Central Sensitization Mechanisms Research Articles

Peripheral Nerve Denervation in Streptozotocin-Induced Diabetic Rats Is Reduced by Cilostazol

Background and Objective: Our previous study demonstrated that consistent treatment of oral cilostazol was effective in reducing levels of painful peripheral neuropathy in streptozotocin-induced type I diabetic rats. As diabetic neuropathy is characterized by hyperglycemia-induced nerve damage in the periphery, this study aims to examine the neuropathology as well as the effects of cilostazol treatments on the integrity of peripheral small nerve fibers in type I diabetic rats. Materials and Methods: A total of ninety adult male Sprague-Dawley rats were divided into the following groups: (1) naïve (control) group; (2) diabetic rats (DM) group for 8 weeks; DM rats receiving either (3) 10 mg/kg oral cilostazol (Cilo10), (4) 30 mg/kg oral cilostazol (Cilo30), or (5) 100 mg/kg oral cilostazol (Cilo100) for 6 weeks. Pain tolerance thresholds of hind paws toward thermal and mechanical stimuli were assessed. Expressions of PGP9.5, P2X3, CGRP, and TRPV-1 targeting afferent nerve fibers in hind paw skin and glial cells in the spinal dorsal horn were examined via immunohistochemistry and immunofluorescence. Results: Oral cilostazol ameliorated the symptoms of mechanical allodynia but not thermal analgesia in DM rats. Significant reductions in PGP9.5-, P2X3-, CGRP, and TRPV-1-labeled penetrating nerve fibers in the epidermal layer indicated denervation of sensory nerves in the hind paw epidermis of DM rats. Denervation significantly improved in groups that received Cilo30 and Cilo100 in a dose-dependent manner. Cilostazol administration also suppressed microglial hyperactivation and increased astrocyte expressions in spinal dorsal horns. Conclusions: Oral cilostazol ameliorated hyperglycemia-induced peripheral small nerve fiber damage in the periphery of diabetic rats and effectively mitigated diabetic neuropathic pain via a central sensitization mechanism. Our findings present cilostazol not only as an effective option for managing symptoms of neuropathy but also for deterring the development of diabetic neuropathy in the early phase of type I diabetes.

Trial protocol for a multicenter randomized controlled trial to assess the efficacy and safety of intravenous ketamine for chronic daily headaches: the “KetHead” trial

BackgroundChronic daily headaches (CDH) are common and associated with significant morbidity, poor quality of life, and substantial burden on the healthcare system. CDH tends to be refractory to conventional medical management and/or patients cannot afford expensive treatments. It is stipulated that CDH share a mechanism of central sensitization in the trigeminocervical complex, mediated by activation of the N-methyl-d-aspartate (NMDA) receptors. Ketamine, a non-competitive NMDA antagonist, has been used in the treatment of chronic pain, but its role in CDH has not been completely established. This trial aims to evaluate the effect of high-dose IV ketamine infusions (compared to placebo) on the number of headache days at 28 days post-infusion.MethodsA multicenter, placebo-controlled, randomized controlled trial will be conducted with two parallel groups and blinding of participants and outcome assessors. The study will include 56 adults with a CDH diagnosis as per ICHD-3 criteria. Participants will be randomized (1:1) to either ketamine (1 mg. kg−1 bolus followed by infusion of 1 mg. kg−1. h−1 for 6 h) or placebo (0.9% saline in the same volume and infusion rate as the trial medication) bolus and infusion for 6 h. The impact on the number of monthly headache days, headache intensity, physical activity, mood, sleep, quality of life, analgesic consumption, and adverse effects will be recorded at baseline, immediately post-infusion, and from 1 to 28 days, 29 to 56 days, and 57 to 84 days after the infusionDiscussionDespite advancements in treatment, many patients continue to suffer from CDH. This trial investigates whether high-dose IV ketamine infusions can effectively and safely improve the CDH burden as compared to a placebo infusion. This treatment could become a safe, affordable, and widely available option for patients living with refractory headache.Trial registrationClinicalTrials.gov NCT05306899. Registered on April 1, 2022

Mechanisms of Peripheral and Central Sensitization in Osteoarthritis Pain.

