PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine.

AIMS: Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. METHODS: Sprague-Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. RESULTS: The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. CONCLUSIONS: Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine.

Central sensitisation pain and autonomic deficiencies in fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is associated with central pain sensitisation, autonomic alterations and neuropathy in small nerve fibres. This study aimed to analyse the association between tonic sweating and central pain sensitisation in FM. METHODS: Fifty-eight FM patients and thirty healthy women were assessed in terms of slowly repeated evoked pain (SREP), as a measure of central sensitisation. Sweating was evaluated by skin conductance (SC), as a sympathetic autonomic measure secondarily indexing possible small nerve fibre peripheral neuropathy. Clinical and psychological factors were evaluated through questionnaire measures. RESULTS: FM patients displayed smaller SC values than healthy controls, and SREP sensitisation was only observed in FM patients. Pain threshold and tolerance were also lower in the patient sample. Clinical symptoms (pain, fatigue, insomnia) only correlated significantly with SREP sensitisation. SC was inversely related to SREP sensitisation, and this association persisted after statistically controlling for levels of catastrophising and antidepressant use. CONCLUSIONS: These results suggest that central pain sensitisation, proposed as a main pathophysiological mechanism of FM, may depend on sympathetic autonomic deficiencies, suggestive of small nerve fibres neuropathy. Future studies should aim to replicate these results using other central pain sensitisation measures and direct measures of neuropathy or small nerve fibre density.

Algometry for the assessment of central sensitisation to pain in fibromyalgia patients: a systematic review.

INTRODUCTION: The pathophysiology of fibromyalgia (FM) is related to central sensitisation (CS) to pain. Algometry allows assessing CS based on dynamic evoked pain. However, current algometrýs protocols require optimising, unifying and updating. OBJECTIVES: 1) identify the dynamic pain measures used most frequently to effectively assess CS processes in FM, and 2) consider the future of the algometry assessing CS in these patients. METHODS: Cochrane Collaboration guidelines and PRISMA statements were followed. The protocol was registered in PROSPERO database (ID: CRD42021270135). The selected articles were evaluated using the Cochrane risk of bias (ROB) assessment tool. The PubMed, Scopus, and Web of Science databases were searched. RESULTS: Thirty-four studies were selected, including measures such as temporal summation of pain (TSP), aftersensations (AS), spatial summation of pain (SSP), the noxious flexion reflex (NFR) threshold, conditioned pain modulation (CPM), cutaneous silent period (CuSP), and slowly repeated evoked pain (SREP); and evoked pain combined with neuroimaging. Each measure offered various advantages and limitations. According to ROB, 28 studies were of low quality, 3 of moderate quality, and 3 of high quality. CONCLUSIONS: Several pain indicators have been demonstrated to successfully examine CS involvement in FM in the last years. Algometry, especially when it involves diverse body sites and tissues, might provide further insight into (1) the evaluation of psychological factors known to influence pain experience, (2) new dynamic pain indicators, and (3) the simultaneous use of certain neuroimaging techniques. Further research clarifying the mechanisms underlying some of these measures, and homogenisation and optimisation of the algometrýs protocols, are needed. KEY MESSAGESAlgometry allows for assessing Central Sensitisation by applying dynamic evoked pain.The future of algometry could relapse in its combination with neuroimaging.Recently-emerged pain indicators should be considered for algometrýs new protocols.

Sex Differences in Protein Kinase A Signaling of the Latent Postoperative Pain Sensitization That Is Masked by Kappa Opioid Receptors in the Spinal Cord.

