SIRT1: A promising therapeutic target for chronic pain

Chronic pain remains an unresolved problem. Current treatments have limited efficacy. Thus, novel therapeutic targets are urgently required for the development of more effective analgesics. An increasing number of studies have proved that sirtuin 1 (SIRT1) agonists can relieve chronic pain. In this review, we summarize recent progress in understanding the roles and mechanisms of SIRT1 in mediating chronic pain associated with peripheral nerve injury, chemotherapy‐induced peripheral neuropathy, spinal cord injury, bone cancer, and complete Freund''s adjuvant injection. Emerging studies have indicated that SIRT1 activation may exert positive effects on chronic pain relief by regulating inflammation, oxidative stress, and mitochondrial dysfunction. Therefore, SIRT1 agonists may serve as potential therapeutic drugs for chronic pain.     

卒中后中枢痛的研究进展

卒中后中枢痛是卒中后发生的中枢性神经病理性疼痛综合征,主要表现为与脑损伤区域相对应的躯体部位的疼痛与感觉异常。目前由于临床对卒中后中枢痛缺乏重视,致使患者长期遭受疼痛困扰,严重影响生活质量。为更全面了解卒中后中枢痛,本文对其流行病学、临床特点、病理生理及治疗进展等进行综述。     

Does losing money truly hurt? The shared neural bases of monetary loss and pain

Both monetary loss and pain have been studied for decades, but evidence supporting the relationship between them is still lacking. We conducted a meta‐analysis to explore the overlapping brain regions between monetary loss and pain, including physical pain and social pain. Regardless of the type of pain experienced, activation of the anterior insula was a shared neural representation of monetary loss and pain. The network representation pattern of monetary loss was more similar to that of social pain than that of physical pain. In conclusion, our research provided evidence of the common neural correlates of monetary loss and pain.     

Inhibition of phosphodiesterase‐4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP‐cytokine‐Cx43 signaling in mice

BackgroundThe spinal phosphodiesterase‐4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury‐induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP‐Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity.MethodsFirst, we determined the effect of PDE4 inhibitors rolipram and roflumilast on partial sciatic nerve ligation (PSNL)‐induced mechanical hypersensitivity. Next, we observed the role of cAMP‐Cx43 signaling in the effect of PDE4 inhibitors on PSNL‐induced mechanical hypersensitivity.ResultsSingle or repeated, intraperitoneal or intrathecal administration of rolipram or roflumilast significantly reduced mechanical hypersensitivity in mice following PSNL. In addition, repeated intrathecal treatment with either of PDE4 inhibitors reduced PSNL‐induced downregulation of cAMP and Cx43, and upregulation of proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐1β. Furthermore, the antinociceptive effects of PDE4 inhibitors were attenuated by the protein kinase A (PKA) inhibitor H89, TNF‐α, or Cx43 antagonist carbenoxolone. Finally, PSNL‐induced upregulation of PDE4B and PDE4D, especially the PDE4B subtype, was reduced by treatment with either of the PDE4 inhibitors.ConclusionsThe results suggest that the antinociceptive effect of PDE4 inhibitors is contributed by increasing Cx43 expression via cAMP‐PKA‐cytokine signaling in the spinal dorsal horn.     

α-Ketoheterocycle-based Inhibitors of Fatty Acid Amide Hydrolase (FAAH)

A summary of the initial discovery and characterization of the enzyme fatty acid amide hydrolase (FAAH), and the subsequent advancement of an important class of competitive, reversible, potent and selective inhibitors is presented. Initially explored using substrate-inspired inhibitors bearing electrophilic carbonyls, the examination of α-ketoheterocyle-based inhibitors of FAAH with the benefit of a unique activity-based protein-profiling (ABPP)-based proteome-wide selectivity assay, a powerful in vivo biomarker-based in vivo screen, and subsequent retrospective X-ray co-crystal structures with the enzyme, is summarized. These efforts defined the impact of the central activating heterocycle and its key substituents, provided key simplifications in the C2 acyl side chain and clear interpretations for the unique role and subsequent optimization of the central activating heterocycle, and established the basis for the recent further conformational constraints in the C2 acyl side chain, providing potent, long-acting, orally-active FAAH inhibitors.     

