Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine

Cannabis sativa L. has been utilized for treatment of pain and sleep disorders since ancient times. This review examines modern studies on effects of Delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on sleep. It goes on to report new information on the effects on sleep in the context of medical treatment of neuropathic pain and symptoms of multiple sclerosis, employing standardized oromucosal cannabis-based medicines containing primarily THC, CBD, or a 1 : 1 combination of the two (Sativex). Sleep-laboratory results indicate a mild activating effect of CBD, and slight residual sedation with THC-predominant extracts. Experience to date with Sativex in numerous Phase I-III studies in 2000 subjects with 1000 patient years of exposure demonstrate marked improvement in subjective sleep parameters in patients with a wide variety of pain conditions including multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis, with an acceptable adverse event profile. No tolerance to the benefit of Sativex on pain or sleep, nor need for dosage increases have been noted in safety extension studies of up to four years, wherein 40-50% of subjects attained good or very good sleep quality, a key source of disability in chronic pain syndromes that may contribute to patients' quality of life.     

核心稳定训练联合五禽戏对颈型颈椎病患者颈椎疼痛、颈椎功能和生活质量的影响

目的:观察核心稳定训练联合五禽戏对颈型颈椎病(NTCS)患者颈椎疼痛、颈椎功能和生活质量的影响。方法:选取NTCS患者80例,按随机数字表法分为对照组(核心稳定训练)和研究组(核心稳定训练联合五禽戏)各40例。对比两组疗效、颈椎疼痛、颈椎功能和生活质量。结果:研究组的临床总有效率高于对照组(P<0.05)。两组干预1个月、2个月后、3个月后颈部视觉模拟评分法(VAS)评分逐渐下降,且研究组的下降程度大于对照组(P<0.05)。两组干预3个月后颈椎功能障碍指数(NDI)评分下降,且研究组的下降程度大于对照组(P<0.05),颈椎前屈、后伸、左旋、右旋活动度升高,且研究组的升高程度大于对照组(P<0.05)。两组干预3个月后SF-36各维度评分均较干预前升高,且研究组的升高程度大于对照组(P<0.05)。结论:NTCS患者采用五禽戏、核心稳定训练联合干预,可有效缓解颈椎疼痛,促进颈椎功能恢复,提高患者生活质量,疗效明确。     

Novel histone modifications in microglia derived from a mouse model of chronic pain

As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry-based proteomic approach to screen potential changes of histone protein modifications in microglia isolated from the brain of control and cisplatin-induced neuropathic pain adult C57BL/6J male mice. We identified several novel microglial histone modifications associated with pain, including statistically significantly decreased histone H3.1 lysine 27 mono-methylation (H3.1K27me1, 54.8% of control) and H3 lysine 56 tri-methylation (7.5% of control), as well as a trend suggesting increased H3 tyrosine 41 nitration. We further investigated the functional role of H3.1K27me1 and found that treatment of cultured microglial cells for 4 consecutive days with 1–10 μM of NCDM-64, a potent and selective inhibitor of lysine demethylase 7A, an enzyme responsible for the demethylation of H3K27me1, dose-dependently elevated its levels with a greater than a two-fold increase observed at 10 μM compared to vehicle-treated control cells. Moreover, pretreatment of mice with NCDM-64 (10 or 25 mg/kg/day, i.p.) prior to cisplatin treatment prevented the development of neuropathic pain in mice. The identification of specific chromatin marks in microglia associated with chronic pain may yield critical insight into the contribution of microglia to the development and maintenance of pain, and opens new avenues for the development of novel nonopioid therapeutics for the effective management of chronic pain.     