Latent sensitization (LS) of pain engages pronociceptive signaling pathways in the dorsal horn that include NMDA receptor (NMDAR)→adenylyl cyclase-1 (AC1)→protein kinase A (PKA), and exchange proteins directly activated by cyclic AMP (Epacs). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal κ opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302, which reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but not astrocytes (GFAPs) nor microglia (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission. In both sexes, intrathecal MK-801 (an NMDAR competitive antagonist) prevented LY2456302-evoked reinstatement of hyperalgesia as did AC1 gene deletion or the AC1 inhibitor NB001. NB001 also prevented stimulus-evoked pERK. In both sexes, the Epac inhibitor ESI-09 prevented reinstatement, whereas the Epac activator 8-CPT reinstated hyperalgesia. By contrast, the PKA inhibitor H89 prevented reinstatement only in male mice, whereas the PKA activator 6-bnz-cAMP itself evoked reinstatement at all doses tested (3-30 nmol, i.t.). In neither sex did incision change gene expression of KOR, GluN1, PKA, or Epac1 in dorsal horn. We conclude that sustained KOR signaling inhibits spinal PKA-dependent mechanisms that drive postoperative LS in a sex-dependent manner. Our findings support the development of AC1, PKA, and Epac inhibitors toward a new pharmacotherapy for chronic postoperative pain.SIGNIFICANCE STATEMENT Because of neural mechanisms that are not well understood, men and women respond differently to treatments for chronic pain. We report that surgical incision recruits a pronociceptive latent pain sensitization that persisted for over a year and was kept in check by the sustained analgesic activity of κ opioid receptors. NMDAR→AC1→cAMP→Epac signaling pathways in the dorsal horn of the spinal cord maintain latent sensitization in both males and females; however, only males recruit a PKA-dependent mechanism. This work presents a novel male-specific mechanism for the promotion of chronic postoperative pain.

A randomized double blinded placebo controlled study to evaluate motor unit abnormalities after experimentally induced sensitization using capsaicin.

Central sensitization is a condition that represents a cascade of neurological adaptations, resulting in an amplification of nociceptive responses from noxious and non-noxious stimuli. However, whether this abnormality translates into motor output and more specifically, ventral horn abnormalities, needs to be further explored. Twenty healthy participants aged 20-70 were randomly allocated to topical capsaicin or a placebo topical cream which was applied onto their left upper back to induce a transient state of sensitization. Visual analogue scale (VAS) ratings of pain intensity and brush allodynia score (BAS) were used to determine the presence of pain and secondary allodynia. Surface electromyography (sEMG) and intramuscular electromyography (iEMG) were used to record motor unit activity from the upper trapezius and infraspinatus muscles before and twenty minutes after application of capsaicin/placebo. Motor unit recruitment and variability were analyzed in the sEMG and iEMG, respectively. An independent t-test and Kruskal-Wallis H test were performed on the data. The sEMG results demonstrated a shift in the motor unit recruitment pattern in the upper trapezius muscle, while the iEMG showed a change in motor unit variability after application of capsaicin. These results suggest that capsaicin-induced central sensitization may cause changes in ventral horn excitability outside of the targeted spinal cord segment, affecting efferent pathway outputs. This preclinical evidence may provide some explanation for the influence of central sensitization on changes in movement patterns that occur in patients who have pain encouraging of further clinical investigation.Clinical Trials registration number: NCT04361149; date of registration: 24-Apr-2020.

Minimal Clinically Important Differences for Patient-Reported Outcomes After TKA Depend on Central Sensitization.

BACKGROUND: To our knowledge, it is still unknown if central sensitization (CS) influences the magnitude of the minimal clinically important difference (MCID) for patient-reported outcome measures after total knee arthroplasty (TKA). The purpose of this study was to determine the influence of CS on the MCID for the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score in patients who underwent TKA for knee osteoarthritis. METHODS: A total of 422 patients who underwent unilateral TKA and completed a 2-year follow-up were enrolled in this study. CS was measured using the Central Sensitization Inventory (CSI). The WOMAC score was used to evaluate preoperative and postoperative patient-reported outcomes. The measurement of the MCID was performed separately for patients with and without CS using both the anchor-based method and the distribution method. The change difference method defined the MCID as the difference in preoperative-to-postoperative change between the minimal-improvement group and the no-change group. In addition, the MCID was calculated using receiver operating characteristic (ROC) curve analysis. The percentage of MCID achievement in each group was also compared. RESULTS: According to the change difference method, the MCID for the WOMAC total score was 23.4 points for patients with CS and 14.7 points for patients without CS. The MCID using the ROC cutoff value for the WOMAC total score was 29.5 points for the patients with CS and 26.5 points for the patients without CS. MCID achievement rates in WOMAC pain, function, and total scores were all found to be significantly higher in the patients without CS through the change difference method and the ROC method (all p < 0.05). CONCLUSIONS: The MCID for the WOMAC score of patients with CS after TKA was greater than that for patients without CS. Furthermore, by applying the calculated MCID to the group to which the patients belonged (with or without CS), we determined that patients with CS showed a lower MCID achievement rate than patients without CS. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Correlation Between Central Sensitization and Remote Muscle Performance in Individuals With Chronic Low Back Pain.