Supraspinal nociceptive networks in neuropathic pain after spinal cord injury

Neuropathic pain following spinal cord injury involves plastic changes along the whole neuroaxis. Current neuroimaging studies have identified grey matter volume (GMV) and resting‐state functional connectivity changes of pain processing regions related to neuropathic pain intensity in spinal cord injury subjects. However, the relationship between the underlying neural processes and pain extent, a complementary characteristic of neuropathic pain, is unknown. We therefore aimed to reveal the neural markers of widespread neuropathic pain in spinal cord injury subjects and hypothesized that those with greater pain extent will show higher GMV and stronger connectivity within pain related regions. Thus, 29 chronic paraplegic subjects and 25 healthy controls underwent clinical and electrophysiological examinations combined with neuroimaging. Paraplegics were demarcated based on neuropathic pain and were thoroughly matched demographically. Our findings indicate that (a) spinal cord injury subjects with neuropathic pain display stronger connectivity between prefrontal cortices and regions involved with sensory integration and multimodal processing, (b) greater neuropathic pain extent, is associated with stronger connectivity between the posterior insular cortex and thalamic sub‐regions which partake in the lateral pain system and (c) greater intensity of neuropathic pain is related to stronger connectivity of regions involved with multimodal integration and the affective‐motivational component of pain. Overall, this study provides neuroimaging evidence that the pain phenotype of spinal cord injury subjects is related to the underlying function of their resting brain.     

Discovery of 3-Substituted Aminocyclopentanes as Potent and Orally Bioavailable NR2B Subtype-Selective NMDA Antagonists

A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.     

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain—Meta‐analytic evidence from neuroimaging studies

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta‐analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta‐analysis combined three different meta‐analytic approaches with stringent study selection criteria for case–control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed‐based resting‐state functional connectivity based on a large publicly available dataset combined with a meta‐analytic task‐based approach identified the anterior insular region as a key node of an extended bilateral insula‐fronto‐cingular network, resembling the salience network. Moreover, the meta‐analytic decoding showed that this region presents a high probability to be specifically activated during pain‐related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.     

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy

The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC^-/-) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 μg/5 μL) significantly suppressed autotomy behavior in rats. HDC^-/- mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H₁ receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H₁ receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.     

Anti-NGF在躯体疾病疼痛治疗中的潜在价值

神经生长因子(nerve growth factor,NGF)属神经营养因子家族,广泛分布于中枢及外周神经系统,不仅在神经系统的发育存活中起重要作用,而且参与外周伤害性疼痛感受的产生与调节.近年来由于对NGF在急、慢性疼痛及痛觉过敏-中作用的认识不断增强,一种新的抑痛方法--抗-NGF(anti-NGF)治疗悄然兴起.     

Determination of pain and response to methylprednisolone in Guillain-Barré syndrome

Abstract Pain can be a serious problem in patients with Guillain-Barré syndrome (GBS). Different pain symptoms and the effect of methylprednisolone on pain are evaluated. Methods GBS patients were recruited from a randomized placebo-controlled study comparing intravenous immunoglobulin (IVIg) + methylprednisolone (500 mg for 5 days) versus IVIg + placebo. Presence and severity of pain were prospectively scored at randomization and after 4 weeks. Efficacy of methylprednisolone was evaluated using endpoints: percentage of patients with pain and percentage of patients improving in pain-severity level. Medical records of the subgroup of patients treated in the Erasmus MC were screened retrospectively for different pain symptoms and course. Pain was scored at different time intervals: within 4 weeks before randomization and 0–2, 2–4, 4–24, 24–52 weeks after randomization. Results 123 (55%) of 223 patients had pain at randomization. In 70%, pain already started before onset of weakness. Methylprednisolone did not show a positive effect on the presence and reduction of pain. In the subgroup of 39 patients, backache (33%), interscapular (28%), muscle (24%), radicular pain (18%) and painful par-/dysaesthesiae (18%) were most frequently present within the period of 4 weeks before randomization. Twenty-six percent had extreme pain 0–2 weeks after randomization. Most symptoms of pain decreased after this period, but painful par-/dysaesthesiae and muscle pain often remained present during at least 6 months. Conclusions Pain frequently occurs, often starts before onset of weakness and may cause severe complaints. Especially painful par-/dysaesthesiae and muscle pain may persist for months. Methylprednisolone seems to have no significant effect on the presence and intensity of pain.     