Pain, the primary symptom of osteoarthritis (OA), reduces both the quality and quantity of life for patients. The pathophysiology of OA pain is complex and often difficult to explain solely by radiological structural changes. One reason for this discrepancy is pain sensitization (peripheralsensitization [PS] and central sensitization [CS]) in OA. Thus, an understanding of pain sensitization is important when considering treatment strategies and development for OA pain. In recent years, pro-inflammatory cytokines, nerve growth factors (NGFs), and serotonin have been identified as causative agents that induce peripheral and central sensitization and are becoming therapeutic targets for OA pain. However, the characteristics of the clinical manifestations of pain sensitization elicited by these molecules remain unclear, and it is not well understood who among OA patients should receive the therapeutic intervention. Thus, this review summarizes evidence on the pathophysiology of peripheral and central sensitization in OA pain and the clinical features and treatment options for this condition. While the majority of the literature supports the existence of pain sensitization in chronic OA pain, clinical identification and treatment of pain sensitization in OA are still in their infancy, and future studies with good methodological quality are needed.

Is central sensitization relevant in acute low back pain?

Is central sensitization relevant in acute low back pain?

Polygenic Contributions to Chronic Overlapping Pain Conditions in a Large Electronic Health Record Sample

Chronic overlapping pain conditions (COPCs) are believed to share common etiological mechanisms involving central sensitization. Genetic and environmental factors putatively combine to influence susceptibility to central sensitization and COPCs. This study employed a genome-wide polygenic risk score approach to evaluate genetic influences on 8 common COPCs. COPCs were identified by International Classification of Disease codes in Vanderbilt's deidentified clinical biorepository (BioVU), with each COPC condition empirically weighted for the level of central sensitization based on prior work. A centralized pain score (CPS) was calculated for 55,340 individuals by summing the weighted number of COPCs. Overall, 12,502 individuals (22.6%) were diagnosed with at least 1 COPC, with females exhibiting nearly twice the mean CPS as males. To assess the genetic influence on centralized pain in COPCs, 6 pain polygenic risk scores (PRSs) were developed using UK Biobank data to predict 6 pain criteria (no pain, neck/shoulder, abdomen, hip, knee, low back pain). These PRSs were then deployed in the BioVU cohort to test for association with CPS. In regression models adjusted for age, sex, and BMI, all pain PRSs except hip pain were significantly associated with CPS. Our findings support a shared polygenic influence across COPCs potentially involving central sensitization mechanisms. PerspectiveThis study used a polygenic risk score approach to investigate genetic influences on chronic overlapping pain conditions. Significant findings in this study provide evidence supporting previous hypotheses that a shared polygenic influence involving central sensitization may underly chronic overlapping pain conditions and can guide future biomarker and risk assessment research.

Mechanisms of chiropractic spinal manipulative therapy for patients with chronic primary low back pain: protocol for a mechanistic randomised placebo-controlled trial

IntroductionChronic low back pain (CLBP) is a highly prevalent and disabling condition. Identifying subgroups of patients afflicted with CLBP is a current research priority, for which a classification system based...

Effects of Danzhen headache capsule on the expression of CREB and ERK in CM rats by mediated central sensitization mechanism

目的: 探讨丹珍头痛胶囊对中枢敏感介导的慢性偏头痛大鼠的干预作用。方法: 将60只SD大鼠随机分为正常组、模型组、盐酸氟桂利嗪组(FNZ)、丹珍头痛胶囊(DZTT)高、中、低剂量组(1.0、0.5、0.25 g/kg)(n=10)。采用连续皮下注射硝酸甘油法制作慢性偏头痛大鼠模型,丹珍头痛胶囊给予大鼠灌胃治疗,每天1次,连续35 d。观测各组大鼠大体状态、耳红出现及消失时间、搔头次数、爬笼次数等疼痛行为学指标,测定眶周及足底的机械痛阈值,RT-PCR及Western blot技术分别检测三叉神经脊束核尾侧(TNC)组织中CREB、ERK的mRNA表达及CREB、pCREB、ERK、pERK蛋白表达水平。结果: 与正常组比较,模型组大鼠行为学评分明显升高,眶周及足底机械痛阈值逐日下降,TNC组织中CREB、ERK基因表达及CREB、pCREB、ERK、pERK蛋白表达水平均显著升高(P＜0.01);与模型组比较,DZTT、FNZ组大鼠疼痛症状明显缓解,疼痛行为学评分显著降低而眶周及足底机械痛阈值显著升高,TNC组织中CREB、ERK基因表达及CREB、pCREB、ERK、pERK蛋白表达水平均显著下降(P＜0.05,P＜0.01);与FNZ组比较,在给药第35日,DZTT高剂量组大鼠疼痛行为学评分、眶周及足底机械痛阈、TNC组织中CREB mRNA表达及ERK、pERK蛋白表达水平差异无显著性(P＞0.05)。结论: DZTT对中枢敏感介导的慢性偏头痛具有一定的治疗作用,抑制CREB、ERK的激活和磷酸化是其可能机制之一。.

