Chronic pain as a reticular formation syndrome

Evidence was previously presented to support the thesis that chronic pain is activated by neuronal elements that make up the multisynaptic short axon core of the reticular system (Andy and Peeler 1985). The present thesis, that chronic pain is a reticular formation syndrome, is based on a retrospective analysis of four patients with chronic pain who were successfully treated with a lesion in the anterior thalamus and stimulation electrode implants in the posterior thalamus and pontomesencephalic brain stem. The reticular formation was the common underlying anatomic substrate at those three sites. In addition to chronic pain, all the patients had other symptoms attributable to other body organs and systems. The number and type of symptoms that made up the syndrome differed between patients. Symptoms making up the core of the syndrome were pain, anxiety, nervousness, insomnia, and depression. Experimental and clinical findings are briefly presented to demonstrate the various reticular formation sites, pragmatically considered "reticular functional systems," from which symptoms may arise. It is hypothesized that the symptoms are recruited by a low threshold "pain oscillator" that is generated at one reticular site and subsequently permeates the rest of the reticular system. Therapeutic stimulation inactivates the low threshold system by "jamming" it.     

Le syndrome douloureux chronique pelvien chez l’homme. Quelle physiopathologie? Quel traitement?

Chronic pelvic pain, in young men or elderly men, has always been a challenge to the medical profession, raising problems of assessment and management. Chronic pelvic pain has a high prevalence, which is underestimated as indicated by the following figures: 4% to 8% of patients consulting chronic pain centres, 15% of patients consulting a urologist for symptoms of chronic prostatitis with alteration of quality of life, 70,000 cases of chronic cystitis per year in the USA. The circumstances of onset are multiple: postoperative, after minor or major trauma or postinfectious, sometimes without any particular aetiology and often in a multifactorial context. The pathophysiology is therefore vague and poorly elucidated, as only about 5% of cases of chronic prostatitis have a bacterial cause. However, any form of stimulation activates pain pathways with neurogenic inflammation followed by central sensitization and modification of neuronal plasticity, and finally chronic refractory pain with organic dysfunction. This mechanism is currently proposed in numerous publications concerning postoperative chronic pelvic pain and refractory cystitis and chronic prostatitis. The pathophysiology of these types of pain is probably therefore neurogenic. In the absence of stimulation, a pudendal nerve tunnel syndrome can be suggested. The treatment of chronic pelvic pain in men can be considered in the following way: aetiological treatment whenever possible, neurogenic medical treatment (tricyclic antidepressants for continuous pain, anticonvulsants for intermittent pain, NMDA receptor antagonists in the case of failure), treatment of organic dysfunction, pudendal nerve analgesic block in the case of suspected tunnel syndrome and global treatment of patient with impaired quality of life. In conclusion, a better pathophysiological approach to these forms of chronic pelvic pain can improve these difficult patients.     

Experimental autoimmune prostatitis induces chronic pelvic pain

Pain is the hallmark of patients with chronic prostatitis (CP) and chronic pelvic pain syndrome (CPPS). Despite numerous hypotheses, the etiology and pathogenesis remain unknown. To better understand CP/CPPS, we used a murine experimental autoimmune prostatitis model to examine the development, localization, and modulation of pelvic pain. Pelvic pain was detected 5 days after antigen instillation and was sustained beyond 30 days, indicating the development of chronic pain. The pain was attenuated by lidocaine treatment into the prostate, but not into the bladder or the colon, suggesting that pain originated from the prostate. Experimental autoimmune prostatitis histopathology was confined to the prostate with focal periglandular inflammatory infiltrates in the ventral, dorsolateral, and anterior lobes of the mouse prostate. Inflammation and pelvic pain were positively correlated and increased with time. Morphologically, the dorsolateral prostate alone showed significantly increased neuronal fiber distribution, as evidenced by increased protein gene product 9.5 expression. Pelvic pain was attenuated by treatment with the neuromodulator gabapentin, suggesting spinal and/or supraspinal contribution to chronic pain. These results provide the basis for identifying mechanisms that regulate pelvic pain and the testing of therapeutic agents that block pain development in CP/CPPS.     

