Responses Of Nociceptive Neurons Research Articles

The role of environmental sensitivity, traumatic experiences, defense mechanisms and mental pain on central sensitivity: testing a path analysis model in chronic headache on quality of life.

Central pain sensitivity (CS) is defined as an increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold inputs. The main aim of this paper is to investigate if and how specific psychological constructs are related with CS burden in patients with chronic headache (CH). Specifically, research question 1 explores the association of temperament, personality, childhood adversities, defense mechanisms and mental pain with CS burden. Research question 2 aims to test the role of the best predictors of CS burden in affecting the quality of life (QoL) using path analysis. A total of 508 women with CH completed a psycho-diagnostic survey. Results showed that higher levels of low sensory threshold (β = 0.200), bodily threat traumatic experiences (β = 0.156), neurotic defenses (β = 0.109) and mental pain (β = 0.343) emerged as the best predictors of higher CS burden. The model presented demonstrated a satisfactory fit (GFI = 0.984; NFI = 0.966; CFI = 0.979; RMSEA = 0.056 [95% CI 0.028-0.085]) with large and medium effect sizes on physical (-0.654) and psychological QoL (-0.246). The study showed a key role of psychological dimensions in CS burden levels and their relationships with QoL in CH patients. From a clinical perspective, these results suggest the importance of evaluating the level of CS burden during the clinical assessment for chronic pain conditions such as CH, since it may contribute to guide patients to tailored psychological and medical treatments, thereby saving time and costs on diagnostic procedures for chronic pain.

Construction of the chronic temporomandibular disorder patients: the association between neural and psychological pathways.

Chronic temporomandibular disorder (cTMD) as a term based on the diagnostic criteria for temporomandibular disorders (DC/TMD) classification refers, in this paper, to the condition listed that has a non-mechanical association without any obvious organic cause. Specifically, this is the condition that falls under the International Classification of Diseases 11th revision (ICD-11) classification of chronic primary and chronic secondary pains. This implies that there is increased responsiveness of nociceptive neurons in the central nervous system, a phenomenon known as central sensitisation. cTMD patients may have their beginning with genetic susceptibility to pain. Although no single gene is exclusively linked to cTMD, various genes associated with nervous and musculoskeletal systems are believed to play a role. Environmental triggers and epigenetic changes are also thought to contribute to cTMD development. The biopsychosocial model emphasises the need to comprehensively address biological, psychological and social factors in cTMD assessment and management. In this study, we leverage the cyclic causation framework within the biopsychosocial model to illuminate the intricate interplay between biological and psychosocial factors in the context of cTMD. The conceptualisation of cTMD involves the dynamic evolution of genetic predispositions, influenced by life events and other biological susceptibilities. These factors collectively contribute to the emergence of nociplastic changes, ultimately manifesting as the distinctive features observed in individuals afflicted with cTMD.

Few-layered graphene increases the response of nociceptive neurons to irritant stimuli.

The unique properties of few-layered graphene (FLG) make it interesting for a variety of applications, including biomedical applications, such as tissue engineering and drug delivery. Although different studies focus on applications in the central nervous system, its interaction with the peripheral nervous system has been so far overlooked. Here, we investigated the effects of exposure to colloidal dispersions of FLG on the sensory neurons of the rat dorsal root ganglia (DRG). We found that the FLG flakes were actively internalized by sensory neurons, accumulated in large intracellular vesicles, and possibly degraded over time, without major toxicological concerns, as neuronal viability, morphology, protein content, and basic electrical properties of DRG neurons were preserved. Interestingly, in our electrophysiological investigation under noxious stimuli, we observed an increased functional response upon FLG treatment of the nociceptive subpopulation of DRG neurons in response to irritants specific for chemoreceptors TRPV1 and TRPA1. The observed effects of FLG on DRG neurons may open-up novel opportunities for applications of these materials in specific disease models.

Central Sensitization and Pain: Pathophysiologic and Clinical Insights.