Giant Lymph Node Hyperplasia (Castleman's Disease) as a Rare Cause of Back Pain

Giant lymph node hyperplasia (Castleman''s disease) is a nonneoplastic lymphoproliferative disorder of unknown etiology that usually occurs in the chest. Its morphological recognition is based on a composition of various histological features. The mass is often asymptomatic, but it can cause nonspecific thoracic symptoms, such as regional pain. This disease can be found wherever lymph nodes are present, but two-thirds of these tumors are found in the chest, along the tracheobronchial tree in the mediastinum or lung hilus. However, we experienced an unusual case of Castleman''s disease as a cause of back pain that was localized in the posterior mediastinum bordering the chest wall.     

右美托咪定复合曲马多在开颅术后镇痛镇静效果的临床观察

目的 观察右美托咪定(Dex)复合曲马多对开颅术后病人镇痛和镇静的效果.方法 60例择期开颅手术病人随机分为对照组、Dex 0.2 μg组和Dex 0.4μg组,每组20例.Dex 0.2 μg组和Dex 0.4μg组均于麻醉诱导前10 min静脉泵人Dex(1μg/kg),而后再分别以0.2、0.4 μg/(kg·h)的速率泵注至术后24h.3组均于硬脑膜缝合完毕时静脉注射曲马多(1.5 mg/kg),术毕连接镇痛泵.并根据视觉模拟量表(VAS)评分、镇痛泵总按压次数和Ramsay评分等指标评价3组开颅术后镇痛、镇静的效果.结果 VAS评分:除术后2h外,Dex 0.4 μg组＜Dex 0.2μg组＜对照组(P＜0.05).Ramsay评分:在术后各时间点,Dex 0.2 μg组和Dex 0.4 μg组均显著高于对照组(P＜0.05);术后6～24 h,Dex 0.4μg组均显著高于Dex 0.2 μg组(P＜0.05).镇痛泵总按压次数:Dex 0.4 μg组＜Dex 0.2 μg组＜对照组(P＜0.05).术后恶心呕吐的发生率:Dex 0.4 μg组明显低于Dex 0.2 μg组和对照组(P＜0.05).结论 Dex能提高曲马多的镇痛效果,并可提供良好的镇静作用,减少术后不良反应的发生率.     

Recent advances in the design and development of novel negative allosteric modulators of mGlu(5)

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu(5)) have remained attractive to researchers as potential therapies for a number of central nervous system related diseases, including anxiety, pain, gastroesophageal reflux disease (GERD), addiction, Parkinson's disease (PD), and fragile X syndrome (FXS). In addition to the many publications with supportive preclinical data with key tool molecules, recent positive reports from the clinic have bolstered the confidence in this approach. During the two year time span from 2009 through 2010, a number of new mGlu(5) NAM chemotypes have been disclosed and discussed in the primary and patent literature. A summary of several efforts representing many diverse chemotypes are presented here, along with a discussion of representative structure activity relationships (SAR) and synthetic approaches to the templates where possible.     

Hypersensitivity and hyperalgesia in somatoform pain disorders

Objective

In psychiatry, pain disorders not explained by structural lesions have been classified for decades as somatoform pain disorders, the underlying concept being somatization. In a parallel move, somatic medicine has defined an expanding group of similar pain disorders, known as functional pain syndromes. Functional pain syndromes are characterized by enhanced pain sensitivity. The aim of our study was to investigate the proportion of patients with somatoform pain disorders who also meet the criteria of functional pain syndromes and the extent to which patients with somatoform pain disorders also show enhanced pain sensitivity.

Methods

Data on pain sensitivity in 120 hospitalized patients were obtained by means of two algometric methods. The group of patients with somatoform pain disorders was further divided into two subsets: patients with and those without a co-diagnosis of a functional pain syndrome. Patients with nociceptive pain served as control group.

Results

Of the 120 in-patients selected, 67 fulfilled the criteria of a somatoform pain disorder of which 41 (61%) also met the co-diagnosis of a functional pain syndrome. Patients with somatoform pain disorder differed from controls in that they showed enhanced pain sensitivity, irrespective of whether a functional pain syndrome was concomitantly present (P< .001).