CCL2 and CCL3 are essential mediators of pelvic pain in experimental autoimmune prostatitis

Experimental autoimmune prostatitis (EAP) is a murine model of chronic prostatitis/chronic pelvic pain syndrome (CPPS) in men, a syndrome characterized by chronic pelvic pain. We have demonstrated that chemokine ligands CCL2 and CCL3 are biomarkers that correlate with pelvic pain symptoms. We postulated that CCL2 and CCL3 play a functional role in CPPS and therefore examined their expression in EAP. Upon examination of the prostate 5 days after induction of EAP, CCL2 mRNA was elevated 2- to 3-fold, CCL8 by 15-fold, CCL12 by 12- to 13-fold, and CXCL9 by 2- to 4-fold compared with control mice. At 10 days the major chemokines were CXCL13 and CXCL2; at 20 days CCL2 (1- to 2-fold), CCL3 (2- to 3-fold) and CCL11 (2- to 3-fold); and at 30 days, CCL12 (20- to 35-fold) and smaller increases in CCL2, CCL3, and XCL1. Chemokine elevations were accompanied by increases in mast cells and B cells at 5 days, monocytes and neutrophils at day 10, CD4+ T cells at day 20, and CD4+ and CD8+ T cells at day 30. Anti-CCL2 and anti-CCL3 neutralizing antibodies administered at EAP onset attenuated pelvic pain development, but only anti-CCL2 antibodies were effective therapeutically. CCL2- and its cognate receptor CCR2-deficient mice were completely protected from development of pain symptoms but assumed susceptibility after reconstitution with wild-type bone marrow. CCL3-deficient mice showed resistance to the maintenance of pelvic pain while CCR5-deficient mice did not show any lessening of pelvic pain severity. These results suggest that the CCL2-CCR2 axis and CCL3 are important mediators of chronic pelvic pain in EAP.     

Management of men diagnosed with chronic prostatitis/chronic pelvic pain syndrome who have failed traditional management

For many patients, the traditional biomedical model that physicians have used to manage chronic prostatitis does not work. This article describes innovative treatment strategies for chronic prostatitis/chronic pelvic pain syndrome, with an emphasis on novel biomedical physical therapy and biopsychosocial approaches to the management of individualized patient symptoms.     

Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents

In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latter, rather than the pain, might explain the HPA results. A population study ascertained pain and psychological status in subjects aged 25 to 65 years. Random samples were selected from the following three groups: satisfying criteria for chronic widespread pain; free of chronic widespread pain but with strong evidence of somatisation ('at risk'); and a reference group. HPA axis function was assessed from measuring early morning and evening salivary cortisol levels, and serum cortisol after physical (pain pressure threshold exam) and chemical (overnight 0.25 mg dexamethasone suppression test) stressors. The relationship between HPA function with pain and the various psychosocial scales assessed was modelled using appropriate regression analyses, adjusted for age and gender. In all 131 persons with chronic widespread pain (participation rate 74%), 267 'at risk' (58%) and 56 controls (70%) were studied. Those in the chronic widespread pain and 'at risk' groups were, respectively, 3.1 (95% CI (1.3, 7.3)) and 1.8 (0.8, 4.0) times more likely to have a saliva cortisol score in the lowest third. None of the psychosocial factors measured were, however, associated with saliva cortisol scores. Further, those in the chronic widespread pain (1.9 (0.8, 4.7)) and 'at risk' (1.6 (0.7, 3.6)) groups were also more likely to have the highest serum cortisol scores. High post-stress serum cortisol was related to high levels of psychological distress (p = 0.05, 95% CI (0.02, 0.08)). After adjusting for levels of psychological distress, the association between chronic widespread pain and post-stress cortisol scores remained, albeit slightly attenuated. This is the first population study to demonstrate that those with established, and those psychologically at risk of, chronic widespread pain demonstrate abnormalities of HPA axis function, which are more marked in the former group. Although some aspects of the altered function are related to the psychosocial factors measured, we conclude that the occurrence of HPA abnormality in persons with chronic widespread pain is not fully explained by the accompanying psychological stress.     

Painful channels

Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, OMIM 167400), is an inherited disease causing intense burning rectal, ocular, and submandibular pain and flushing. Fertleman et al. (this issue of Neuron) show that mutations in SCN9A, the gene encoding the sodium channel Na(V)1.7 channels, are responsible for this syndrome. Together with earlier work implicating a distinct class of functional mutations in SCN9A in a distinct inherited pain syndrome, these results point to Na(V)1.7 channels as key players in signaling nociceptive information and as a potential target for drug therapy of chronic pain.     

