Newborn with Giant Non-Involuting Congenital Hemangioma: Mechanisms of Allodynia, Hyperalgesia and Treatment

In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale which rates pain intensity. The baby presented signs of these pathological events over long periods of the disease. They may be attributed to the high amount of the nociceptive ligands in the hemangioma microenviroment and to the elevated concentration of TNF-alpha and IL-6 in the blood. For a long time, the pain was relieved by a combination of opioids, adjuvants and paracetamol, but also by thalidomide and unexpectedly by interferon alpha. A mechanism-based pain treatment needs to take into account the processes underlying pain and also the ongoing pathology.

不同剂量艾司氯胺酮对瑞芬太尼持续输注诱发痛觉过敏的影响

目的探讨不同剂量艾司氯胺酮对瑞芬太尼持续输注诱发术后痛觉过敏的影响。方法选取需在全身麻醉下行腹腔镜子宫全切手术患者90例,采用随机数字表法将其随机分为三组:艾司氯胺酮0.5 mg/kg组(H组)、艾司氯胺酮0.3 mg/kg组(L组)和对照组(C组),每组30例。H组和L组于麻醉诱导前5 min分别静脉注射相应剂量艾司氯胺酮,C组给予等容量生理盐水。分别于术前1 d、术后30 min、6 h、12 h、24 h记录切口周围区域以及非优势手前臂内侧痛阈值。分别于术后30 min、6 h、12 h和24 h记录术后痛觉过敏发生率、视觉模拟评分法(VAS)疼痛评分。记录术后不良反应发生率和补救镇痛率。结果在术后30 min、6 h和12 h C组切口周围和非优势手前臂痛阈均低于术前基线值(P<0.05),H组和L组与术前基线值比较差异无统计学意义(P>0.05);在术后30 min、6 h、12 h H组和L组切口周围和非优势手前臂痛阈均高于C组(P<0.05);术后24 h三组患者切口周围和非优势手前臂痛阈比较,差异无统计学意义(P>0.05)。术后30 min、6 h、12 h H组和L组切口周围和非优势手前臂痛觉过敏发生率均低于C组(P<0.05);H组和L组痛觉过敏发生率比较,差异无统计学意义(P>0.05)。H组和L组术后6 h、12 h VAS评分均低于C组(P<0.05)。H组谵妄幻觉和腺体分泌物发生率高于C组和L组(P<0.05)。C组补救镇痛率高于H组和L组(P<0.05)。结论麻醉诱导时静脉注射艾司氯胺酮0.5 mg/kg或0.3 mg/kg对瑞芬太尼的痛觉过敏有一定的预防作用,其中0.3 mg/kg艾司氯胺酮不良反应发生率更低。

不同剂量艾司氯胺酮预防瑞芬太尼诱发术后痛觉过敏的作用

目的探讨不同剂量艾司氯胺酮预防瑞芬太尼诱发术后痛觉过敏的作用。方法选择妇科择期全身麻醉下行腹腔镜手术病人120例,随机分为对照组(C组)、艾司氯胺酮低剂量组(L组)和艾司氯胺酮高剂量组(H组),每组40例。麻醉诱导前5 min,L组静脉注射艾司氯胺酮0.25 mg/kg,H组静脉注射艾司氯胺酮0.50 mg/kg,C组静脉注射等容量生理盐水。对3组机械痛阈、视觉模拟评分法(VAS)评分等指标进行比较。结果与C组和L组比较,H组睁眼时间、拔管时间延长(F=64.697、68.195,P<0.05)。与C组比较,L组和H组术后2、18 h时非优势手前臂和手术切口周围机械痛阈显著升高(F=80.458~387.248,P<0.05)。与术前1 d时比较,C组术后2、18 h时非优势手前臂和手术切口周围机械痛阈显著降低(F=2615.864,P<0.05)。与C组比较,L组和H组术后2、18 h时VAS评分显著降低(H=53.736、42.971,P<0.05)。3组术中瑞芬太尼用量、手术时间、术后补救镇痛率和不良反应发生率比较差异无统计学意义(P>0.05)。结论麻醉诱导前静脉注射艾司氯胺酮可减轻瑞芬太尼诱发的术后痛觉过敏,应用艾司氯胺酮0.25 mg/kg较应用0.50 mg/kg病人睁眼时间、拔管时间更短。

