Dual role of osteoblastic proenkephalin derived peptides in skeletal tissues

Proenkephalin encodes a group of small peptides with opiate-like activity, the endogenous opioids, known to function as neurohormones, neuromodulators, and neurotransmitters. Recently, we have demonstrated that in addition to its abundance in fetal brain tissue, proenkephalin is highly expressed in nondifferentiated mesodermal cells of developing fetuses. We identified the skeletal tissues, bone, and cartilage as major sites of proenkephalin expression. To examine the possibility that proenkephalin is involved in bone development we have studied the expression of this gene in bone-derived cells, its modulation by bone active hormones, and the effects of enkephalin-derived peptides on osteoblastic phenotype. Our studies revealed that osteoblastic cells synthesize high levels of proenkephalin mRNA which are translated, and the derived peptides are secreted. Reciprocal interrelationships between osteoblast maturation and proenkephalin expression were established. These results together with our observations demonstrating inhibitory effects of proenkephalin-derived peptides on osteoblastic alkaline phosphatase activity, strongly support the notion that proenkephalin is involved in bone development. A different direction of research by other investigators has established the capability of the opioid system in the periphery to participate in the control of pain. On the basis of these two lines of observation, we would like to present the following hypothesis: The potential of embryonic skeletal tissue to synthesize proenkephalin-derived peptides is retained in the adult in small defined undifferentiated cell populations. This potential is realized in certain situations requiring rapid growth, such as remodeling or fracture repair. We suggest that in these processes, similarly to the situation in the embryo, the undifferentiated dividing cells produce the endogenous opioids. In the adult these peptides may have a dual function, namely participating in the control of tissue regeneration and in the control of pain. © 1994 Wiley-Liss, Inc.     

福尔马林致痛提高大鼠中枢μ阿片受体密度及电针的加强作用

用放射自显影方法观察到;（１）大鼠脚掌注射福尔马林后,某些与镇痛有关的脑区如尾核头部、伏隔核、杏仁核、中央灰质、脚间核、中缝大核、脊髓背角等结构中μ阿片受体密度明显增加（Ｐ＜０．０５,Ｐ＜０．０１）;（２）给予电针抑制痛反应的大鼠,在其大部分上述结构及扣带回、隔区、视前内侧区、内膝体、上丘、中缝背核及中央上核受体密度明显增加;与福尔马林注射组相比,脚间核、中央灰质尾端腹外侧区、腰膨大背角的受体密度进一步增加。从而在受体水平支持伤害性刺激可以激活体内内阿片肽能活动,而电针可以加强这一活动的设想。     

Ligand recognition in μ opioid receptor: experimentally based modeling of μ opioid receptor binding sites and their testing by ligand docking

For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed opioid receptor-ligand interaction based on the receptor's 3D model. As a first step, we have constructed molecular models for the multiple opioid receptor subtypes using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping the three-dimensional structure of the μ opioid receptor, including the nature of the agonist-mediated conformational change that permits G protein-coupling to ‘second messenger’ effector molecules, and in identifying specific ligand-binding contacts with the μ opioid receptor. The analyses of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments.     

催产素在脊髓水平对电针镇痛的影响

采用玻璃微电极胞外记录和脊髓表面给药的方法观察了催产素（ＯＴ）、抗催产素血清（ＡＯＴＳ）以及电针穴位对背角神经元伤害性诱发放电的影响。结果表明：电针穴位或脊髓表面施加ＯＴ可部分抑制脊髓背角神经元的伤害性诱发放电;在电针的基础上施加ＯＴ则明显加强电针的抑制效应;相反,用ＡＯＴＳ预处理后,电针的抑制作用放取消。提示ＯＴ在脊髓水平参与了对痛觉信息的调制,并与一定频率的针刺镇痛有关。     

An analog of ACTH/MSH (4–9), ORG-2766, reduces cerebral uptake of morphine

The uptake of morphine was significantly reduced in most regions of the brains of conscious, unrestrained rats within 10 minutes after treatment with an analog of ACTH/MSH (4–9), ORG-2766. The effect was most obvious in regions with significant densities of enkephalin receptors, namely basal ganglia, hippocampus and cortex. The results explain, in part, how some fragments and analogs of ACTH/MSH may antagonize behavioral actions of morphine, even though some of these peptides lack significant opiate receptor binding properties. We believe that this effect of ORG-2766 is related to an action on the permeability characteristics of the brain microvasculature. The underlying mechanism is unknown.     