OBJECTIVE: The purpose of this study was to examine associations between the degree of central sensitization (CS) and remote muscle performance in people with chronic low back pain (CLBP). METHODS: The 2011 fibromyalgia (FM) criteria and severity scales (2011 FM survey) were used as a surrogate measure of CS to divide the participants into 2 groups: FM-positive CLBP and FM-negative CLBP. Measures related to central sensitization included the 2011 FM survey and pressure pain threshold of the thumbnail. Measures related to muscle performance included neck flexor muscle strength and endurance and plantar flexor muscle strength. Between-groups and correlation analyses were performed. RESULTS: Sixty people with CLBP were enrolled (30 FM-positive, 30 FM-negative). There was no significant difference between the subgroups in age, sex, or pain duration (P > .05). The FM-positive CLBP group showed poorer neck flexor muscle endurance (P = .01) and plantar flexor muscle strength (P = .002) than the FM-negative CLBP group, whereas neck flexor muscle strength was not different between the groups (P = .175). Scores for FM and values for pressure pain thresholds of the thumbnail were associated with neck flexor muscle strength (respectively, r = -0.320, P = .013, and r = 0.467, P < .001), endurance (r = -0.242, P < .001, and r = 0.335, P = .009), and plantar flexor muscle strength (r = -0.469, P < .001, and r = 0.500, P < .001). CONCLUSION: We found associations between the degree of CS and remote muscle strength and endurance, suggesting that poor remote muscle performance is possibly a clinical sign of CS in people with CLBP.

Does preoperative neuropathic-like pain and central sensitisation affect the post-operative outcome of knee joint replacement for osteoarthritis? A systematic review and meta analysis.

BACKGROUND: Almost a third of those undergoing knee replacement for osteoarthritis have poor outcomes despite technically successful surgery. Preoperative neuropathic-like pain and/or pain sensitisation may increase the risk of pain following joint replacement. OBJECTIVE: To examine whether preoperative neuropathic-like pain and pain sensitisation predicts pain, function and satisfaction following joint replacement for knee osteoarthritis. DESIGN: Systematic review with meta-analysis. METHODS: Medline, EMBASE and CINAHL were systematically searched until March 2020. Studies detecting neuropathic-like pain and/or sensitisation using self-report questionnaires prior to knee replacement for osteoarthritis, and relating this to post-operative outcomes were identified. Data extraction, risk of bias assessment and meta-analysis were performed, where appropriate. RESULTS: Five manuscripts, including one preprint, examining six cohorts were included: four used painDETECT or modified painDETECT, one the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs, and another the Central Sensitisation Inventory to identify preoperative characteristics. Three studies showed preoperative neuropathic-like pain or sensitisation was associated with more intense post-operative pain. All four studies examining the risk of significant pain after knee replacement suggested it was increased after >3 months. The only study examining patient satisfaction and function found reduced satisfaction, but no difference in function in those with preoperative sensitisation. Meta-analysis found the relative risk of increased pain following knee replacement in those with neuropathic-like pain (painDETECT ≥13) to be 2.05 (95% confidence intervals 1.51, 2.79). CONCLUSION: These results provide consistent but limited evidence that self-report tools detecting neuropathic-like pain and/or pain sensitisation, predict patients at higher risk of pain following knee replacement.

Nutritional intervention in chronic pain: an innovative way of targeting central nervous system sensitization?