To explain how the notion of central sensitization has changed our understanding of pain conditions, discuss how this knowledge can be used to improve the management of pain, and highlight knowledge gaps that future research needs to address. Overview of definitions, assessment methods, and clinical implications. Human pain models, and functional and molecular imaging have provided converging evidence that central sensitization occurs and is clinically relevant. Measures to assess central sensitization in patients are available; however, their ability to discriminate sensitization of central from peripheral neurons is unclear. Treatments that attenuate central sensitization are available, but the limited understanding of molecular and functional mechanisms hampers the development of target-specific treatments. The origin of central sensitization in human pain conditions that are not associated with tissue damage remains unclear. The knowledge of central sensitization has revolutionized our neurobiological understanding of pain. Despite the limitations of clinical assessment in identifying central sensitization, it is appropriate to use the available tools to guide clinical decisions towards treatments that attenuate central sensitization. Future research that elucidates the causes, molecular and functional mechanisms of central sensitization would provide crucial progress towards the development of treatments that target specific mechanisms of central sensitization.

Central sensitivity in fibromyalgia: testing a model to explain the role of psychological factors on functioning and quality of life.

Central sensitivity (CS) is defined as an increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold inputs. CS has recently been linked to the psychological burden associated with chronic pain, such as fibromyalgia (FM). The primary objective of this study is to investigate the impact of specific psychological constructs on CS in patients with FM. In Study 1, we explore the influence of temperament, personality, childhood trauma, defence mechanisms, and mental pain on CS. In Study 2, our goal is to test the role of the best predictors of CS in influencing quality of life (QoL) and FM functioning through a path analysis model. A total of 510 women with FM participated online, completing a self-administered protocol. Data collection took place between April and June of 2023. In Study 1, higher levels of low sensory threshold (β=0.210), traumatic experiences of physical threat (β=0.141), neurotic defences (β=0.124), and mental pain (β=0.241) emerged as the strongest predictors of increased CS. In Study 2, the presented model demonstrated a satisfactory fit (chi2=27.200; df=10; p=0.002; GFI=0.984; NFI=0.949; CFI=0.967; RMSEA=0.061 [95% CI 0.034-0.090]) with large and medium effect sizes on physical (-0.576) and psychological (-0.190) QoL. The study underscores the pivotal role of psychological dimensions in influencing CS levels and their relationships with QoL in patients with FM.

Central sensitization adversely affects quality of recovery following lumbar decompression surgery

BackgroundCentral sensitization (CS) is defined as increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. The CS phenomenon is caused by continuous, intense nociceptor inputs triggering a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in the central nociceptive pathway. Most patients undergoing surgery for lumbar spinal stenosis (LSS) experience symptoms for more than three months; therefore, it is possible that CS is associated with postoperative symptoms of LSS. The aim of this study was to clarify the influence of CS in patients who underwent surgery for LSS. MethodsWe used the Central Sensitization Inventory (CSI) to evaluate CS preoperatively. Clinical and neurological symptoms were assessed before surgery and three months after surgery using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOA-BPEQ) and the Oswestry Disability Index (ODI). To evaluate the correlation between the preoperative CSI score and each parameter of the JOA-BPEQ before and three months after surgery, a Pearson correlation coefficient was used. We also evaluated the correlation between preoperative CSI and improvement scores for each parameter of the JOA-BPEQ for surgery. Similarly, the ODI was assessed. ResultsThis study included 118 patients. After surgery, the parameters of lumbar function disorder, social life function disorder, and mental health disorder revealed a statistically significant relationship (r = −0.289, −0.0354, and −0.493, respectively). There was no significant correlation between CSI and improvement scores of the JOA-BPEQ. The ODI assessment after surgery revealed a statistically significant relationship (r = 0.344). There was no significant correlation between the CSI and ODI improvement scores. ConclusionThis study showed that the severity of the CSI influenced the postoperative outcomes, and that surgical treatment improved the symptoms of LSS regardless of the occurrence of CS preoperatively.

Do "central sensitization" questionnaires reflect measures of nociceptive sensitization or psychological constructs? A systematic review and meta-analyses.