Intrathecal Morphine Use in Adolescent Idiopathic Scoliosis Surgery is Associated with Decreased Opioid Use and Decreased Length of Stay

BackgroundLength of stay (LOS) in the hospital following posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) has decreased over the past decade due to well-defined postoperative clinical pathways, earlier mobilization, and improved pain control methods. Historically, liberal use of parenteral and oral opioids for pain control caused side effects, resulting in delayed discharge. Intraoperative intrathecal morphine (ITM) has been posited to reduce the need for postoperative opioids and to expedite the discharge process. This study examines the relationship between the use of ITM with average required postoperative opioid usage and with average LOS.MethodsThis IRB-approved retrospective cohort study examined 105 patients with AIS who received PSF with instrumentation split into two cohorts. One cohort underwent PSF via standard surgical protocol (n=40) while the other cohort received intraoperative ITM with the standard surgical protocol (n=65). Power analysis demonstrated a study power of 0.8. LOS and total postoperative opioid analgesic medication (morphine milligram equivalent, MME) data were collected. Age at surgery, gender, number of spinal levels fused, estimated intraoperative blood loss (EBL), preoperative Cobb angle, and any complications related to the use of ITM were also recorded. Continuous variables were analyzed with Student’s t-test and categorical variables were analyzed with chi-square independent-sample tests using SAS 9.4 (α = 0.05).ResultsPatients who were treated with ITM displayed shorter LOS (p<0.0001) and reduced postoperative analgesic requirement (p<0.0001). Patients who received ITM spent an average of 1.8 fewer midnights in the hospital and received an average of 221.2 MME less than patients who received standard protocol (57% decrease). There were no significant differences between the two groups for any other variable.ConclusionIntraoperative ITM is a simple and effective treatment for scoliosis surgeons to better control postoperative pain in patients, reduce the risk of dependency, and achieve earlier discharge from the hospital. Shortened LOS reduces the overall cost of care, benefitting patients, hospitals, and insurance companies. Based on the results of this study and several earlier studies, the authors recommended that scoliosis surgeons consider incorporating use of ITM into their standard operative protocols. Level of Evidence: IV     

吗啡降低大鼠脊髓内cAMP的含量

有资料表明,吗啡或脑啡肽可影响脑内 cAMP 与 cGMP 的含量,但对脊髓内 cAMP 与cGMP 的含量有何影响,未见报道。本实验采用放射免疫分析(RIA)方法研究的结果表明,吗啡可使大鼠离体与在体脊髓内 cAMP 的含量明显降低;而对脊髓内 cGMP 的含量则无明显影响;纳洛酮可特异阻断吗啡对脊髓内 cAMP 含量的抑制效应。提示:吗啡的上述作用是通过大鼠脊髓内阿片受体所介导。脑和脊髓内 cAMP 含量的变化可能部分介导了吗啡作用的中枢机制。     

左旋四氢巴马汀加强电针对兔大脑皮层牙髓诱发电位的抑制作用

家兔6只,用氨基甲酸乙酯和氯醛糖麻醉,电刺激牙髓,在对侧大脑皮层体感Ⅰ区引导其诱发电位,观察诱发电位各成分与痛的关系。结果观察到,在P1、N1、P2和 N2 4个波中,P1和 P2波相对稳定。其中,P2波(波峰潜伏期:66.1±1.9ms)具有较高的阈值,且不受无镇痛作用的中枢抑制剂安定的影响,而受小剂量镇痛剂度冷丁的抑制,提示 P2波与痛有关。以 P2波的波幅为指标,进一步在12只家兔上观察了 L-THP 和电针及两者合用对诱发电位的影响。结果显示,L-THP 和电针对诱发电位均有抑制作用,且两者在作用强度和时间上存在明显的协同,提示 L-THP 具有加强电针对兔大脑皮层牙髓诱发电位中痛相关成分的抑制作用。     