INTRODUCTION: Few treatment programs for chronic pain nowadays take a dietary pattern or adipose status into account. AREAS COVERED: An important role of neuroinflammation in chronic pain is now well established, at least in part due to increased central nervous system glial activation. Based on preclinical studies, it is postulated that the interaction between nutrition and central sensitization is mediated via bidirectional gut-brain interactions. This model of diet-induced neuroinflammation and consequent central sensitization generates a rationale for developing innovative treatments for patients with chronic pain. Methods: An umbrella approach to cover the authors' expert opinion within an evidence-based viewpoint. EXPERT OPINION: A low-saturated fat and low-added sugar dietary pattern potentially decreases oxidative stress, preventing Toll-like receptor activation and subsequent glial activation. A low-saturated fat and low-added sugar diet might also prevent afferent vagal nerve fibers sensing the pro-inflammatory mediators that come along with a high-(saturated) fat or energy-dense dietary pattern, thereby preventing them to signal peripheral inflammatory status to the brain. In addition, the gut microbiota produces polyamines, which hold the capacity to excite N-methyl-D-aspartate receptors, an essential component of the central nervous system sensitization. Hence, a diet reducing polyamine production by the gut microbiota requires exploration as a therapeutic target for cancer-related and non-cancer chronic pain.

Enthesitis in psoriatic arthritis (Part 3): clinical assessment and management.

Enthesitis is a common clinical feature of PsA, which is characterized by inflammation at the site of insertion of tendons, ligaments and joint capsule fibres into bone. Enthesitis is relatively unique to the spondyloarthritides, setting this group of diseases apart from other rheumatological conditions. The pathophysiological underpinnings of this clinical domain, and the imaging assessment of it, are described in accompanying articles in this supplement. The focus of this article is on the assessment of enthesitis by physical examination, the impact of enthesitis on function and quality of life, the impact of concomitant FM on clinical assessment, and the evidence for therapy of enthesitis garnered in trials of biologic and targeted synthetic DMARDs. Several physical examination measures of enthesitis have been developed and have proved reliable in assessment of enthesitis. Enthesitis has a significant deleterious impact on function and quality of life. The presence of concomitant FM in ≤20% of patients may result in artefactual worsening of assessment of disease severity and hinder achievement of the goal of low disease activity or remission. Several targeted therapies, which, for example, target the TNF, IL-17, IL-23, phosphodiesterase 4 or Janus kinase pathways, have shown significant efficacy in the treatment of enthesitis, resulting in improvement of function and quality of life for patients with PsA.

Microglia P2X4R-BDNF signalling contributes to central sensitization in a recurrent nitroglycerin-induced chronic migraine model.

BACKGROUND: According to our previous study, microglia P2X4 receptors (P2X4Rs) play a pivotal role in the central sensitization of chronic migraine (CM). However, the molecular mechanism that underlies the crosstalk between microglia P2X4Rs and neurons of the trigeminal nucleus caudalis (TNC) is not fully understood. Therefore, the aim of this study is to examine the exact P2X4Rs signalling pathway in the development of central sensitization in a CM animal model. METHODS: We used an animal model with recurrent intermittent administration of nitroglycerin (NTG), which closely mimics CM. NTG-induced basal mechanical and thermal hypersensitivity were evaluated using a von Frey filament test and an increasing-temperature hot plate apparatus (IITC). We detected P2X4Rs, brain-derived neurotrophic factor (BDNF) and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) expression profiles in the TNC. We investigated the effects of a P2X4R inhibitor (5-BDBD) and an agonist (IVM) on NTG-induced hyperalgesia and neurochemical changes as well as on the expression of p-p38-MAPK and BDNF. We also detected the effects of a tropomyosin-related kinase B (TrkB) inhibitor (ANA-12) on the CM animal model in vivo. Then, we evaluated the effect of 5-BDBD and SB203580 (a p38-MAPK inhibitors) on the release and synthesis of BDNF in BV2 microglia cells treated with 50 µM adenosine triphosphate (ATP). RESULTS: Chronic intermittent administration of NTG resulted in chronic mechanical and thermal hyperalgesia, accompanied by the upregulation of P2X4Rs and BDNF expression. 5-BDBD or ANA-12 prevented hyperalgesia induced by NTG, which was associated with a significant inhibition of the NTG-induced increase in phosphorylated extracellular regulated protein kinases (p-ERK) and calcitonin gene related peptide (CGRP) release in the TNC. Repeated administration of IVM produced sustained hyperalgesia and significantly increased the levels of p-ERK and CGRP release in the TNC. Activating P2X4Rs with ATP triggered BDNF release and increased BDNF synthesis in BV2 microglia, and these results were then reduced by 5-BDBD or SB203580. CONCLUSIONS: Our results indicated that the P2X4R contributes to the central sensitization of CM by releasing BDNF and promoting TNC neuronal hyper-excitability. Blocking microglia P2X4R-BDNF signalling may have an effect on the prevention of migraine chronification.