纳布啡联合菱形肌-肋间肌阻滞抑制电视胸腔镜肺叶切除术后急性痛觉过敏的效果

目的探讨纳布啡联合菱形肌-肋间肌阻滞(RIB)抑制电视胸腔镜肺叶切除术后急性痛觉过敏的效果。方法前瞻性选择2021年2月至2023年3月在汉中市中心医院接受电视胸腔镜肺叶切除术的非小细胞肺癌患者96例,按照随机数字表法分为A、B、C组,各32例。A组男18例,女14例,年龄(64.25±7.41)岁;B组男20例,女12例,年龄(64.89±7.56)岁;C组男16例,女16例,年龄(65.18±7.20)岁。C组麻醉诱导前于超声引导下行菱形肌-肋间肌阻滞;麻醉诱导前3 min,A组静脉注射2 ml生理盐水,B、C组静脉注射2 ml纳布啡。对比3组术中用药情况、术后恢复、疼痛情况、机械痛阈值、应激反应、免疫功能、血流动力学、不良反应与并发症。采用单因素方差分析、重复测量方差分析、LSD-t检验、χ^(2)检验。结果C组丙泊酚用量、瑞芬太尼用量、补救镇痛率、血管活性药物使用率均低于A组、B组,且B组均低于A组(均P<0.05)。3组术后住院时间、术后首次下地时间、术后首次进食时间、并发症与不良反应总发生率比较差异均无统计学意义(均P>0.05)。3组切口周围、前臂内侧机械痛阈值:术后6 h、48 h均低于同组术前,术后48 h均高于同组术后6 h(均P<0.05);C组术后6 h、48 h均高于A组、B组[(76.25±7.03)g比(41.31±5.22)g、(58.06±6.10)g,(81.19±8.24)g比(63.44±6.38)g、(76.30±7.21)g,(85.39±7.01)g比(72.06±5.23)g、(79.24±6.15)g,(95.07±8.36)g比(79.43±6.28)g、(87.31±7.12)g],B组术后6 h、48 h均高于A组,差异均有统计学意义(均P<0.05)。3组VAS评分:术后48 h均低于同组术后1 h、6 h,术后6 h均低于同组术后1 h(均P<0.05);C组术后1 h、6 h、48 h均低于A组、B组,且B组均低于A组(均P<0.05)。术后24 h,3组血清皮质醇、促肾上腺皮质激素、去甲肾上腺素水平均较同组术前升高,且C组均低于A组、B组,B组均低于A组(均P<0.05)。术后24 h,3组CD3+、CD4+水平均较同组术前降低,C组均高于A组、B组,B组均高于A组(均P<0.05)。3组心率、平均动脉压:麻醉结束时(T2)均比麻醉诱导后5 min(T1)低、比麻醉诱导前5 min(T0)高,且3组T1时刻均高于T0时刻(均P<0.05);T1、T2时刻C组均低于A组、B组,B组均低于A组(均P<0.05)。结论纳布啡联合RIB可抑制电视胸腔镜肺叶切除术患者的术后急性痛觉过敏,改善免疫功能,降低术中麻醉药物用量,减轻术后疼痛与应激反应,维持血流动力学稳定,且安全可靠。