肋间神经阻滞复合全麻联合静脉自控镇痛对胸腔镜肺大疱切除术患者术后镇痛效果及恢复情况的影响

摘要 目的：探讨在胸腔镜肺大疱切除术中应用肋间神经阻滞复合全麻联合静脉自控镇痛的术后镇痛效果及患者恢复情况。方法：研究对象选取进行胸腔镜肺大疱切除术的80例患者,依据简单数字表法分为对照组和观察组,每组各40例。对照组接受全麻联合静脉自控镇痛,观察组在此基础上复合肋间神经阻滞,比较两组术后镇痛效果及恢复情况。结果：与术前比,术后12 h、24 h两组患者的CD4⁺、CD4⁺/CD8⁺均先降低后升高,且观察组各时间点均高于对照组;两组患者的CD8⁺均先升高后降低,且观察组各时间点均低于对照组（P<0.05）。术后24 h、48 h,观察组比对照组在镇痛泵按压次数和输注镇痛药物总量有减少（P<0.05）。与对照组比,观察组患者的术毕到拔管时间、下床活动时间、住院时间均更短（P<0.05）。与对照组（22.50%、20.00%）比,观察组患者的并发症、不良反应总发生率（2.50%、5.00%）更低（P<0.05）。结论：在胸腔镜肺大疱切除术中应用肋间神经阻滞复合全麻联合静脉自控镇痛,取得了显著的镇痛成效,不仅能够减轻患者的术后疼痛,还能减轻机体免疫抑制,同时不增加并发症和不良反应发生风险,临床应用安全性较高。     

经皮穴位电刺激联合常规镇痛对无痛人流术后宫缩痛镇痛效果及机制研究

摘要 目的：探讨经皮穴位电刺激联合常规镇痛对无痛人流术后宫缩痛镇痛效果及机制。方法：选择来我院行无痛人流患者100例。根据随机数字表法分为两组。对照组行术后常规镇痛治疗,同时在内关、合谷、三阴交最酸胀处黏贴电极但是不进行穴位刺激。观察组在术后常规镇痛基础上行经皮穴位电刺激治疗。对比不同时间点两组患者的机体一般情况、不同时间点两组患者的宫缩痛疼痛情况、T3时正性负性情绪量表评分、T3时血清P物质、前列腺素、5-羟色胺、β-内啡肽、强啡肽水平、T4点时的心理状态评分及满意度评分。结果：对照组T1、T2点时的BP、HR、RR、SpO₂明显较同组T0点低,对照组T3点与观察组T1、T2、T3点时BP、HR、RR、SpO₂与同组T0点对比无统计学意义（P>0.05）;对照组T1、T2点时的BP、HR、RR、SpO₂明显较观察组同时间点低（P<0.05）。T0点,两组VAS评分对比无统计学意义（P>0.05）;T1、T2、T3点时间,观察组的VAS评分明显较对照组低（P<0.05）;对照组T1、T2点的VAS评分明显较同组T0点高,观察组T1、T2、T3点的VAS评分明显较T0点低（P<0.05）。观察组的正性情绪明显较对照组高,负性情绪明显较对照组低（P<0.05）。观察组的血清P物质、前列腺素、5-羟色胺、β-内啡肽、强啡肽水平明显较对照组低（P<0.05）。观察组的心理状态评分明显较对照组低,满意度评分明显较对照组高（P<0.05）。结论：经皮穴位电刺激联合常规镇痛可明显改善无痛人流术后宫缩痛镇痛效果、患者心理状态及满意度,可能与其可降低血清P物质、前列腺素、5-羟色胺、β-内啡肽、强啡肽水平有关。