Central sensitization (CS) is defined as an increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state associated with noxious inputs (eg, polyarthritis). The concept of CS has recently been adopted in clinical assessments of chronic pain, but its diagnosis in humans may now include a wide range of hypervigilant responses. The purpose of this review is to ascertain whether self-report questionnaires linked with CS are associated with enhanced nociceptive responses or whether they measure sensitivity in a broader sense (ie, emotional responses). According to our published, PROSPERO-registered review protocol (CRD42021208731), a predefined search of studies that involve the Central Sensitization Inventory (CSI) or Pain Sensitivity Questionnaire (PSQ), correlated with either nociceptive sensory tests or emotional hypervigilance was conducted on MEDLINE, PsycINFO, and Web of Science. Correlations between the CSI or PSQ with our primary outcomes were extracted and meta-analysed. A review of 66 studies totalling 13,284 participants found that the CSI (but not the PSQ) strongly correlated with psychological constructs: depression, anxiety, stress, pain catastrophising, sleep, and kinesiophobia. The CSI and PSQ showed weak or no correlations with experimental measures of nociceptive sensitivity: pain thresholds, temporal summation, or conditioned pain modulation. The PSQ did, however, correlate strongly with phasic heat and tonic cold pain tests. The studies reviewed did not provide sufficient evidence that self-report measures reflect a canonical understanding of CS. The CSI more closely reflects psychological hypervigilance than increased responsiveness of nociceptive neurons.

No evidence for an effect of selective spatial attention on the development of secondary hyperalgesia: A replication study.

Central sensitization refers to the increased responsiveness of nociceptive neurons in the central nervous system after repeated or sustained peripheral nociceptor activation. It is hypothesized to play a key role in the development of chronic pain. A hallmark of central sensitization is an increased sensitivity to noxious mechanical stimuli extending beyond the injured location, known as secondary hyperalgesia. For its ability to modulate the transmission and the processing of nociceptive inputs, attention could constitute a promising target to prevent central sensitization and the development of chronic pain. It was recently shown that the experimental induction of central sensitization at both forearms of healthy volunteers using bilateral high-frequency electrocutaneous stimulation (HFS), can be modulated by encouraging participants to selectively focus their attention to one arm, to the detriment of the other arm, resulting in a greater secondary hyperalgesia on the attended arm as compared to the unattended one. Given the potential value of the question being addressed, we conducted a preregistered replication study in a well-powered independent sample to assess the robustness of the effect, i.e., the modulatory role of spatial attention on the induction of central sensitization. This hypothesis was tested using a double-blind, within-subject design. Sixty-seven healthy volunteers performed a task that required focusing attention toward one forearm to discriminate innocuous vibrotactile stimuli while HFS was applied on both forearms simultaneously. Our results showed a significant increase in mechanical sensitivity directly and 20 min after HFS. However, in contrast to the previous study, we did not find a significant difference in the development of secondary hyperalgesia between the attended vs. unattended arms. Our results question whether spatial selective attention affects the development of secondary hyperalgesia. Alternatively, the non-replication could be because the bottom-up capture of attention caused by the HFS-mediated sensation was too strong in comparison to the top-down modulation exerted by the attentional task. In other words, the task was not engaging enough and the HFS pulses, including those on the unattended arm, were too salient to allow a selective focus on one arm and modulate nociceptive processing.

Chronic temporomandibular disorders are associated with higher propensity to develop central sensitization: a case-control study.

Temporomandibular disorders (TMD) include a group of musculoskeletal disorders that may involve increased responsiveness of nociceptive neurons in the central nervous system (ie, central sensitization). To test this hypothesis further, this study examined whether, as compared with healthy subjects, patients with chronic TMD have a greater propensity to develop secondary mechanical hyperalgesia-a phenomenon that can be confidently attributed to central sensitization. In this case-control study, we assessed the area of secondary mechanical hyperalgesia induced experimentally by delivering high-frequency electrical stimulation (HFS) to the volar forearm skin in 20 participants with chronic TMD and 20 matched healthy controls. High-frequency electrical stimulation consisted in 12 trains of constant-current electrical pulses (5 mA) delivered at 42 Hz. The area of secondary mechanical hyperalgesia was evaluated 30 minutes after applying HFS. The area of secondary mechanical hyperalgesia induced by HFS was on average 76% larger in the chronic TMD group (M = 67.7 cm 2 , SD = 28.2) than in the healthy control group (M = 38.4 cm 2 , SD = 14.9; P = 0.0003). Regarding secondary outcomes, there was no group difference in the intensity of secondary mechanical hyperalgesia, but allodynia to cotton after HFS was more frequent in the chronic TMD group. To the best of our knowledge, this is the first study to show that individuals with chronic TMD have an increased propensity to develop secondary hyperalgesia in a site innervated extratrigeminally. Our results contribute to a better understanding of the pathophysiology of chronic TMD.