艾司氯胺酮对全麻剖宫产患者术后痛觉过敏的效果

目的 探讨s全麻剖宫产患者应用艾司氯胺酮对其术后痛觉过敏的作用效果,以期为全麻剖宫产患者提供有效的干预方案。方法 选择2021年1月至2023年12月收治的全麻剖宫产患者82例,以单双数字法将其分为试验组和对照组,每组41例。2组均开展全麻剖宫产,试验组于硬膜外阻滞完成后静脉注射少量的艾司氯胺酮;对照组于硬膜外阻滞完成后静脉注射等量的0.9%氯化钠溶液。对比2组前臂、切口周围痛阈,苏醒时间、拔管时间、镇痛药用量以及按压次数,不良反应。结果 试验组术后6 h、12 h以及24 h时的前臂周围痛阈高于对照组(均P<0.05)。试验组术后6 h、12 h以及24 h时的切口周围痛阈高于对照组(均P<0.05)。试验组镇痛药用量以及按压次数低于对照组(均P<0.05)。2组恶心呕吐、头晕以及瘙痒发生率差异无统计学意义(P>0.05)。结论 全麻剖宫产患者应用艾司氯胺酮可显著改善术后痛觉过敏情况,且不会增加不良反应发生风险,值得推广应用。

艾司氯胺酮对瑞芬太尼痛觉过敏影响的临床观察

目的观察术前应用小剂量艾司氯胺酮对瑞芬太尼所致痛觉过敏的影响。方法选取大连市第三人民医院2021-06/2022-12期间择期行甲状腺切除术的患者100例,采用随机数字表法将患者分为艾司氯胺酮组(A组,n=50)和空白对照组(B组,n=50),ASA分级Ⅰ或Ⅱ级,年龄21~69岁,BMI 18~28 kg/m^(2),手术时间60 min。开放上肢静脉通路,缓慢静脉注射咪达唑仑0.03 mg/kg,舒芬太尼0.4μg/kg,依托咪酯0.2 mg/kg,罗库溴铵0.6 mg/kg,A组注射艾司氯胺酮0.3 mg/kg,B组注射等容积生理盐水。采用静吸复合麻醉,七氟醚1%,持续泵注丙泊酚2 mg/(kg·h),瑞芬太尼0.1μg/(kg·min),间断追加罗库溴铵,术毕停药。术前测量患者非优势手前臂和手术切口处皮肤的机械痛阈值,由麻醉护士记录术后2、4、8、12、24 h VAS评分。记录2组患者头晕(患者自述)、定向力(正确)、计算能力(正确)、复视、梦幻、谵妄等精神症状的发生情况。结果与B组比较,A组术后非优势手前臂和手术切口处皮肤的机械痛阈值具有统计学意义(P<0.05),2组患者术后(2、4、8、12、24 h)VAS评分比较均无统计学意义(P>0.05),2组患者围麻醉期精神症状(头晕、定向力、计算能力、复视、梦幻、谵妄)的比较均无统计学意义(P>0.05)。结论术前应用小剂量艾司氯胺酮(0.3 mg/kg)能够很好的抑制瑞芬太尼的痛觉过敏,改善患者苏醒期质量,提高了围术期患者满意度。

基底外侧杏仁核小胶质细胞参与单关节炎小鼠痛觉敏化和痛相关厌恶行为

目的研究基底外侧杏仁核(basolateral amygdala,BLA)小胶质细胞对小鼠膝关节单关节炎诱导的痛觉敏化与痛相关负性情绪的影响。方法61只小鼠用于行为学测试(对照组14只,模型组47只),6只小鼠用于形态学实验(对照组与模型组各3只)。通过向小鼠膝关节腔注射完全弗氏佐剂(complete Freund’s adjuvant,CFA)建立膝关节单关节炎动物模型。采用von Frey test和Hargreaves test分别测试小鼠的机械痛阈和热痛阈,用于评估小鼠的痛觉敏化。采用条件位置回避装置检测小鼠的痛相关厌恶行为,采用旷场和高架十字迷宫测试小鼠痛相关焦虑样行为。通过免疫荧光染色与Imaris软件对BLA脑区小胶质细胞进行3D重构,进而评估CFA造模后BLA脑区小胶质细胞的形态学变化。结果与对照组相比,CFA造模后小鼠术侧产生显著的机械触诱发痛与热痛觉敏化,并至少持续12和19天。CFA造模能够引起小鼠产生痛相关厌恶行为和焦虑样行为,并伴随BLA小胶质细胞的显著激活。抑制BLA小胶质细胞激活能够缓解CFA造模引起的痛觉敏化和痛相关厌恶行为,但对焦虑样行为无显著影响。结论小鼠膝关节注射CFA能够引发痛觉敏化、痛相关厌恶行为以及焦虑样行为,其中痛觉敏化和痛相关厌恶行为可能与BLA脑区小胶质细胞的激活相关。

