Effects Of Intrathecal Nefopam Hydrochloride And Morphine On Spinal C-fos Expression In A Rat Model Of Incisional Pain

Objective To investigate whether the interaction of nefopam and of morphine is synergistic and the spinal analgesic mechnism of them by surveying the median effective dose of antinociception and expression of c-fos in the spinal cord level after the intrathecal administration of nefopam and morphine in a rat model of incisional pain.Methods The experimentation adopted the Isobologram-analytical method what Tallarida and Murray proposed,to abstain the respective median effective analgesic doses of nefopam and morphine firstly,combinational injection 1/2,1/4,1/8,1/16 of their the respective median effective analgesic doses could get the respective median effective analgesic dose of the combination.about nefopam and morphine,then with median effective analgesic dose of the combination and median effective analgesic dose of each drugs making isobologram,to determine whether the interaction of nefopam and of morphine is synergistic.According to Yang-jianping making intrathecal tube, alternating without dyskinesia,85 male-SD-rats of verifying intrathecal tube by the dolicaine were divided randomly into five groups:control group,nefopam groups, morphine groups,nefopam-morphine groups and c-fos groups,The control group were injected intrathecally 20μl normal saline after postoperation 30 min.20 health male-SD-rats in the nefopam group were divided five dose(50μg,65.8μg,86.6μg, 113.9μg,150μg)according to the geometric proportion 1.316,carried out sequential trial,then seek the median effective dose of nefopam's antinociceptic effect in the spine,identically seeking the median effective dose in the morphine and nefopam-morphine groups using the sequential analysis,according to the method of Breunan making incisional pain model.Pain behavior was assessed at 1h after incision by cumulative pain score,the quantum-effect curve of intrathecal injection nefopam and morphine were obtained by cumulative pain score.Immunohisto-chemistry was administered to survey inhibition ratio of FLI in the c-fos groups in orde to study and research their interaction.Result①The median effective analgesic dose(median value and 95%confidence interval)of intrathecal injection nefopam(50～150μg)and morphine(3～10μg)after incisional pain were,respectively,88.5μg(80.4-97.4μg)and 5.30μg(3.81～7.37μg).The median effective analgesic dose of the combination was 10μg(8.31～12.2μg)for nefopam and 0.60μg(0.50～0.73μg)for morphine.②Cumulative pain score of 1h after incision in nefopam groups,morphine groups and nefopam—morphine groups was significantly lower than that in control group.Cumulative pain score of 1h after incision in the their combination was significantly lower than that in nefopam groups,morphine groups,both can produce dose-dependant antinociception as the result of linear correlation.③The realital value of cumulative pain score in nefopam-morphine groups leave out the theorial cumulative significantly on the Isobologram and the 95%confidence interval did not coincident with theorial cumulative spot.nefopam and morphine were synergistic according to the result of t-test(p_x=0.028;p_y=0.036).④The number of FLI(Fos like immunoreactive)of the spinal cord in control group were significantly more than those in the sham operated.In nefopam groups,morphine groups and nefopam-morphine groups the number of FLI in the spinal cord were significantly less than those in control group(P＜0.05).the number of FLI in the spinal cord in nefopam-morphine groups were significantly less than those in nefopam groups,morphine groups.Their Inhibition was at the LayerⅠ-ⅡandⅤ-Ⅵ,and the LayerⅠ-Ⅱsignificantly,Inhibition-percentage in the 1/2 the median effective dose both nefopam and morphine group was more than in the median effective dose of them alone(P＜0.05).According to the analysis methods of Berebaum,two drugs was synergistic on inhibition-percentage of Fos like immunoreactive.⑤The number of FLI were high significantly after incisional pain in the control group,and were positive linear correlation as cumulative pain score.Nefopam,Morphine,Nefopam-Morphine declined the number of FLI,and were positive linear correlation as cumulative pain score.Conclusion In a rat model of incisional pain,intrathecal injection of nefopam and morphine could create dose-response relative antinociceptic effect and inhibit the expression of c-fos gene in spinal cord relativly.Their combination could produce synergistic interaction.