Recurrent Abdominal Pain, Medical Intervention, and Biofeedback: What Happened to the Biopsychosocial Model?

Recurrent abdominal pain (RAP) is a significant and common problem among pediatric populations. Based on results from randomized controlled trials there are no established efficacious treatments for this disorder. Biofeedback (BFB) and other psychological treatments offer logically appealing alternatives or adjuncts to medical interventions and there is some evidence to support their use. This paper presents a typical case of RAP that exemplifies how the lack of integration of the biopsychosocial model may result in less than optimal treatment. Specifically, it demonstrates that the patient was exposed to potentially risky treatments that lack evidence to support their use and were not beneficial. Although there was evidence of psychological involvement early in the treatment, this was only attended to following numerous medical trials and exploratory surgery over three years. The patient was finally referred for BFB and during a course of seven sessions over five months that variously included heart rate variability and skin temperature feedback along with extensive home practice of paced breathing and hand warming the patient achieved significant symptom reduction and improved coping abilities. This case vividly illustrates the need for multidisciplinary collaboration and full implementation and integration of the biopsychosocial model of health and illness.     

Glial glutamate transporter and glutamine synthetase regulate GABAergic synaptic strength in the spinal dorsal horn

Decreased GABAergic synaptic strength ('disinhibition') in the spinal dorsal horn is a crucial mechanism contributing to the development and maintenance of pathological pain. However, mechanisms leading to disinhibition in the spinal dorsal horn remain elusive. We investigated the role of glial glutamate transporters (GLT-1 and GLAST) and glutamine synthetase in maintaining GABAergic synaptic activity in the spinal dorsal horn. Electrically evoked GABAergic inhibitory post-synaptic currents (eIPSCs), spontaneous IPSCs (sIPSCs) and miniature IPSCs were recorded in superficial spinal dorsal horn neurons of spinal slices from young adult rats. We used (2S,3S)-3-[3-[4-(trifluoromethyl)benzoylamino]benzyloxy]aspartate (TFB-TBOA), to block both GLT-1 and GLAST and dihydrokainic acid to block only GLT-1. We found that blockade of both GLAST and GLT-1 and blockade of only GLT-1 in the spinal dorsal horn decreased the amplitude of GABAergic eIPSCs, as well as both the amplitude and frequency of GABAergic sIPSCs or miniature IPSCs. Pharmacological inhibition of glial glutamine synthetase had similar effects on both GABAergic eIPSCs and sIPSCs. We provided evidence demonstrating that the reduction in GABAergic strength induced by the inhibition of glial glutamate transporters is due to insufficient GABA synthesis through the glutamate-glutamine cycle between astrocytes and neurons. Thus, our results indicate that deficient glial glutamate transporters and glutamine synthetase significantly attenuate GABAergic synaptic strength in the spinal dorsal horn, which may be a crucial synaptic mechanism underlying glial-neuronal interactions caused by dysfunctional astrocytes in pathological pain conditions.     

Ca++/CaMKII switches nociceptor‐sensitizing stimuli into desensitizing stimuli

Many extracellular factors sensitize nociceptors. Often they act simultaneously and/or sequentially on nociceptive neurons. We investigated if stimulation of the protein kinase C epsilon (PKCε) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKCs is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKCε signaling pathway resulted in PKCε translocation. We identified a novel inhibitory cascade to branch off upstream of PKCε, but downstream of Epac via IP3‐induced calcium release. This signaling branch actively inhibited subsequent translocation and even attenuated ongoing translocation. A second ‘sensitizing’ stimulus was rerouted from the sensitizing to the inhibitory branch of the signaling cascade. Central for the rerouting was cytoplasmic calcium increase and CaMKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a CaMKII‐dependent manner. This mechanism was also observed by in vivo C‐fiber electrophysiology corroborating the peripheral location of the switch. Thus, we conclude that the net effect of signaling in nociceptors is defined by the context of the individual cell's signaling history.     

TRPV1-tubulin complex: involvement of membrane tubulin in the regulation of chemotherapy-induced peripheral neuropathy

Existence of microtubule cytoskeleton at the membrane and submembranous regions, referred as 'membrane tubulin' has remained controversial for a long time. Since we reported physical and functional interaction of Transient Receptor Potential Vanilloid Sub Type 1 (TRPV1) with microtubules and linked the importance of TRPV1-tubulin complex in the context of chemotherapy-induced peripheral neuropathy, a few more reports have characterized this interaction in in vitro and in in vivo condition. However, the cross-talk between TRPs with microtubule cytoskeleton, and the complex feedback regulations are not well understood. Sequence analysis suggests that other than TRPV1, few TRPs can potentially interact with microtubules. The microtubule interaction with TRPs has evolutionary origin and has a functional significance. Biochemical evidence, Fluorescence Resonance Energy Transfer analysis along with correlation spectroscopy and fluorescence anisotropy measurements have confirmed that TRPV1 interacts with microtubules in live cell and this interaction has regulatory roles. Apart from the transport of TRPs and maintaining the cellular structure, microtubules regulate signaling and functionality of TRPs at the single channel level. Thus, TRPV1-tubulin interaction sets a stage where concept and parameters of 'membrane tubulin' can be tested in more details. In this review, I critically analyze the advancements made in biochemical, pharmacological, behavioral as well as cell-biological observations and summarize the limitations that need to be overcome in the future.     

Dynamic changes to the endocannabinoid system in models of chronic pain

The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.     