妇科腹腔镜手术中应用艾司氯胺酮对患者术后痛觉过敏的影响

目的:探讨妇科腹腔镜手术应用艾司氯胺酮对患者手术指标、疼痛情况、痛敏阈值、痛敏面积、舒芬太尼用量和安全性的影响。方法:选取本院2022年9月-2023年12月拟全身麻醉下行腹腔镜子宫病损切除术或腹腔镜卵巢病损切除术患者94例,随机数字表法分为常规组和观察组各47例,麻醉诱导前观察组注射艾司氯胺酮,常规组注射等量生理盐水。对比两组手术指标、术前术后静态和动态疼痛情况、术后切口和臂内侧的机械痛敏阈值、机械痛敏面积、术后舒芬太尼用量、不良反应。结果:观察组睁眼时间(12.11±1.38 min)和气管导管拔除时间(14.89±2.46 min)均低于常规组(13.24±1.69 min、16.03±2.51 min),术后静态和动态视觉模拟评分(1.57±0.87分、2.06±1.04分)均低于常规组(2.23±1.09分、2.74±1.18分),术后切口和臂内侧的机械痛敏阈值(52.03±8.29g、54.87±8.34g)高于观察组(40.56±7.62g、43.55±7.68g),切口和臂内侧机械痛敏面积(52.36±6.55 cm^(2)、50.21±6.94 cm^(2))低于常规对照组(64.18±7.69 cm^(2)、63.42±7.58 cm^(2)),舒芬太尼麻醉恢复室给药(17.16±2.31μg)、离开6h用量(19.24±3.10μg)和18h用量(16.13±2.57μg)均低于观察组(19.54±3.14μg、22.79±3.58μg、16.13±2.57μg),不良反应发生率(12.8%)低于常规组(34.0%)(均P<0.05)。结论:妇科腔镜手术中应用艾司氯胺酮可有效抑制患者术后痛觉过敏,改善手术恢复指标,不良反应降低,安全性较好。

地佐辛靶向TLR4/NF-κB信号通路减轻瑞芬太尼诱导的痛觉过敏机制研究

目的探讨地佐辛对瑞芬太尼诱导的痛觉过敏的影响及机制。方法将40只健康雄性SD大鼠,随机分为对照组(C组)、切口痛组(I组)、瑞芬太尼输注+切口痛组(R+I组)、瑞芬太尼联合地佐辛输注+切口痛组(R+D+I组),每组10只。其中,C组不做任何处理。R+I组和R+D+I组于造模前静脉输注瑞芬太尼,I组输注等量0.9%氯化钠溶液。随后,基于左后足底切口术对I组、R+I组和R+D+I组大鼠建立切口痛模型。R+D+I组大鼠在瑞芬太尼输注前通过尾静脉注射给予地佐辛预处理。采用痛觉行为学实验评估大鼠在术前和术后不同时间点的机械缩足反应阈(paw withdrawal threshold,PWT)和热缩足反应潜伏期(paw withdrawal latency,PWL);酶联免疫吸附(enzyme-linked immunosorbent assay,ELISA)检测4组大鼠脊髓背角相关炎性因子肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)及IL-10的表达水平;实时荧光定量PCR(quantitative real-time PCR,qRT-PCR)检测4组大鼠脊髓背角TLR4、NF-κB和TRPA1的mRNA表达水平;Western blot检测组大鼠脊髓背角TLR4、NF-κB和TRPA1的蛋白表达水平。结果成功构建瑞芬太尼诱导的大鼠术后痛觉过敏模型,与C组比较,I组在术后PWT值和PWL值均显著降低,脊髓背角促炎因子TNF-α、和IL-1β表达升高,而抗炎因子IL-10表达降低,TLR4、NF-κB、TRPA1蛋白和mRNA水平均明显增加(P<0.05);与I组比较,R+I组在术后PWT值和PWL值均明显下降,脊髓背角促炎因子TNF-α、和IL-1β表达升高,而抗炎因子IL-10表达降低以及TLR4、NF-κB、TRPA1蛋白和mRNA水平均明显增加(P<0.05);与R+I组比,R+D+I组在术后PWT值和PWL值均明显升高,脊髓背角促炎因子TNF-α、和IL-1β表达降低,而抗炎因子IL-10表达升高以及TLR4、NF-κB、TRPA1蛋白和mRNA水平均明显降低(P<0.05)。结论地佐辛通过抑制TLR4/NF-κB信号通路,下调TRPA1蛋白和mRNA表达,减少脊髓背角炎症,达到减轻瑞芬太尼诱导的术后痛觉过敏的效果。