Intrathecal pertussis toxin attenuates the morphine withdrawal syndrome in normal but not in arthritic rats

The effect of intrathecal pertussis toxin on morphine dependence was studied in rats suffering from chronic pain (Freund's adjuvant-induced arthritis). Animals were rendered tolerant-dependent by subcutaneous implantation of 3 pellets of 75 mg morphine base each. In both, normal and arthritic animals, 1 microgram pertussis toxin reduced the analgesia induced by morphine in the tail-flick test. Naloxone (1 mg/kg, s.c.) precipitated a withdrawal syndrome in arthritic animals that was milder in respect to the one produced in normal rats. Pretreatment with pertussis toxin significantly diminished the incidence of withdrawal signs such as jumps, squeak on touch, chattering, ptosis, body shakes and diarrhoea in tolerant-dependent normal rats, while this effect could not be observed in animals suffering from chronic pain. This differential activity of the toxin could be due to the altered tonus of certain neurotransmitter systems that accompanies the chronic situation of pain.     

Functional Reorganization of the Default Mode Network across Chronic Pain Conditions

Chronic pain is associated with neuronal plasticity. Here we use resting-state functional magnetic resonance imaging to investigate functional changes in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA). We isolated five meaningful resting-state networks across the groups, of which only the default mode network (DMN) exhibited deviations from healthy controls. All patient groups showed decreased connectivity of medial prefrontal cortex (MPFC) to the posterior constituents of the DMN, and increased connectivity to the insular cortex in proportion to the intensity of pain. Multiple DMN regions, especially the MPFC, exhibited increased high frequency oscillations, conjoined with decreased phase locking with parietal regions involved in processing attention. Both phase and frequency changes correlated to pain duration in OA and CBP patients. Thus chronic pain seems to reorganize the dynamics of the DMN and as such reflect the maladaptive physiology of different types of chronic pain.     

Th1-Th17 Cells Contribute to the Development of Uropathogenic Escherichia coli-Induced Chronic Pelvic Pain

The etiology of chronic prostatitis/chronic pelvic pain syndrome in men is unknown but may involve microbes and autoimmune mechanisms. We developed an infection model of chronic pelvic pain in NOD/ShiLtJ (NOD) mice with a clinical Escherichia coli isolate (CP-1) from a patient with chronic pelvic pain. We investigated pain mechanisms in NOD mice and compared it to C57BL/6 (B6) mice, a strain resistant to CP-1-induced pain. Adoptive transfer of CD4+ T cells, but not serum, from CP-1-infected NOD mice was sufficient to induce chronic pelvic pain. CD4+ T cells in CP-1-infected NOD mice expressed IFN-γ and IL-17A but not IL-4, consistent with a Th1/Th17 immune signature. Adoptive transfer of ex-vivo expanded IFN-γ or IL-17A-expressing cells was sufficient to induce pelvic pain in naïve NOD recipients. Pelvic pain was not abolished in NOD-IFN-γ-KO mice but was associated with an enhanced IL-17A immune response to CP1 infection. These findings demonstrate a novel role for Th1 and Th17-mediated adaptive immune mechanisms in chronic pelvic pain.     

Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome

Fibromyalgia (FM) pain is frequent in the general population but its pathogenesis is only poorly understood. Many recent studies have emphasized the role of central nervous system pain processing abnormalities in FM, including central sensitization and inadequate pain inhibition. However, increasing evidence points towards peripheral tissues as relevant contributors of painful impulse input that might either initiate or maintain central sensitization, or both. It is well known that persistent or intense nociception can lead to neuroplastic changes in the spinal cord and brain, resulting in central sensitization and pain. This mechanism represents a hallmark of FM and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established only minimal nociceptive input is required for the maintenance of the chronic pain state. Additional factors, including pain related negative affect and poor sleep have been shown to significantly contribute to clinical FM pain. Better understanding of these mechanisms and their relationship to central sensitization and clinical pain will provide new approaches for the prevention and treatment of FM and other chronic pain syndromes.     