Resistive vibration exercise during bed-rest reduces motor control changes in the lumbo-pelvic musculature

To understand the effects of a resistive vibration exercise (RVE) countermeasure on changes in lumbo-pelvic muscle motor control during prolonged bed-rest, 20 male subjects took part in the Berlin Bed-Rest Study (in 2003-2005) and were randomised to a RVE group or an inactive control group. Surface electromyographic signals recorded from five superficial lumbo-pelvic muscles during a repetitive knee movement task. The task, which required stabilisation of the lumbo-pelvic region, was performed at multiple movement speeds and at multiple time points during and after bed-rest. After excluding effects that could be attributed to increases in subcutaneous fat changes and improvements in movement skill, we found that the RVE intervention ameliorated the generalised increases in activity ratios between movement speeds (p ? 0.012), reductions in lumbo-pelvic extensor and flexor co-contraction (p = 0.058) and increases in root-mean-square electromyographic amplitude (p = 0.001) of the lumbar erector spinae muscles. Effects of RVE on preventing increases in amplitude-modulation (p = 0.23) of the lumbar erector spinae muscles were not significant. Few significant changes in activation-timing were seen. The RVE intervention during bed-rest, with indirect loading of the spine during exercise, was capable of reducing some, but not all, motor control changes in the lumbo-pelvic musculature during and after bed-rest.     

经胸前壁入路内镜甲状腺手术与传统甲状腺手术的 对照研究

目的:通过临床非随机性对照研究,比较经胸前壁入路内镜甲状腺手术与传统甲状腺手术在手术时间、术中出血量、术后引流量、术后疼痛、功能恢复、术后住院时间、住院费用及美容效果上的不同,探讨经胸前壁入路内镜甲状腺手术的可行性及临床效果。方法:回顾性分析86例甲状腺手术,其中46例患者采用经胸前壁入路内镜甲状腺手术的患者为内镜组,40例行传统甲状腺手术为传统组。结果:两组患者均顺利完成手术,术后恢复良好,均未发生术后大出血、喉返神经、喉上神经及甲状旁腺损伤等并发症。两组患者的术后住院时间及术后引流量无显著差异。与传统组比较,内镜组手术时间明显延长(P<0.05),术中出血量明显减少(P<0.05),术后疼痛明显降低(P<0.05),功能恢复即术后自行下床洗漱时间明显缩短(P<0.05),住院费用显著增加(P<0.05),手术美容效果满意度明显提高(P<0.05)。结论:相对传统甲状腺手术,经胸前壁入路内镜甲状腺手术具有切口小、出血量少、术后疼痛轻、功能恢复快、美容满意度高等优点,是治疗甲状腺疾病安全、有效的手术方法。     

外周神经损伤引起的神经病理性痛：对神经损伤 的一种适应不良反应

外周神经损伤可引起对神经系统的一种适应不良反应,其产生神经病理性痛的主要特点为痛觉增敏和异常疼痛。目前文献报道多种机制涉及此反应,包括离子通道改变引起的异常放电、突触易化、多种轴突水平抑制作用缺失导致的中枢敏化、神经元细胞的凋亡以及异常的突触连接等结构的改变,另外神经损伤引起的神经免疫之间的相互作用在神经病理性痛的持续性发展中发挥着不可替代的作用。了解外周神经损伤引起的神经病理性的发病机制将对我们寻找治疗靶点和治疗策略提供坚实的理论基础。     

Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury

Toll-like receptors (TLRs) play an essential role in innate immune responses and in the initiation of adaptive immune responses. Microglia, the resident innate immune cells in the CNS, express TLRs. In this study, we show that TLR3 is crucial for spinal cord glial activation and tactile allodynia after peripheral nerve injury. Intrathecal administration of TLR3 antisense oligodeoxynucleotide suppressed nerve injury-induced tactile allodynia, and decreased the phosphorylation of p38 mitogen-activated protein kinase, but not extracellular signal-regulated protein kinases 1/2, in spinal glial cells. Antisense knockdown of TLR3 also attenuated the activation of spinal microglia, but not astrocytes, caused by nerve injury. Furthermore, down-regulation of TLR3 inhibited nerve injury-induced up-regulation of spinal pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Conversely, intrathecal injection of the TLR3 agonist polyinosine–polycytidylic acid induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury. Indeed, TLR3-deficient mice did not develop tactile allodynia after nerve injury or polyinosine–polycytidylic acid injection. Our results indicate that TLR3 has a substantial role in the activation of spinal glial cells and the development of tactile allodynia after nerve injury. Thus, blocking TLR3 in the spinal glial cells might provide a fruitful strategy for treating neuropathic pain.     

川芎嗪对慢性压迫性损伤大鼠神经病理痛行为学的影响

目的探讨川芎嗪对慢性压迫性损伤（CCI）大鼠行为学的影响。方法建立大鼠坐骨神经CCI神经病理痛模型,取40只雄性大鼠随机分成4组,Ⅰ组为空白对照组,Ⅱ组为假手术组,Ⅲ组为CCI＋川芎嗪治疗组,Ⅲ组在术后第1天开始腹腔注射100 mg/kg川芎嗪注射液,Ⅳ组为CCI手术组。分别于术前（0 d）及术后1、3、5、7、91、1、14 d以von Frey细丝法和热辐射法测定机械缩足反射阈值（mechanical withdrawal threshold,MWT）和热缩足反射潜伏期（thermal withdrawal latency,TWL）,观察CCI大鼠神经病理痛的行为学变化。结果术后14 d,Ⅳ组和I、Ⅱ、Ⅲ组相比较,大鼠后爪的机械和热痛敏阈值明显降低（P〈0.01）;I、Ⅱ、Ⅲ组之间相比,大鼠后爪的机械和热痛敏阈值差异没有显著性（P〉0.05）。结论川芎嗪可以缓解CCI大鼠的慢性神经病理痛行为学表现。