Cross-cultural Adaptation and Psychometric Properties of the Greek Version of the Central Sensitization Inventory.

OBJECTIVES: Recent studies support the opinion that central sensitization (CS) plays an important role in the pathophysiology of many chronic pain conditions. CS refers to hyperexcitability of the central nervous system, which can result in pain hypersensitivity and other somatosensory symptoms. Recognition of CS-related symptomology is crucial in chronic pain evaluation and rehabilitation. The Central Sensitization Inventory (CSI) was created to evaluate symptoms that have been found to be associated with CS. The aim of the current study was the cross-cultural adaptation of the CSI into Greek (CSI-Gr). METHODS: To evaluate discriminate validity, 200 patients with chronic pain and 50 healthy control subjects participated. The sample was divided into 4 diagnostic groups (fibromyalgia, single pain complaints, multiple pain complaints, and a control group) and into 5 CSI severity subgroups, from subclinical to extreme. Convergent validity was determined by evaluation of the relationship between the CSI-Gr and the Pain Catastrophizing Scale (PCS). Additionally, 30 patients completed the CSI a second time for the purpose of a test/retest analysis. RESULTS: The results showed high internal consistency (Cronbach's alpha = 0.994) and test-retest reliability (intraclass correlation coefficient = 0.993). The standard error of measurement was 2.1. The CSI-Gr correlated moderately with the PCS (r = 0.68). Statistically significant differences were found among the 3 comparison groups, with patients who had fibromyalgia reporting the highest CSI severity and healthy control subjects reporting the lowest severity. CONCLUSIONS: As determined in the present study, the CSI-Gr was found to be a reliable and valid tool for recognition of CS-related symptomology.

Can cortisol levels predict the severity of acute whiplash-associated disorders?

BACKGROUND: The exact underlying mechanism of whiplash-associated disorders still remains obscure. Central sensitization of the brain to painful stimulus and disturbances in the hypothalamic-pituitary-adrenal axis has been suggested to contribute to the development of whiplash-associated disorders. Although cortisol is a well-known factor in the acute stress response and its effects on chronic pain sensation were studied, information is lacking regarding the relation between acute phase cortisol concentrations and the intensity of whiplash-associated disorders. The aim of this prospective observational study was to investigate the relationship between acute serum cortisol concentrations and the severity of whiplash-associated disorders. METHODS: 55 patients enrolled in the study and they answered a pertinent questionnaire. A blood sample was drawn to determine serum cortisol concentration. RESULTS: The mean cortisol concentration of the whiplash-associated disorder score 2-3 patients was significantly lower compared to the whiplash-associated disorder score 1 patients, 9.5 ± 6.9 vs. 13.22 ± 8.3 µg% (p = 0.02). The mean cortisol concentrations increased significantly from mild through moderate to serious grade of severity of accident as perceived by the patient, 9.64 ± 4.82, 11.59 ± 6.85, 17.39 ± 12.1 µg% (p = 0.02). CONCLUSIONS: The study supports the possibility that cortisol plays a role in the development of whiplash-associated disorders. Low or relatively low cortisol concentrations might be associated with more severe forms of the disorder.