Alpha-blockers for the treatment of prostatitis-like syndromes

Prostatitis is a common medical diagnosis. The etiology of this symptomatic syndrome can be an acute or chronic bacterial infection, a noninfectious initiator (the most common cause), or iatrogenic heat or radiation; the syndrome may coexist with benign prostatic hyperplasia. Alpha-blockers have a role in the treatment of the prostatitis syndromes. In Category I, acute bacterial prostatitis, alpha-blockers have been shown to possibly ameliorate obstructive and irritative voiding symptoms. In Category II, chronic bacterial prostatitis, alpha-blockers seem to reduce the risk of clinical and bacteriological recurrence. In Category III, chronic pelvic pain syndrome, alpha-blockers improve symptoms and quality of life. Alpha-blockers also seem to ameliorate the symptoms and reduce the risk of acute urinary retention in patients who suffer from either heat- or radiation-induced prostatic inflammation. Alpha-blockers improve lower urinary tract symptoms, including pain, in patients who are diagnosed with both prostatitis and benign prostatic hyperplasia. Evidence has proven there is definitely a role for alpha-blockers in the management of the prostatitis syndromes.     

Possible Molecular Mediators Involved and Mechanistic Insight into Fibromyalgia and Associated Co-morbidities

Neurochemical Research - Fibromyalgia is a chronic complex syndrome of non-articulate origin characterized by musculoskeletal pain, painful tender points, sleep problems and co-morbidities...     

慢性应激致肠易激综合征大鼠模型的建立与评价

目的建立一种模拟肠易激综合征临床症状的动物模型,为相关药物的研究提供实验基础。方法采用孤养附加慢性不可预见性刺激建立IBS模型,每只大鼠受到的刺激因子包括:24h禁水、24h禁食、昼夜颠倒、4℃冰水游泳15min、45℃高温5min、钳尾致痛1min、束缚制动5～8h、高速震荡15min等共8种,每种刺激因子出现5次,共40d。用腹部回撤反射压力阈值(AWR)和排便粒数检测动物的内脏感觉和胃肠运动功能变化;用敞箱行为评分和蔗糖水偏嗜度评价动物神经精神活动变化。结果造模2～3周腹部回撤反射压力阈值明显降低,排便粒数明显增加;造模3～4周模型组动物敞箱实验行为评分和蔗糖水偏嗜度明显降低。造模40d时,上述变化趋势仍存在。结论慢性应激加孤养可诱导动物胃肠运动亢进、内脏感觉致敏和神经精神活动的改变,模拟IBS患者的临床特征,可作为一种有效的IBS动物模型,用于评价相关药物。     

The Urinary Proteomic Profile Implicates Key Regulators for Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Research Network Study

Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 participants was performed. The participants included patients with UCPPS (n = 82), healthy controls (HC) (n = 94), and disparate chronic pain diseases, termed positive controls (PC) (n = 68). Using training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n = 9) and UCPPS from PC (n = 3). The validated UCPPS: HC proteins were predominantly extracellular matrix/extracellular matrix modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by the members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue, and increased bleeding. Comparison with the PC cohort enabled the evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, interleukin-6, epidermal growth factor, and transforming growth factor beta 1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.     

伴血嗜酸性粒细胞增高的腹痛临床分析

目的探讨伴血嗜酸性粒细胞(Eosinophil,EOS)增高的腹痛病因、诊断、治疗方法。方法对我院31例伴血EOS增高的腹痛患者的临床表现、实验室检查、特殊检查结果进行分析,总结伴血EOS增高的腹痛病因及治疗方法。结果伴血EOS升高的腹痛的病因以寄生虫、变态反应性疾病为主,此外亦有可能为嗜酸性胃肠炎(Eosinophilic Gastroenteritis,EG)、恶性肿瘤、药物所致,少见病因为炎症性肠病、慢性胰腺炎、特发性嗜酸性细胞增多症(Idiopathic Hypereosinophilic Syndrome,HES)等。大部分EOS升高的腹痛以治疗原发病为主,EG及HES以激素治疗为主。结论伴血EOS升高的腹痛病因多样,大部分病因治疗原发病后EOS可自行下降,EG及HES以激素治疗效果好,作用迅速。     

Prostatite chronique, syndrome douloureux pelvien chronique et dysfonctions sexuelles

In 1995, the NIH (National Institutes of Health, USA) proposed a new classification of chronic prostatitis (CP), no longer considered in the strict framework of the prostate, but based on the concept of pelvic pain. This classification introduced the term chronic pelvic pain syndrome (CPPS). The definition of this syndrome indicates that pain is sometimes associated with sexual disorders. Many surveys have demonstrated the considerable prevalence of CP/CPPS and have confirmed the impact of these diseases on quality of life, but only limited epidemiological data concerning the links between CP/CPPS and sexuality are available at the present time. The pathophysiology of sexual dysfunction associated with CP/CPPS (alteration of desire, erectile dysfunction and premature ejaculation) also remains poorly elucidated. A psychological factor is very probably involved, but many uncertainties persist concerning the other mechanisms possibly involved.     