Central Sensitization in Migraine: A Narrative Review.

Central sensitization (CS) is an increase in the responsiveness of nociceptive neurons in the central nervous system to their normal afferent input. As a result, even minor irritation can induce severe pain, leading to the chronicity and severity of various diseases, such as neurological disorders. CS is associated with migraine, which is a major neurological disorder that inflicts a high disability in daily life. Specifically, CS is thought to be involved in the pathogenesis of cutaneous allodynia as well as chronification of migraine. In this article, we reviewed the association between CS and migraine, including pathophysiological aspects and evidence from clinical studies. We suggest that appropriate screening and management of CS in migraine could further improve the quality of life of migraine patients.

Differences in central sensitisation between healthy men and women in Switzerland: a single-centre trial

<h2>Abstract</h2><h3>Background</h3> Many chronic pain conditions exhibit differences between men and women regarding prevalence, pain intensity, or treatment effects. Mechanisms underlying these differences are poorly understood. Central sensitisation, defined as an increased responsiveness of nociceptive neurons in the CNS to normal or subthreshold afferent input, is considered an important mechanism that can differ between men and women with chronic pain conditions. We aimed to assess differences in central sensitisation between healthy men and women, with the hypothesis that central sensitisation is more pronounced in healthy women than in men. <h3>Methods</h3> This single-centre trial followed a within-subject design and was conducted at the Balgrist University Hospital in Switzerland after approval by the Cantonal Ethics Board of Zurich. Healthy, pain-free adults aged 18–40 years with a BMI of less than 30 kg/m² and no history of chronic pain were recruited using advertisement and word-of-mouth. Biological sex (male or female) was self-reported. A validated sensitisation protocol was used by applying a contact thermode to the innervation area of the sural nerve on one foot. A sham protocol was used on the other foot. The protocols were performed in counterbalanced order. All participants were masked to the study design and protocols. The primary endpoint before and after the protocols, was the area of secondary hyperalgesia relative to the thermode, serving as a proxy of central sensitisation. Additionally, the nociceptive withdrawal reflex was repeatedly elicited at the sural nerve with two currents (corresponding to 120% and 140% of the individual reflex threshold current) and recorded from the biceps femoris by surface electromyography. The magnitude of the reflex response in the 90 ms to 150 ms post-elicitation interval was compared before and after the protocols. This study was registered with ClinicalTrials.gov, NCT05031286. <h3>Findings</h3> Between April 22, 2021, and Feb 19, 2022, 66 healthy participants were included in the trial. The median age of participants was 26 years (IQR 21–31) and 33 (50%) were women. Following the sensitisation protocol, secondary hyperalgesia was greater in women than men (12·4 cm² [SD 8·41] <i>vs</i> 8·2 cm² [6·90]; two-sided <i>t</i> test p=0·031). The effect of the sensitisation protocol on the magnitude of the biceps femoris nociceptive withdrawal reflex was stronger in women than in men for both currents (Cohen's d 0·32 <i>vs</i> 0·07 for 120% and 0·31 <i>vs</i> 0·15 for 140% reflex threshold current) with 99·6% versus 95·6% probability (Bayesian normal–normal model). No adverse effects were recorded during the trial. <h3>Interpretation</h3> The two tested outcomes (extent of secondary hyperalgesia and magnitude of the nociceptive withdrawal reflex) indicate that central sensitisation processes are more pronounced in healthy women than men. Because central sensitisation is suggested to influence pain chronification, more pronounced central sensitisation processes might constitute a sex-specific risk factor for developing chronic pain. <h3>Funding</h3> The Swiss National Science Foundation.

Thermal grill illusion of pain in patients with chronic pain: a clinical marker of central sensitization?