Conclusions

Somatoform pain disorders show considerable overlap with functional pain syndromes, including enhanced pain sensitivity. This suggests the relevance of integrating somatosensory aspects of pain into a modified understanding of somatoform pain disorders.     

Network properties and regional brain morphology of the insular cortex correlate with individual pain thresholds

Pain thresholds vary considerably across individuals and are influenced by a number of behavioral, genetic and neurobiological factors. However, the neurobiological underpinnings that account for individual differences remain to be fully elucidated. In this study, we used voxel‐based morphometry (VBM) and graph theory, specifically the local clustering coefficient (CC) based on resting‐state connectivity, to identify brain regions, where regional gray matter volume and network properties predicted individual pain thresholds. As a main finding, we identified a cluster in the left posterior insular cortex (IC) reaching into the left parietal operculum, including the secondary somatosensory cortex, where both regional gray matter volume and the local CC correlated with individual pain thresholds. We also performed a resting‐state functional connectivity analysis using the left posterior IC as seed region, demonstrating that connectivity to the pre‐ as well as postcentral gyrus bilaterally; that is, to the motor and primary sensory cortices were correlated with individual pain thresholds. To our knowledge, this is the first study that applied VBM in combination with voxel‐based graph theory in the context of pain thresholds. The co‐location of the VBM and the local CC cluster provide first evidence that both structure and function map to the same brain region while being correlated with the same behavioral measure; that is, pain thresholds. The study highlights the importance of the posterior IC, not only for pain perception in general, but also for the determination of individual pain thresholds.     

Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics

This Review describes recent activity in the advancement of ligands for the metabotropic glutamate 4 receptor subtype and their potential utility as central nervous system (CNS) therapeutics. Until recently, there was a paucity of compounds with suitable selectivity and druglike properties to elucidate the value of this target. The search for selective entities has led several groups to the investigation of allosteric modulators as a path to optimization of potential ligands. Recent efforts, discussed here, have afforded a variety of derivatives with improvements in potency, solubility, and pharmacokinetic properties that garner support for continued investigation and optimization.     

Behavioral evidence showing the predominance of diffuse pain stimuli over discrete stimuli in influencing perception

This experiment was directed toward determining the relative effectiveness of discrete and diffuse pain stimuli in influencing perception and behavior. Shocks to the footpads were use to activate the discrete pain pathways. In the first phase of this experiment, cats were trained to escape from foot shock in a shuttle box. Current applied to the feet was varied in ascending and descending sequences for each animal according to the psychophysical method of limits and each animal was trained until stable thresholds for escape responding were achieved. In the second phase of the experiment, the effect on behavior of simultaneous activation of both the discrete and diffuse pain systems was assessed. The principal finding in this experiment was that escape responding that was well established when foot shock was presented alone was routinely abolished on trials when tooth shock and foot shock were presented together. These results were interpreted as indicating that the diffuse pain system was prepotent in influencing behavior when both the discrete and diffuse pain systems were activated simultaneously.     

Aβ peptides as one of the crucial volume transmission signals in the trophic units and their interactions with homocysteine. Physiological implications and relevance for Alzheimer’s disease

Summary. Amyloid peptides (Aβ) can operate as volume transmission (VT) signals since they are continuously released from cells of the central nervous system and diffuse in the extra-cellular space of the brain. They have both regulatory and trophic functions on cellular networks. In agreement with Aβ regulatory actions on glial-neuronal networks, the present paper reports new findings demonstrating that intrastriatal injections of Aβ peptides reduce striatal tyrosine hydroxylase, increase striatal GFAP immunoreactivities and lower pain threshold in experimental rats. Furthermore, it has been demonstrated that exogenous homocysteine (Hcy) binds Aβ(1-40) favouring its β-sheet conformation both in vitro and in vivo and hence the formation of β-fibrils and development of neurotoxicity. Thus, the hypothesis is discussed that Aβ peptides represent crucial VT-signals in the brain and their action is altered by dysmetabolic signals such as high Hcy extra-cellular levels, known to be an important risk factor for Alzheimer’s disease.