Osteoarthritis: New Insight on Its Pathophysiology.

Understanding of the basis of osteoarthritis (OA) has seen some interesting advancements in recent years. It has been observed that cartilage degeneration is preceded by subchondral bone lesions, suggesting a key role of this mechanism within the pathogenesis and progression of OA, as well as the formation of ectopic bone and osteophytes. Moreover, low-grade, chronic inflammation of the synovial lining has gained a central role in the definition of OA physiopathology, and central immunological mechanisms, innate but also adaptive, are now considered crucial in driving inflammation and tissue destruction. In addition, the role of neuroinflammation and central sensitization mechanisms as underlying causes of pain chronicity has been characterized. This has led to a renewed definition of OA, which is now intended as a complex multifactorial joint pathology caused by inflammatory and metabolic factors underlying joint damage. Since this evidence can directly affect the definition of the correct therapeutic approach to OA, an improved understanding of these pathophysiological mechanisms is fundamental. To this aim, this review provides an overview of the most updated evidence on OA pathogenesis; it presents the most recent insights on the pathophysiology of OA, describing the interplay between immunological and biochemical mechanisms proposed to drive inflammation and tissue destruction, as well as central sensitization mechanisms. Moreover, although the therapeutic implications consequent to the renewed definition of OA are beyond this review scope, some suggestions for intervention have been addressed.

Phenotypes of gastroesophageal reflux disease: classification, pathogenesis and diagnostic criteria: A review

The literature review focuses on the current understanding of visceral hypersensitivity mechanisms in the esophagus. Mechanisms of peripheral and central sensitization and their relation to heartburn symptoms are covered in detail. Diagnostic criteria and algorithms for non-erosive reflux disease, functional heartburn, and esophagus hypersensitivity based on pH-impedance testing and high-resolution esophageal manometry data are presented.

Altered Cortical Trigeminal Fields Excitability by Spreading Depolarization Revealed with in Vivo Functional Ultrasound Imaging Combined with Electrophysiology.

Spreading depolarization, usually termed cortical spreading depression has been proposed as the pathophysiological substrate of migraine aura and as an endogenous trigger of headache pain. The links between neurovascular coupling and cortical craniofacial nociceptive activities modulated by SD were assessed by combining in vivo local field potential (LFP) recordings in the primary somatosensory cortex (S1) with functional ultrasound imaging of S1 and caudal insular (INS) cortices of anesthetized male rats. A single SD wave triggered in the primary visual cortex elicited an ipsilateral, quadriphasic hemodynamic and electrophysiological response in S1 with an early phase consisting of concomitant increases of relative cerebral blood volume (rCBV) and LFPs. A transient hypoperfusion was then correlated with the beginning of the neuronal silence, followed by a strong increase of rCBV, whereas synaptic activities remained inhibited.LFPs and rCBV recovery period was followed by a progressive increase in S1 and INS baseline activities and facilitation of cortical responses evoked by periorbital cutaneous receptive field stimulation. Sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles, and was significantly reduced by pretreatment with an NMDA antagonist. Combined high-resolution assessing of neurovascular coupling and electrophysiological activities has revealed a useful preclinical tool for deciphering central sensitization mechanisms involved in migraine attacks.SIGNIFICANCE STATEMENT A crucial unsolved issue is whether visual aura and migraine headache are parallel or sequential processes. Here, we show that a single spreading depolarization wave triggered from the primary visual cortex is powerful enough to elicit progressive, sustained increases of hemodynamic and sensory responses to percutaneous periorbital noxious stimuli recorded in S1 and insular ophthalmic fields. Sensitization of cortical ophthalmic fields by SD was bilateral, occurred with precise spatiotemporal profiles, and was significantly reduced by pretreatment with an NMDA antagonist. Combined high-resolution assessing of neurovascular coupling and electrophysiological activities has revealed a useful preclinical tool for deciphering central sensitization mechanisms involved in migraine attacks.