The thermal grill illusion of pain (TGIP) is a paradoxical burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode ("thermal grill") consisting of interlaced heated and cooled bars. Its neurophysiological mechanisms are unclear, but TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, through the involvement of N-methyl- d -aspartate receptors. However, few studies have investigated TGIP in patients with chronic pain and its clinical relevance is uncertain. We hypothesized that the TGIP would be increased in comparison with controls in patients with fibromyalgia or irritable bowel syndrome, which are regarded as typical "nociplastic" primary pain syndromes related to changes in central pain processing. We compared the sensations elicited by a large range of combinations of temperature differentials between the warm and cold bars of a thermal grill applied to the hand between patients with fibromyalgia (n = 30) or irritable bowel syndrome (n= 30) and controls (n = 30). The percentage of TGIP responses and the intensity and unpleasantness of TGIP were significantly greater in patients than controls. Furthermore, positive correlations were found between TGIP intensity and clinical pain intensity and between TGIP intensity and the cold pain threshold measured on the hand. These results are consistent with our working hypothesis of shared mechanisms between TGIP and clinical pain mechanisms in patients with nociplastic chronic pain syndromes and suggest that TGIP might represent a clinical marker of central sensitization in these patients.

KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT1B/1D and opioid receptors.

We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

POS1338 CENTRAL SENSITIZATION AND RELATED FACTORS IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER

BackgroundCentral sensitization (CS) is an increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input is an important manifestation involved in many different rheumatic diseases [1].ObjectivesThis study aims to investigate the CS in patients with Familial Mediterranean Fever (FMF) and its associations with other parameters.MethodsThis ongoing study included 73 patients (57 female, 16 male) who were diagnosed with FMF according to the Tel-Hashomer criteria. Clinical characteristics including age, gender, disease duration, age at onset, genetic mutations, comorbid disease and medications were noted. Disease activity was assessed with a PRAS disease activity score. Evaluations included the Health Assessment Questionnaire (HAQ), FMF quality of life (FMF-QoL), Pittsburg Sleep Quality Index (PSQI), Fibromyalgia Rapid Screening Tool (FiRST), and the Hospital Anxiety and Depression Scale (HADS). The symptoms of CS were assessed with the Central Sensitization Inventory (CSI; range 0-100) which is a self-report outcome measure designed to identify patients who have symptoms that may be related to CS or central sensitivity syndromes (CSS) such as fibromyalgia, neck injury, temporomandibular joint disorder or migraine/tension headaches [2]. Descriptive analysis was performed for all parameters. The Mann-Whitney U-test and chi-squared test were used in statistical analysis. P&lt;0.05 was considered statistically significant.ResultsThe mean age of the patients was 37.6 (SD:13.6) years. Sacroiliitis occurred in 8 patients (11%), amyloidosis in 1 (1.4%), and erysipelas-like erythema in 8 (11%). The most prevalent genetic mutation was M694/any compound heterogeneous (16.4%) followed by M69V homogeneous (15.1%). Disease activity was mild in 42.5%, moderate in 32.9% and severe in 12.3% of the patients. The mean CSI was 38.4 (SD:18.7) and thirty-four (46.6 %) of 73 patients had CS according to the CSI. CSI scores were significantly higher in females than in males (p=0.009). Eleven (15%) patients had colchicine resistance, and those with colchicine resistance had significantly higher CS scores. In patients with central sensitization, PRAS, HAQ FMF-QoL, FiRST, PSQI, and HADS scores were significantly higher than in patients without central sensitization (Table 1).Table 1.Disease characteristics in terms of central sensitizationCentral sensitization Yes (n=34)Central sensitization No (n=39)pGender, female31 (91.2%)26 (66.7%)0.02BMI, kg/m228.8 (8.8)26.2 (6.8)0.282Disease duration9.3 (6.9)12.9 (9.9)0.156Number of attacks in the last 3 months2.05 (2.1)0.8 (1.6)&lt;0.001Number of attacks in the last 6 months3.7 (3.3)1.5 (3.2)&lt;0.001PRAS6.3 (2.1)4.8 (2.3)0.004HAQ0.4 (0.6)0.08 (0.2)FMF-QoL38.2 (13.7)17.3 (15.2)&lt;0.001FiRST3.9 (1.9)1.7 (1.7)&lt;0.001PSQI9.9 (3.9)6.4 (2.8)&lt;0.001HAD-Anxiety9.6 (4.4)4.9 (3.8)&lt;0.001HAD-Depression7.08 (4)4.4 (3.2)0.003BMI: Body Mass Index, HAQ: Health Assessment Questionnaire, FiRST: Fibromyalgia Rapid Screening Tool, FMF-QoL: Familial Mediterranean Fever Quality of Life, PSQI: The Pittsburgh Sleep Quality Index, HADS: the Hospital Anxiety and Depression ScaleConclusionCS is present in approximately half of FMF patients. CS in patients with FMF was associated with high disease activity, fibromyalgia, anxiety, depression, impaired function, poor quality of life and sleep.