腰痹通胶囊与布洛芬缓释胶囊联合用药治疗慢性腰痛疗效的随机对照研究

摘要 目的：观察腰痹通胶囊与布洛芬缓释胶囊联合用药治疗慢性腰痛的临床疗效。方法：将168例在我院门诊接受治疗的慢性腰痛患者随机分为A组、B组与C组（各56例）,A组给予口服腰痹通胶囊 (3粒/次),3次/d,饭后服药;B组给予布洛芬缓释胶囊治疗 (300 mg/次),2次/d,饭后口服;C组同时口服腰痹通胶囊和布洛芬缓释胶囊（用法同前）,3组均治疗1个疗程。观察治疗前后3组患者的临床疗效、视觉模拟评分（VAS）、Oswestry功能障碍指数（ODI）评分、日本骨科协会腰椎治疗评价量表（JOA）评分、血清炎性因子和药物副作用等各项指标,并进行对比分析。结果：所有患者均完成了研究,没有退出或脱落病例。A组的总有效率为76.79%,B组的总有效率为82.14%,C组的总有效率为96.43%,经统计学分析,AB两组之间没有显著的统计学差异（P>0.05）,而C组与A组或B组之间均有显著性差异（P<0.05）。3组的VAS、ODI、JOA评分在治疗前后具有显著的统计学差异（P<0.05）,其中C组治疗后的相关评分优于其他两组（P<0.05）。C组患者治疗后的炎性因子包括C反应蛋白(CRP)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平均低于A组、B组(P<0.05)。A组的药物副作用最少,B组的药物副作用最多,A组和C组的不良反应发生率低于B组（P<0.05）。结论：腰痹通胶囊联合布洛芬缓释胶囊口服治疗慢性腰痛的疗效明显优于这两种药物单独使用,可缓解患者腰部疼痛,改善腰椎功能,降低血清炎性因子水平。     

鞘内注射干扰素调节因子8小干扰RNA对术后持续性疼痛大鼠痛阈及脊髓小胶质细胞活化的影响*

目的: 探究鞘内注射干扰素调节因子8小干扰RNA(IRF8 SiRNA)对PPsP大鼠痛阈及脊髓小胶质细胞活化的影响。方法: 120只雄性SD大鼠随机分为假手术组(SH,n=12),模型组(SM,n=48),溶媒组(SD,n=12)和IRF8沉默组(SS,n=48),其中,SM组于大鼠后足中部隐静脉内侧按皮肤/肌肉切开牵拉(SMIR)法建立术后持续性疼痛(PPsP)模型,SH组仅切开不牵拉;SD组与SS组建模前一周先于L4/5椎间隙行鞘内置管术, SS组于建模后第5、6日连续鞘内给予IRF8 SiRNA溶液20 μl(溶于DEPC水中,150 pmol),SD组给予等量DEPC水。测量并记录建模前(D0),建模后第1(D1)、3(D3)、7(D7)、12(D12)、22(D22)、33(D33)日等时点各组大鼠术侧后足机械刺激缩足反应阈值 (PWT); 建模后第12日各取6只,Western blot法检测脊髓背角Iba-1蛋白表达情况,并取SH组和SM组各3只,取术野隐神经行电镜观察其超微结构改变;再取SM组和SS组于上述各时点各6只,流式细胞术检测脊髓背角小胶质细胞活化情况。结果: 与D0相比, SM组在D1～D22PWT降低(P＜0.05或P＜0.01),并在D33恢复至正常水平(P＞0.05);与SH组相比,SM组PWT在D1～D22均降低(P＜0.05或P＜0.01);与SD组相比,SS组PWT在D7～D22增高(P＜0.05或P＜0.01);与SH组相比,SS组D7～D22降低(P＜0.05或P＜0.01);隐神经髓鞘平均厚度: SH组为(377.03± 69.60) nm,SM组为(369.50±73.26) nm,两组间相比无统计学意义(P＞0.05);与SH组相比,SM组Iba-1明显上调(P＜0.01);与SD组相比,SS组Iba-1表达受到抑制(P＜0.05),与SH组相比,SS组Iba-1表达也具有统计学差异(P＜0.05),而SM组与SD组之间,Iba-1的表达无统计学意义(P＞0.05);与D0相比,SM组小胶质细胞活化比率在D3～D22均显著增加(P＜0.01),而SS组小胶质细胞活化于D3达到高峰(P＜0.01);鞘内给药后,SS组脊髓背角小胶质细胞活化比率明显下降,与SM组相比,在D7～D12显著下降(P＜0.01)。结论: SMIR诱导的PPsP大鼠显著且持续的机械痛觉过敏为非明显的外周神经损伤所致,可能是基于脊髓背角小胶质细胞活化所介导,而鞘内给予IRF8小干扰RNA可抑制脊髓背角小胶质细胞的激活,并逆转SMIR诱导的痛觉过敏。     