Patterns of change of multisite pain over 1 year of follow-up and related risk factors.

Multisite musculoskeletal pain is common and disabling. This study aimed to prospectively investigate the distribution of musculoskeletal pain anatomically, and explore risk factors for increases/reductions in the number of painful sites. Using data from participants working in 45 occupational groups in 18 countries, we explored changes in reporting pain at 10 anatomical sites on two occasions 14months apart. We used descriptive statistics to explore consistency over time in the number of painful sites, and their anatomical distribution. Baseline risk factors for increases/reductions by ≥3 painful sites were explored by random intercept logistic regression that adjusted for baseline number of painful sites. Among 8927 workers, only 20% reported no pain at either time point, and 16% reported ≥3 painful sites both times. After 14months, the anatomical distribution of pain often changed but there was only an average increase of 0.17 painful sites. Some 14% workers reported a change in painful sites by ≥3. Risk factors for an increase of ≥3 painful sites included female sex, lower educational attainment, having a physically demanding job and adverse beliefs about the work-relatedness of musculoskeletal pain. Also predictives were as follows: older age, somatizing tendency and poorer mental health (each of which was also associated with lower odds of reductions of ≥3 painful sites). Longitudinally, the number of reported painful sites was relatively stable but the anatomical distribution varied considerably. These findings suggest an important role for central pain sensitization mechanisms, rather than localized risk factors, among working adults. Our findings indicate that within individuals, the number of painful sites is fairly constant over time, but the anatomical distribution varies, supporting the theory that among people at work, musculoskeletal pain is driven more by factors that predispose to experiencing or reporting pain rather than by localized stressors specific to only one or two anatomical sites.

Results of an open multicenter non-interventional study of clinical efficacy and tolerability of etoricoxib in osteoarthritis and nonspecific back pain with additional evaluation of the effect of the drug on the «central» manifestations of pain

The formation of chronic musculoskeletal pain (MSP) is a multifactorial process, in its pathogenesis mechanism of central sensitization (CS) plays an important role.Objective: to evaluate the effectiveness of etoricoxib at a dose of 60 mg per day in diseases accompanied by moderate/severe chronic MPS, with an additional analysis of the effect of this drug on the manifestations of CS.Patients and methods. An open observational study, 790 patients (71.6% women, mean age 54.5±13.0 years) with osteoarthritis and chronic nonspecific back pain received etoricoxib 60 mg/day for 2 weeks. The dynamics of pain, dysfunction, fatigue, sleep disturbances, general health assessment (GHA) on a numerical rating scale (NRS 0–10), as well as signs of CS according to part A of the CSI questionnaire were assessed.Results and discussion. After 2 weeks, the intensity of pain during movement, at rest and at night decreased on average by 58.8±24.1, 69.7±32.6 and 70.1±32.8% respectively; functional insufficiency by 58.2±22.5%, fatigue by 52.2±25.8%, GHA by 50.0±22.6%, sleep improvement by 54.3±25.8% was observed (p<0.001 for all parameters). There was a decrease in the CSI value by an average of 33.1±14.5% (p<0.001), as well as a decrease in the number of patients with highly probable CS (CSI ≥40) from 35.3 to 10.3% (p<0.001). No serious drug-related complications were recorded. The overall frequency of adverse reactions was 5.9%, with dyspepsia and hypertension being the most common.Conclusion. Etoricoxib is an effective and relatively safe treatment for chronic MSP. It reduces the severity of CS, one of the central mechanisms of the pathogenesis of chronic MSP.

