “closed”. While the gate activity is also affected by the central system controlling. Thus, spinal SG is a candidate site for the development of new analgesic drugs. With the continuous development of human medical research,holistic integrated medicine was proposed in this new period rather than previous traditional medicine, that is to say, integrate different areas of medicine will make a quite advanced medical discovery.Rufinamide,the triazole derivatives, was applied into clinic in 2008 after the US FDA approbation and was mainly used in adjunctive treatment of 4 years or older children and adults with seizures attributed to Lennox-Gastant syndrome(LGS). In recent years, with more research of epilepsy and pain mechanisms, potential analgesic effect of rufinamide was proposed. However, the effects of rufinamide on superficial spinal dorsal horn neurons and the synaptic transmission are still unclear. The main subject of this art icle is to evaluate the effects of rufinamide on SG neurons, as well as the impact on synaptic transmission by using whole-cell patch clamp recordings.Experiment one: The analgesic effect of rufinamide on SNL neuropathic pain model.Objective: To observe the analgesic effect of rufinamide on SNL model.Methods: 180~220g SD rats were used. Mechanical paw withdrawal threshold(PWMT) and thermal withdraw latency(TWL) were measured before the SNL model. The successful models were divided into three groups:(1) High-dose experimental group: 50 mg/kg rufinamide dissolved with 1% DMSO and diluted with saline to 1ml, single intraperitoneal injection.(2) Low doses of the experimental group: 25 mg/kg rufinamide dissolved with 1% DMSO diluted with saline to 1ml, single intraperitoneal injection.(3) Control group: the s ame volume of 1% DMSO without rufinamide, single intraperitoneal injection. Pain behavior were assessed at 20 min, 40 min, 60 min, 4h, 12 h, 24 h after injection.Results: Rufinamide can effectively alleviate neuropathic pain caused by nerve ligation in a dose-dependent manner.(P<0.05, compared to corresponding control).Experiment two: The effects of rufinamide on the excitability of SG neurons.Objective: To examine the effects of rufinamide on action potential(AP) of SGMethods: 4-5 week-old male SD rats were chosen, and sagittal lumbosacral slices(400-500μm thick) with reserved dorsal root(0.5cm length) was made under deep anesthesia. In whole-cell recording, voltage-clamp was obtained from an SG neuron. The holding current was 0 p A. AP frequency of SG neurons was challenged by bath perfusion of rufinamide.Results: Rufinamide significantly suppresses the frequency of the action potential in SG neurons(P<0.01, paired t-test). The inhibitory effect can be reversed after washout.(P<0.01, paired t-test).Experiment three: The effects of rufinamide on nociceptive primary afferent mediated synaptic transmission in spinal SG.Objective: To examine the effects of rufinamide on Aδ and C fiber mediated excitatory postsynaptic currents(e EPSCs).Methods: The preparation of spinal cord slices and whole cell recordings were performed as described in experiment two. The membrane potential was held at-70 m V. The segmental dorsal root was stimulated by a duction electrode. Graded stimulation was applied. Bath applied rufinamide was used to test its effects on Aδ and C fiber mediated e EPSCs. The effects of rufinamide on s EPSCs were also tested.Results:(1) Single perfusion of 200 μM rufinamide had little effect, if any, on Aδ fiber mediated e EPSCs(P>0.05, paired t-test).(2) Amplitude of monosynaptic e EPSCs dominated by C fibers was significantly inhibited after rufinamide perfusion(P<0.01, one-way AVOVA).(3)The frequency of s EPSCs in SG neurons was decreased by the superfusion of rufinamide, while the amplitude of s EPSCs was not affected.Conclusions:1. Rufinamide effectively alleviates neuropathic pain caused by nerve injury in a dose-dependent manner. 2. Rufinamide decreases the action potential firing frequency in spinal cord dorsal horn neurons. 3. Rufinamide attenuates the peak amplitude of monosynaptic e EPSCs mediated by primary C fibers, but had little effect, if any, on Aδ fiber mediated e EPSCs. |
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