完全弗氏佐剂诱导大鼠慢性骨盆疼痛综合征炎性痛模型的制备*

目的: 建立大鼠慢性骨盆疼痛综合征(CPPS)炎性痛模型并进行评价,为CPPS炎症引起的慢性骨盆疼痛的外周及中枢机制研究提供可靠的动物模型。方法: 将60只SD雄性大鼠随机分成空白组,假手术组和模型组,每组20只。采用向大鼠前列腺腹侧叶注射完全弗氏佐剂(CFA)的方法制备CPPS炎性痛模型。术后观察大鼠一般情况变化;分别于造模后7 d,14 d,21 d,28 d,35 d测定大鼠足底和阴囊热刺激疼痛阈值;取材后前列腺组织称重计算前列腺指数;显微镜下观察大鼠前列腺组织病理变化并用半定量法评价前列腺组织损伤程度,以评价模型是否成功。结果: 模型成功17只,成模率为85%。与空白组和假手术组比较,造模后大鼠的活动度、毛发光泽度降低,排尿量增加。足底和阴囊热刺激疼痛阈值显著降低并可稳定维持1个月以上(P＜0.01)。前列腺湿重和前列腺指数均显著性提高(P＜0.01)。前列腺组织肉眼可见明显水肿,与周围组织粘连严重;镜下可见腺腔萎缩,间质内大量炎性细胞浸润。结论: 利用向大鼠前列腺腹侧叶注射CFA的方法,可成功复制CPPS炎性痛模型,这将为后续CPPS发病机制的研究,特别是疼痛行为与潜在炎症和神经损伤之间的机制联系提供有价值的工具。     

Quercetin relieved diabetic neuropathic pain by inhibiting upregulated P2X4 receptor in dorsal root ganglia

The upregulation of nociceptive ion channels expressed in dorsal root ganglia (DRG) contributes to the development and retaining of diabetic pain symptoms. The flavonoid quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a component extracted from various fruits and vegetables and exerts anti-inflammatory, analgesic, anticarcinogenic, antiulcer, and antihypertensive effects. However, the exact mechanism underlying quercetin's analgesic action remains poorly understood. The aim of this study was to investigate the effects of quercetin on diabetic neuropathic pain related to the P2X₄ receptor in the DRG of type 2 diabetic rat model. Our data showed that both mechanical withdrawal threshold and thermal withdrawal latency in diabetic rats treated with quercetin were higher compared with those in untreated diabetic rats. The expression levels of P2X₄ messenger RNA and protein in the DRG of diabetic rats were increased compared with the control rats, while quercetin treatment significantly inhibited such enhanced P2X₄ expression in diabetic rats. The satellite glial cells (SGCs) enwrap the neuronal soma in the DRG. Quercetin treatment also lowered the elevated coexpression of P2X₄ and glial fibrillary acidic protein (a marker of SGCs) and decreased the upregulation of phosphorylated p38 mitogen-activated protein kinase (p38MAPK) in the DRG of diabetic rats. Quercetin significantly reduced the P2X₄ agonist adenosine triphosphate-activated currents in HEK293 cells transfected with P2X₄ receptors. Thus, our data demonstrate that quercetin may decrease the upregulation of the P2X₄ receptor in DRG SGCs, and consequently inhibit P2X₄ receptor-mediated p38MAPK activation to relieve the mechanical and thermal hyperalgesia in diabetic rats.