Preoperative Predictors of Complex Regional Pain Syndrome Outcomes in the 6 Months Following Total Knee Arthroplasty

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a “warm CRPS” phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P’s < .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P’s < .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P’s < .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P’s < .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PerspectiveThis article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.

Somatosensory assessments in patients with inflammatory bowel disease: a cross-sectional study examining pain processing pathways and the role of multiple patient factors.

Pain affects the majority of patients with inflammatory bowel disease (IBD), where pain experiences may be influenced by multiple patient factors and changes within central pain processing pathways, termed central sensitization. The current study aimed to investigate pain processing pathways in patients with IBD through somatosensory testing and associations with multiple patient factors. A cross-sectional study of adults with IBD. Assessments included: somatosensory tests [i.e. pressure pain thresholds (PPT), temporal summation (TS), conditioned pain modulation (CPM)], and patient factors (i.e. demographics, comorbidity, sleep quality, psychological, pain severity and interference, and IBD features). Multiple regression analyses explored associations between somatosensory tests and multiple patient factors. Decreased CPM in participants (N = 51) was associated with worse abdominal pain severity and use of biologic therapies (R2 = 0.30, F(5,44) = 5.18, P = 0.001). Increased TS was associated with biologic use (R2 = 0.11, F(1,49) = 6.13, P = 0.017). Decreased PPT at the low back (R2 = 0.29, F(2,48) = 11.21, P < 0.001) and Tibialis anterior (R2 = 0.41, F(2,48) = 18.26, P < 0.001) were associated with female sex and the absence of a stoma. Study results demonstrated associations between multiple patient factors and somatosensory tests in patients with IBD. The absence of a stoma and female sex was associated with greater sensitivity to pressure in two remote body regions, suggestive of widespread hyperalgesia. Worse abdominal pain severity and biologic use were associated with decreased pain inhibition, and biologic use was also associated with increased pain facilitation. These findings suggest the presence of altered pain processing and mechanisms of central sensitization in patients with IBD.

Wound Infusion of 0.35% Levobupivacaine Reduces Mechanical Secondary Hyperalgesia and Opioid Consumption After Cesarean Delivery: A Prospective, Randomized, Triple-Blind, Placebo-Controlled Trial.

Some patients still report moderate-to-severe postoperative pain after cesarean delivery. Local anesthetic wound infusion improves acute pain and might act on peripheral and central sensitization mechanisms; however, no studies have proved this hypothesis. We evaluated the potential benefits of continuous wound infusion of levobupivacaine after cesarean delivery on secondary hyperalgesia (primary end point) and primary hyperalgesia, pain relief, persistent pain, and inflammatory and metabolic stress response. Healthy women scheduled for elective cesarean delivery participated in this prospective, randomized, triple-blind, placebo-controlled trial (NCT01458431). All patients received spinal anesthesia with 0.5% hyperbaric bupivacaine with fentanyl and a multiholed wound catheter placed under the fascia. Women were randomized to receive continuous wound infusion (0.35% levobupivacaine 7 mL/h for 48 hours; group L) or an equal volume of saline (group S). Secondary hyperalgesia to punctate mechanical stimuli was evaluated using dynamic tests, and primary hyperalgesia was evaluated using an electronic von Frey anesthesiometer; both were assessed at 24, 48, and 72 hours. The following variables were collected: intensity of postoperative parietal and visceral pain at rest and on movement rated on a visual analog scale >72 hours, time to first bolus of patient-controlled analgesia (PCA), cumulative dose of rescue morphine (PCA) and acetaminophen, ability to sleep and sleep quality, and patient satisfaction. Persistent postoperative pain was evaluated during a telephone interview at 1, 3, 6, and 12 months after surgery. C-reactive protein, acid glycoprotein, preprandial glucose, insulin, cortisol, prolactin, growth hormone, and interleukin-6 were measured before cesarean delivery and at 8, 24, and 48 hours. Adverse events and patient outcomes were recorded. Seventy women were included. In group L, the area of secondary hyperalgesia was significantly reduced (43.4 [18.5-80] vs 68.4 [39.0-136] cm2 and 45.1 [0.9-89.8] vs 67.3 [31.3-175] cm2 at 24 and 48 hours, respectively; group:time interaction P value < .001), the mechanical pain threshold was significantly higher at 24 hours (633 [441-802] vs 417 [300-572] g.mm-2; P = .001), and morphine consumption was significantly lower at 24 hours (4 [2-11] vs 11[6-23]; P = .003) compared with group S. Levobupivacaine had no effect on persistent postoperative pain at 1, 3, 6, and 12 months. Plasma insulin levels in the immediate postoperative period and at 8, 24, and 48 hours were significantly lower in group L (P < .001). There were no significant differences in other biochemical parameters of inflammatory and endocrine-metabolic response. Levobupivacaine wound infusion provides adequate analgesia and might be an effective antihyperalgesic adjunct.