Analgesic action of suspended moxibustion in rats with chronic visceral hyperalgesia correlates with enkephalins in the spinal cord

Rats that modeled chronic visceral hyperalgesia received suspended moxibustion at bilateral Tianshu （ST25） and Shangjuxu （ST37） once daily over a period of 7 days. Results show that suspended moxibustion significantly depressed abdominal withdrawal reflex scores and increased enkephalin concentration in the spinal cord. The experimental findings suggest that spinal enkephalins contributed to the analgesic effect of suspended moxibustion in rats with chronic visceral hyperalgesia.

Mild moxibustion at Tianshu (ST 25) decreases expression of prokineticin-1 and prokineticin receptor-1 in colon tissue of rats with chronic visceral hyperalgesia

Prokineticin-1 and prokineticin receptor-1 play important roles in visceral hypersensitivity and in-flammatory pain. Visceral hypersensitivity is closely associated with irritable bowel syndrome. Mild moxibustion can relieve chronic visceral hyperalgesia in rats with irritable bowel syndrome. We hypothesized that prokineticin-1 and prokineticin receptor-1 is the key target in the mechanism. This study established chronic visceral hyperalgesia rat models by colorectal distention. Protein and mRNA expression of prokineticin-1 and prokineticin receptor-1 were determined by immunohisto-chemical method and fluorescence quantitative-PCR, respectively, and were found to be signifi-cantly increased in visceral hyperalgesic rats. Mild moxibustion at Tianshu （ST 25） decreased prokineticin-1 and prokineticin receptor-1 expression in chronic visceral hyperalgesia rats and lessen the chronic visceral hyperalgesia in rats with irritable bowel syndrome at different levels of colorectal distention pressure.

Shugan-decoction relieves visceral hyperalgesia and reduces TRPV1 and SP colon expression