Effect of preoperative duloxetine treatment on postoperative chronic residual pain after total hip or knee arthroplasty: a randomised controlled trial

ObjectivesA key predictor for developing chronic residual pain after total knee or hip arthroplasty (TKA/THA) is sensitisation. Sensitisation can be defined as an ‘increased responsiveness of nociceptive neurons in the...

Do "central sensitization" questionnaires reflect measures of nociceptive sensitization or psychological constructs? Protocol for a systematic review.

Central sensitization (CS) was first defined in animal studies to be increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state. Recently, the concept of CS has been adopted in clinical assessments of chronic pain, but its diagnosis in humans has expanded to include the enhancement of a wide range of nociceptive, sensory, and emotional responses. Many poorly understood pain disorders are referred to as "central sensitivity syndrome," a term associated with a broad range of hypervigilant sensory and emotional responses. Diagnosis often involves a review of medical records and an assessment of behaviour, emotional disposition, and overall sensitivity of a patient. Obviously, these assessments are unable to directly capture the responsiveness of nociceptive neurons. The purpose of this review is to ascertain whether self-report questionnaires associated with central sensitization and the diagnosis of central sensitivity syndrome are associated with enhanced nociceptive responses or whether they more validly measure sensitivity in a broader sense (ie, including emotional responses). Following the PRISMA guidelines, a detailed search of studies that involve the Central Sensitization Inventory or Pain Sensitivity Questionnaire correlated with either nociceptive sensory tests (quantitative sensory testing) or emotional hypervigilance (anxiety, depression, stress, etc) will be conducted on MEDLINE, PsychINFO, and Web of Science. The review is expected to synthesize correlations between sensitivity questionnaires and nociceptive or emotional sensitivity to determine whether these questionnaires reflect a broadened understanding of the term "central sensitization."

Voluntary Forelimbs Exercise Reduces Immobilization-Induced Mechanical Hyperalgesia in the Rat Hind Paw.

Voluntary exercise is sufficient to protect against neuropathic pain. However, it is unclear whether voluntary exercise reduces immobilization-induced hyperalgesia. We examined the effect of voluntary forelimb exercise on immobilized-induced hyperalgesia in hind paws of rats. Wistar rats were randomly divided into the (1) both hind limbs immobilized group (IM group), (2) immobilization and exercise with nonimmobilized fore limbs group (EX group), and (3) control group. In the IM and EX groups, the bilateral ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for eight weeks. In the EX group, voluntary exercise using nonimmobilized forelimbs in the running wheel was administered during the immobilization period, while hind limbs were kept immobilized (60 min/day, 5 days/week). Mechanical hyperalgesia in the hind paw was measured using a digital von Frey device every week. To investigate the abnormality of primary sensory neurons and central sensitization, the number of calcitonin gene-related peptide-positive cells in the dorsal root ganglion and the expression level of calcitonin gene-related peptide in the spinal dorsal horn were analyzed by immunohistochemical staining. Immobilization-induced mechanical hyperalgesia was inhibited in the EX group compared to the IM group at three weeks after immobilization. In the EX group, the number of calcitonin gene-related peptide-positive cells in the dorsal root ganglion and the expression level of calcitonin gene-related peptide were significantly decreased compared to those in the IM group. Our results therefore suggest that voluntary forelimb exercise during hind limb immobilization partially reduces immobilization-induced hyperalgesia by suppressing that the plastic changes of the primary sensory nerves that excessively transmit pain and increased responsiveness of nociceptive neurons in the spinal dorsal horn.