Self-Report of Severity of Ocular Pain Due to Light as a Predictor of Altered Central Nociceptive System Processing in Individuals With Symptoms of Dry Eye Disease

Dry eye disease (DED) is a diagnosis given to individuals with a heterogeneous combination of symptoms and/or signs, including spontaneous and evoked ocular pain. Our current study evaluated whether and which ocular pain assessments could serve as screening tools for central sensitization in individuals with DED. A cohort of individuals with DED symptoms (n = 235) were evaluated for ocular pain, DED signs (tear production, evaporation), evoked sensitivity to mechanical stimulation at the cornea, and evidence of central sensitization. Central sensitization was defined for this study as the presence of pain 30 seconds after termination of a thermal noxious temporal summation protocol (ie, aftersensations) presented at a site remote from the eye (ventral forearm). We found that combining ratings of average intensity of ocular pain, ratings of average intensity of pain due to light, response to topical anesthetic eye drops, and corneal mechanical pain thresholds produced the best predictive model for central sensitization (area under the curve of .73). When examining ratings of intensity of ocular pain due to light alone (0–10 numerical rating), a cutoff score of 2 maximized sensitivity (85%) and specificity (48%) for the presence of painful aftersensations at the forearm. Self-reported rating of pain sensitivity to light may serve as a quick screening tool indicating the involvement of central nociceptive system dysfunction in individuals with DED. PerspectiveThis study reveals that clinically-relevant variables, including a simple 0 to 10 rating of ocular pain due to light, can be used to predict the contribution of central sensitization mechanisms in a subgroup of individuals with DED symptoms. These findings can potentially improve patient stratification and management for this complex and painful disease.

Mechanisms of Peripheral and Central Pain Sensitization: Focus on Ocular Pain.

Persistent ocular pain caused by corneal inflammation and/or nerve injury is accompanied by significant alterations along the pain axis. Both primary sensory neurons in the trigeminal nerves and secondary neurons in the spinal trigeminal nucleus are subjected to profound morphological and functional changes, leading to peripheral and central pain sensitization. Several studies using animal models of inflammatory and neuropathic ocular pain have provided insight about the mechanisms involved in these maladaptive changes. Recently, the advent of new techniques such as optogenetics or genetic neuronal labelling has allowed the investigation of identified circuits involved in nociception, both at the spinal and trigeminal level. In this review, we will describe some of the mechanisms that contribute to the perception of ocular pain at the periphery and at the spinal trigeminal nucleus. Recent advances in the discovery of molecular and cellular mechanisms contributing to peripheral and central pain sensitization of the trigeminal pathways will be also presented.

Cross cultural adaptation, validity, and reliability of Central Sensitization Inventory in Arabic language