AIM:To evaluate the therapeutic effect of Shugan-decoction(SGD)on visceral hyperalgesia and colon gene expressions using a rat model.METHODS:Ninety-six adult male Wistar rats were randomized into six equal groups for assessment of SGD effects on psychological stress-induced changes using the classic water avoidance stress(WAS)test.Untreated model rats were exposed to chronic(1 h/d for 10 d consecutive)WAS conditions;experimental treatment model rats were administered with intragastric SGD at1 h before WAS on consecutive days 4-10(low-dose:0.1g/mL;mid-dose:0.2 g/mL;high-dose:0.4 g/mL);control treatment model rats were similarly administered with the irritable bowel syndrome drug,dicetel(0.0042g/mL);untreated normal control rats received no drug and were not subjected to the WAS test.At the end of the 10-d WAS testing period,a semi-quantitative measurement of visceral sensitivity was made by assessing the abdominal withdrawal reflex(AWR)to colorectal balloon-induced distension(at 5 mmHg increments)to determine the pain pressure threshold(PPT,evidenced by pain behavior).Subsequently,the animals were sacrificed and colonic tissues collected for assessment of changes in expressions of proteins related to visceral hypersensitivity(transient receptor potential vanilloid 1,TRPV1)and sustained visceral hyperalgesia(substance P,SP)by immunohistochemistry and real-time polymerase chain reaction.Inter-group differences were assessed by paired t test or repeated measures analysis of variance.RESULTS:The WAS test successfully induced visceral hypersensitivity,as evidenced by a significantly reduced AWR pressure in the untreated model group as compared to the untreated normal control group(190.4±3.48 mmHg vs 224.0±4.99 mmHg,P<0.001).SGD treatments at mid-dose and high-dose and the dicetel treatment significantly increased the WAS-reduced PPT(212.5±2.54,216.5±3.50 and 217.7±2.83 mmHg respectively,all P<0.001);however,the low-dose SGD treatment produced no significant effect on the WAS-reduced PPT(198.3±1.78 mmHg,P>0.05).These trends corresponded to the differential expressions observed for both TRPV1 protein(mid-dose:1.64±0.08 and high-dose:1.69±0.12 vs untreated model:3.65±0.32,P<0.001)and mRNA(0.44±0.16 and0.15±0.03 vs 1.39±0.15,P<0.001)and SP protein(0.99±0.20 and 1.03±0.23 vs 2.03±0.12,P<0.01)and mRNA(1.64±0.19 and 1.32±0.14 vs 2.60±0.33,P<0.05).These differential expressions of TRPV1 and SP related to mid-and high-dose SGD treatments were statistically similar to the changes induced by dicetel treatment.No signs of overt damage to the rat system were observed for any of the SGD dosages.CONCLUSION:Shugan-decoction can reduce chronic stress-induced visceral hypersensitivity in rats,and the regulatory mechanism may involve mediating the expressions of TRPV1 and SP in colon tissues.

Puerarin ameliorates allodynia and hyperalgesia in rats with peripheral nerve injury

Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.

Mechanism of persistent hyperalgesia in neuropathic pain caused by chronic constriction injury

Transmembrane member 16 A(TMEM16 A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16 A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16 A selective antagonist(10 μg T16 Ainh-A01) was intrathecally injected at L5–6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days,once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16 A expression in the L4–6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16 A in the L4–6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4–6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats.Additionally, TMEM16 A expression and the number of TMEM16 A positive cells in the L4–6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4–6 dorsal root ganglion. These findings were inhibited by T16 Ainh-A01 and confirm that TMEM16 A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16 A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China(approval No. A2017-170-01) on February 27, 2017.

Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3

Orthodontic tooth movement elicits alveolar bone remodeling and orofacial pain that is manifested by tooth mechanical hyperalgesia.Nerve growth factor(NGF)is upregulated in periodontium and may modulate tooth mechanical hyperalgesia.The objectives were to examine the role of NGF in tooth mechanical hyperalgesia and to elucidate the underlying mechanisms.Tooth mechanical hyperalgesia was induced by ligating closed coil springs between incisors and molars in Sprague–Dawley rats.Retrograde labeling was performed by periodontal administration of fluor-conjugated NGF and the detection of fluorescence in trigeminal ganglia(TG).Lentivirus vectors carrying NGF shRNA were employed to knockdown the expression of NGF in TG.The administration of agonists,antagonists,and virus vectors into TG and periodontium was conducted.Tooth mechanical hyperalgesia was examined through the threshold of biting withdrawal.Our results revealed that tooth movement elicited tooth mechanical hyperalgesia that could be alleviated by NGF neutralizing antibody and that NGF was upregulated in periodontium(mainly in periodontal fibroblasts)and TG.Retrograde labeling revealed that periodontal NGF was retrogradely transported to TG after day 1.Acid-sensing ion channel 3(ASIC3)and NGF were co-expressed in trigeminal neurons and the percentage of co-expression was significantly higher following tooth movement.The administration of NGF and NGF neutralizing antibody into TG could upregulate and downregulate the expression of ASIC3 in TG,respectively.NGF aggravated tooth mechanical hyperalgesia that could be alleviated by ASIC3 antagonist(APETx2).Moreover,NGF neutralizing antibody mitigated tooth mechanical hyperalgesia that could be recapitulated by ASIC3 agonist(GMQ).NGF-based gene therapy abolished tooth mechanical hyperalgesia and downregulated ASIC3 expression.Taken together,in response to force stimuli,periodontal fibroblasts upregulated the expressions of NGF that was retrogradely transported to TG,where NGF elicited tooth mechanical hyperalgesia through upregulating ASIC3.NGF-based gene therapy is a viable method in alleviating tooth-movement-induced mechanical hyperalgesia.