Central Sensitization in Chronic Low Back Pain: A Population-Based Study of a Japanese Mountain Village.

PurposeCentral sensitization (CS) is defined as the increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS has been proposed as an underlying mechanism of chronic pain in musculoskeletal disorders including low back pain (LBP). A Central Sensitization Inventory (CSI) has recently been developed for screening participants with CS. However, the association of CS with chronic LBP (cLBP) in the general population remains unknown. The purpose of this study was to investigate the association of CS with cLBP using the CSI in a population-based cohort of a Japanese mountain village.Participants and MethodsParticipants aged more than 50 years were recruited from the inhabitants of a mountain village in Japan. Participants completed the following patient-reported outcome measures. Severity of CS was assessed by the CSI. LBP intensity was measured on a numerical rating scale (NRS). Health-related quality of life (QOL) was measured using the EuroQol 5-dimension (EQ-5D), EuroQol-visual analogue scales (EQ-VAS), and the Oswestry Disability Index (ODI). The association of CS and each parameter was statistically evaluated.ResultsA total of 272 participants (average age: 72.1 years-old) were analyzed in this study, and 28.3% had cLBP. Average NRS, ODI and CSI scores were significantly higher in the cLBP group than in the without LBP (LBP−) group. There was a significant correlation between CSI and NRS scores (r=0.34, P<0.0001), ODI (r=0.60, P<0.0001), EQ5D (r=−0.55, P<0.0001) and EQ-VAS (r=−0.52, P<0.0001). A multiple regression analysis identified that ODI, EQ-VAS and age were factors significantly associated with CSI.ConclusionThe results of this study suggest that CS is involved in the pathological condition of cLBP in the local residents of a Japanese mountain village.

High Rate of Pain Sensitization in Musculoskeletal Shoulder Diseases: A Systematic Review and Meta-analysis.

Pain sensitization, defined as an increased responsiveness of nociceptive neurons to normal input, is detected in several musculoskeletal diseases, but there are no systematic reviews or meta-analyses about pain sensitization in shoulder pain. The aim of the study was to document pain sensitization rate and its impact in patients with shoulder pain. PubMed, Cochrane Library, and Web of Science were searched on January 8, 2020. Level I-IV studies, evaluating pain sensitization in musculoskeletal shoulder disorders through validated methods (questionnaires/algometry) were included. The primary outcome was pain sensitization rate. Secondary outcomes were the pain sensitivity level measured as pressure pain threshold, temporal summation, conditioned pain modulation, and suprathreshold heat pain response. Associated demographic and psychosocial factors were evaluated. The rate of abnormal pressure pain threshold in patients with shoulder pain varied from 29% to 77%. Questionnaires detected pain sensitization in 11% to 24% of patients. This meta-analysis showed no difference in pressure pain threshold and central pain modulation but documented a significant difference in terms of suprathreshold heat pain response, indicating a hypersensitivity state in patients with shoulder pain versus asymptomatic controls. The only factor that was constantly found to correlate with higher sensitivity was a lower postoperative outcome. Pain sensitization has a high rate among patients with musculoskeletal shoulder pain, regardless of the specific etiology, and this may lead to worse clinical outcome after treatment of the primary disease. The best way to assess pain sensitization still needs to be identified as the assessment methods results in used high variability in the documented pain sensitization rate.

Ultrasound Stimulations Induce Prolonged Depolarization and Fast Action Potentials in Leech Neurons.

Objective: Ultrasound (US) stimulation carries the promise of a selective, reversible, and non-invasive modulation of neural activity without the need for genetic manipulation of neural structures. However, the mechanisms of US-induced generation of action potentials (APs) are still unclear. Methods: Here we address this issue by analyzing intracellularly recorded responses of leech nociceptive neurons to controlled delivery of US. Results: US induced a depolarization linearly accumulating in time and outlasting the duration of the stimulation. Spiking activity was reliably induced for an optimal US intensity range. Moreover, we found that APs induced by US differ in smaller amplitude and faster repolarization from those induced by electrical stimulation in the same cell but display the same repolarization rate. Conclusions: These results shed light on the mechanism by which spikes are induced by US and pave the way for designing more efficient US stimulation patterns.