Purpose The Central Sensitization Inventory (CSI) is a tool that aid in identifying symptoms associated with nociplastic pain. The aim of this study is to adapt CSI to Arabic language, and to examine its psychometric properties. Methods Adaptation process followed recommended guidelines. Participants with self-reported chronic pain completed a web-based survey. The internal consistency was calculated. Test–retest reliability was examined by allowing 7–9 day gap between two rounds of measurements. Convergent validity was examined by measuring the correlation with Pain Catastrophizing Scale (PCS), EQ-VAS, and EQ-5D-3L. Discriminant validity was examined by testing four priori hypotheses. Factor analysis with principal components extraction was conducted. Results CSI-Arabic (CSI-Ar) was successfully produced. Its internal consistency and test–retest reliability were excellent (Cronbach's α = 0.88 and ICC2,1=0.94). The standard error of measurement and minimal detectable change 95% were 3.45 and 9.57, respectively. CSI total score correlation with PCS, EQ-5D-3L, and EQ-VAS was moderate. The results lend support to the four hypothesis related to discriminant validity. Factor analysis revealed a four-factor structure of CSI-Ar. Conclusions CSI-Ar showed an internal consistency, test–retest reliability, and validity that are comparable to similar studies. The results support the use of CSI-Ar in assessing chronic pain in Arabic-speaking population. Implications for rehabilitation Central sensitization (CS) mechanisms are thought to contribute to chronic pain. Identifying the presence of CS would personalize management. The Central Sensitization Inventory (CSI) is a valid and reliable tool to aid in identifying symptoms associated with CS. The Arabic version of the CSI is valid and reliable to use in Arabic speaking patients suffering from chronic pain.

Central sensitization in burning mouth syndrome: a practical approach using questionnaires

Some experts have suggested that burning mouth syndrome (BMS) should be included in the family of central sensitivity syndromes, a group of similar medical disorders linked by the central sensitization (CS) mechanism. Our objective is to assess the presence of CS in patients with BMS by performing a clinical examination and administering questionnaires to measure the generalized extent of pain, the presence of associated symptoms, and the number of other concurrent chronic pain conditions. We conducted a case-control study in 82 subjects (40 patients with BMS and 42 controls). Patients with BMS were diagnosed using The International Classification of Headache Disorders 3rd edition, beta version (ICHD-IIIβ) criteria. The Widespread Pain Index (WPI) and Symptom Severity (SS) Score questionnaires were used to determine the degree of central sensitivity. The number of other concurrent chronic pain conditions was determined with the Neblett inventory. Data indicative of CS show a statistically significant association with BMS. Both SS Score and Widespread Pain Index scores higher in patients with BMS. Additionally, patients with BMS reported a significantly higher number of other central sensitivity syndromes. Patients with BMS could present a CS component as well as other chronic pain conditions. The use of questionnaires may be useful to determine the degree of central sensitivity in patients with BMS.

Central sensitization of dorsal root potentials and dorsal root reflexes: An in vitro study in the mouse spinal cord.

Axo-axonic contacts onto central terminals of primary afferents modulate sensory inputs to the spinal cord. These contacts produce primary afferent depolarization (PAD), which serves as a mechanism for presynaptic inhibition, and also produce dorsal root reflexes (DRRs), which may regulate the excitability of peripheral terminals and second order neurons. We aimed to identify changes in these responses as a consequence of peripheral inflammation. In vitro spinal cord recordings of spontaneous activities in dorsal and ventral roots were performed in control mice and following paw inflammation. We also used pharmacological assays to define the neurotransmitter systems implicated in such responses. Paw inflammation increased the frequency and amplitude of spontaneous dorsal root depolarizations, the occurrence of DRRs and the amplitude of ventral roots depolarizations. PAD was classified in two different patterns based on their relation to ventral activity: time-locked and independent events. Both patterns increased in amplitude after paw inflammation, and independent events also increased in frequency. The circuits that were responsible for this activity implicated both glutamatergic and GABAergic transmission. Adrenergic modulation differentially affected both types of PAD, and this modulation changed after paw inflammation. Our findings suggest the existence of independent spinal circuits at the origin of PAD and DRRs. Inflammation modulates these circuits differentially, unveiling varied mechanisms of spinal sensitization. This in vitro approach provides an isolated model for the study of the mechanisms of central sensitization and for the performance of pharmacological assays with the purpose of identifying and testing novel antinociceptive targets. Spinal circuits modulate activity of primary afferents acting on central terminals. Under in vitro conditions, dorsal roots show spontaneous activity in the form of depolarizations and action potentials. Our findings are consistent with the existence of several independent generator circuits. Experimental paw inflammation reduced mechanical withdrawal threshold and significantly increased the spontaneous activity of dorsal roots, which may be secondary to an enhanced output of spinal generators. This can be considered as a novel sign of central sensitization.