The Urinary Proteomic Profile Implicates Key Regulators for Urologic Chronic Pelvic Pain Syndrome (UCPPS): A MAPP Research Network Study

Urologic chronic pelvic pain syndrome (UCPPS) is a condition of unknown etiology characterized by pelvic pain and urinary frequency and/or urgency. As the proximal fluid of this syndrome, urine is an ideal candidate sample matrix for an unbiased study of UCPPS. In this study, a large, discovery-phase, TMT-based quantitative urinary proteomics analysis of 244 participants was performed. The participants included patients with UCPPS (n = 82), healthy controls (HC) (n = 94), and disparate chronic pain diseases, termed positive controls (PC) (n = 68). Using training and testing cohorts, we identified and validated a small and distinct set of proteins that distinguished UCPPS from HC (n = 9) and UCPPS from PC (n = 3). The validated UCPPS: HC proteins were predominantly extracellular matrix/extracellular matrix modifying or immunomodulatory/host defense in nature. Significantly varying proteins in the UCPPS: HC comparison were overrepresented by the members of several dysregulated biological processes including decreased immune cell migration, decreased development of epithelial tissue, and increased bleeding. Comparison with the PC cohort enabled the evaluation of UCPPS-specific upstream regulators, contrasting UCPPS with other conditions that cause chronic pain. Specific to UCPPS were alterations in the predicted signaling of several upstream regulators, including alpha-catenin, interleukin-6, epidermal growth factor, and transforming growth factor beta 1, among others. These findings advance our knowledge of the etiology of UCPPS and inform potential future clinical translation into a diagnostic panel for UCPPS.     

Unique Microstructural Changes in the Brain Associated with Urological Chronic Pelvic Pain Syndrome (UCPPS) Revealed by Diffusion Tensor MRI,Super-Resolution Track Density Imaging,and Statistical Parameter Mapping: A MAPP Network Neuroimaging Study

Studies have suggested chronic pain syndromes are associated with neural reorganization in specific regions associated with perception, processing, and integration of pain. Urological chronic pelvic pain syndrome (UCPPS) represents a collection of pain syndromes characterized by pelvic pain, namely Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) and Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS), that are both poorly understood in their pathophysiology, and treated ineffectively. We hypothesized patients with UCPPS may have microstructural differences in the brain compared with healthy control subjects (HCs), as well as patients with irritable bowel syndrome (IBS), a common gastrointestinal pain disorder. In the current study we performed population-based voxel-wise DTI and super-resolution track density imaging (TDI) in a large, two-center sample of phenotyped patients from the multicenter cohort with UCPPS (N = 45), IBS (N = 39), and HCs (N = 56) as part of the MAPP Research Network. Compared with HCs, UCPPS patients had lower fractional anisotropy (FA), lower generalized anisotropy (GA), lower track density, and higher mean diffusivity (MD) in brain regions commonly associated with perception and integration of pain information. Results also showed significant differences in specific anatomical regions in UCPPS patients when compared with IBS patients, consistent with microstructural alterations specific to UCPPS. While IBS patients showed clear sex related differences in FA, MD, GA, and track density consistent with previous reports, few such differences were observed in UCPPS patients. Heat maps illustrating the correlation between specific regions of interest and various pain and urinary symptom scores showed clustering of significant associations along the cortico-basal ganglia-thalamic-cortical loop associated with pain integration, modulation, and perception. Together, results suggest patients with UCPPS have extensive microstructural differences within the brain, many specific to syndrome UCPPS versus IBS, that appear to be localized to regions associated with perception and integration of sensory information and pain modulation, and seem to be a consequence of longstanding pain.     

Protective Effect of Esculetin,Natural Coumarin in Mice Model of Fibromyalgia: Targeting Pro-Inflammatory Cytokines and MAO-A

Neurochemical Research - Fibromyalgia is a refractory syndrome characterized by chronic wayward pain and complex co-morbid psychological trepidation. The current treatments have a limited role and...