Effects of Dexamethasone, Clonidine, Tramadol and Nalbuphine on Fentanyl-Induced Hyperalgesia in Rats

Opioids are drugs used to alleviate pain. However, studies have demonstrated that these drugs can cause an increase in pain sensitivity, which is called opioid-induced hyperalgesia. The objective of this study was to describe the effects of dexamethasone, clonidine, tramadol and nalbuphine on fentanyl-induced hyperalgesia in rats. After obtaining approval from the Committee for the Ethical Use of Animals (CEUA), 36 male Wistar rats were divided into 6 groups: Group 1 (GCSSL) wherein the rats received 1 ml 0.9% saline solution in two injections;Group 2 (GFTSL), received fentanyl at a dose of 100 ug·kg-1 followed by 1 ml 0.9% saline solution via intraperitoneal;the remaining groups (3, 4, 5, 6) received fentanyl at a dose of 100 ug·kg-1 following doses via intraperitoneal: Group 3 (GFTDX), dexamethasone at a dose of 1.0 mg·kg-1;Group 4 (GFTCL), clonidine at a dose of 20 mg·kg-1;Group 5 (GFTTR), tramadol at a dose of 50 mg·kg-1, and Group 6 (GFTNB), nalbuphine at a dose of 5 mg·kg-1. Under general anestesia using isoflurane, the animals were submitted to a surgical incision. Hyperalgesia was evaluated by applying Von Frey filaments at 2 hours after the incision and on the 1st, 3rd and 5th days afterward. At 2 hours after the surgical procedure, there was lower intensity of pain in the fentanyl group (GFTSL) compared to the other groups, and on the fifth day there were no significant differences for pain intensity between groups. The results suggest the presence of fentanyl-induced hyperalgesia and efficacy in its reduction by dexamethasone, clonidine, tramadol and nalbuphine.

Role of NO in the inhibition of formalin-induced hyperalgesia after intraspinal injection of ACTH in rats

Objective: To study the role of nitric oxide (NO) in the inhibition of formalin-induced hyperalgesia aller intraspinal injection of adrenocorticotropic hormone (ATCH) in rats. Methods: NADPH-d histochemistry assay of the spinal cord, immuno-histochemical staining of c-fos protein (fos) and determination of the content of gama-aminobutyric acid (CABA) of ’ the spinal spinal cord tissue were performed Results: lntraspinal injection,of ACTH significantly inhibited the increase of nitrie oxide synthetase (NOS)positive . neurons, fos-positive neurons and the elevation of GABA level in the lumbar seg ment of the spinal cord which could be partially reversed with the adminnistration of 10 μmol L-arginine (Arg)Conclu- sion:The decrease of NO synthesis might play a part in the inhibition of formalin -induced hyperalgesia after intraspinal injec- tion of ACTH

Effects of Ketoprofen, Ketamine, Lidocaine and Propofol on Fentanyl-Induced Hyperalgesia in Rats

Opioid-induced hyperalgesia negatively affects physiological pain management and presents a complex causal mechanism, involving, pharmacodynamic and pharmacokinetic factors of interactions with receptors, opioid-independent ascending systems and with pro-nociceptive systems. After approval by the CEUA, 42 male Wistar rats were divided into 7 groups: In group 1 (GCSSL) the animals received 1 ml of 0.9% saline solution intraperitoneally (IP);in group 2 (GFTSL), they received fentanyl at a dose of 100 ug·kg-1 IP;in the remaining groups (3, 4, 5, 6 and 7) the animals received IP, fentanyl at a dose of 100 ug·kg-1 followed also by IP route of: group 3 (GFTKP) ketoprofen at a dose of 5 mg·kg-1;group 4 GFTKT), ketamine up to a dose of 10.0 mg·kg-1;group 5 (GFTLI), incisional lidocaine up to a dose of 10 mg·kg-1;group 6 (GFTLP), intraperitoneal lidocaine up to a dose of 10 mg·kg-1 and group 7 (GFTPP), propofol up to a dose of 60 mg·kg-1. Under general anesthesia, all animals with a plantar surgical incision. Hyperalgesia was evaluated by applying Von Frey filaments on the 2nd, 1st, 3rd and 5th days after treatment. In the 2nd hour and on the 5th day after the procedure, there was no hyperalgesia associated with the use of fentanyl, however, on the 1st and 3rd postoperative days there was hyperalgesia that was attenuated by ketoprofen, ketamine, lidocaine infiltrated in the incision and intraperitoneally, an effect not observed with the use of propofol. The results suggest fentanyl-induced hyperalgesia and the efficacy of ketoprofen, ketamine, incisional lidocaine and intraperitoneal lidocaine in reducing this effect.

Evidence for Positive Effects of Date Extract That Attenuates Thermal Hyperalgesia in a Diabetic Rat Model of Neuropathic Pain

Aim: Diabetic neuropathic pain is one of the pains which hardly respond to pharmaceutical treat. Today, various chemical and herbal compounds have been used to reduce pain. The aim of this study is to compare the effect of date extract and melatonin in preventing pain in diabetic rats.Method: To study hyperalgesia response and to compare the effect of date extract and melatonin in preventing pain, hot plate and tail flick tests were used. After prescribing single dose of streptozotocin to rats and approving their diabetes, treatment rats received date extract (4ml/kg/day) or melatonin [10 mg/kg/day, intraperitoneally (i.p.)] for a period of 6 weeks. At the end of the sixth week, control and treated rats were examined by thermal pain response and explorative activity tests.Results: According to hot plate results, response time to thermal pain in treated group showed a significant decrease in comparison with the control group (P 0.01). Prescription of date extract increased response time to thermal pain in comparison with treated group (P 0.01), so that response time approximated to control group. Although melatonin approximated to the response time to control group, the significant difference was not observed among melatonin receivers and other groups. In the assessment of diabetic neuropathy on the explorative activity of rats in an open field behavioral test, total distance moved and rearing frequency were significantly decreased, while administration of date extract did also improve motor deficits induced by STZ. Conclusions:Findings of this study showed that date extract decreased thermal hyperalgesia and can prevent pain resulted from diabetic neuropathy.

The nucleus tractus solitarius mediates hyperalgesia induced by chronic pancreatitis in rats

Central sensitizationis critical for chronic pain sensation induced by chronic pancreatitis(CP).We hypothesized that the nucleus tractus solitarius(NTS),a primary central site that integrates pancreatic afferents apart from the thoracic spinal dorsal horn,plays a key role in the pathogenesis of visceral hypersensitivity in a rat model of CP.In order to investigate the role of the NTS in the visceral hypersensitivity induced by chronic pancreatitis,CP was induced by the intraductal injection of trinitrobenzene sulfonic acid(TNBS)in rats.Pancreatic hyperalgesia was assessed by referred somatic pain via von Frey filament assay.Neural activation of the NTS was indicated by Fos-immunohistochemical staining.