Associations Among Sleep Latency, Subjective Pain, and Thermal Pain Sensitivity in Gynecologic Cancer.

OBJECTIVE: Pain is common among women with gynecologic cancer and contributes to depressed mood, sleep disturbances, and likelihood of future chronic pain. Little is known about how psychosocial factors are associated with central sensitization of pain in gynecologic cancer. This study examined relations among depressive symptoms, sleep, subjective pain, and aftersensation pain (a proxy for central sensitization of pain) in gynecologic cancer. METHODS: Participants were 42 women (mean age [SD] = 59.60 [10.11] years) enrolled in a randomized clinical trial examining psychological intervention effects on sleep, pain, mood, and stress hormones/cytokines in gynecologic cancer. Six to eight weeks after surgery, participants completed an assessment of depressive symptoms, sleep, and subjective pain and a temporal summation of pain protocol via quantitative sensory testing (QST). RESULTS: Controlling for recent chemotherapy, history of chronic pain, and analgesic medication use, regression analyses revealed that longer sleep onset latency (SOL; B = 3.112, P = 0.039, bias-corrected and accelerated (BCa) 95% confidence interval [CI] = 0.371 to 6.014) and greater sensory pain (B = 0.695, P = 0.023, BCa 95% CI = 0.085 to 1.210) were associated with greater aftersensation pain at 15 seconds. Greater sensory pain scores were associated with greater aftersensation pain at 30 seconds (B = 0.286, P = 0.045, BCa 95% CI = 0.008 to 0.513). Depression was not associated with aftersensation pain. The overall models accounted for 44.5% and 40.4% of the variance in aftersensation pain at 15 and 30 seconds, respectively. Conclusions. Longer SOL and higher subjective sensory pain were related to greater aftersensation of experimentally induced pain in women postsurgery for gynecologic cancers. Interventions that improve sleep and subjective sensory pain during the perisurgical period may reduce risk for central sensitization of pain.

Expression of glycine receptor α3 subunit in neuropathic and inflammatory central pain sensitization

INTRODUCTION: Increasing evidence suggests that changes in the balance of excitatory/inhibitory neurotransmission are involved in the development of the majority of chronic pain forms. In this context, impairment in glycine mediated inhibitory neurotransmission is thought to play a critical role in the disinhibition that accounts for the development and maintenance of central pain hypersensitivity. AIMS: The goal of this study was to evaluate the Glycine Receptor α3 subunit (α3GlyR) expression in neuropathic (Chronic Constriction Injury, CCI) and inflammatory (Zymosan A injected) animal models of chronic pain. RESULTS AND CONCLUSION: RT-qPCR analysis of spinal cord samples showed that glra3 gene expression does not change after 3 days of CCI and 4 hours of Zymosan A injection. However, we found that protein levels evaluated by Western blot increased after inflammatory pain. These data suggest that central sensitization is differentially regulated depending on the type of pain. α3GlyR protein expression plays an important role in the first step of inflammatory pain establishment.

New concepts of pain.

Active research is being conducted on musculoskeletal pain, and recent concepts will help clinicians and researchers to develop better approaches: -the new pain taxonomy recently has been modified with a third descriptor with the concept of nociplastic pain. -the latest International Classification of Diseases (ICD-11) includes an IASP task force that developed a new classification system for pain. In this new classification, one can differentiate primary musculoskeletal pain including fibromyalgia and low back pain and secondary musculoskeletal pain related to specific etiologies. -the concept of central sensitization in inflammatory rheumatic diseases is increasingly discussed. In these conditions, even with very active biological treatment, almost a third of patients are still complaining of persisting pain. These persisting pain states under adequate treatment, without any sign of inflammation, led researchers to look for evidence of central sensitization states.

A Subgroup of Chronic Low Back Pain Patients With Central Sensitization.

BACKGROUND: Our knowledge of central sensitization (CS) in chronic low back pain (CLBP) is limited. 2011 fibromyalgia criteria and severity scales (2011 FM survey) have been used to determine FM positive as a surrogate of CS. The major features of CS including widespread hyperalgesia and dysfunction of the descending inhibitory pathways can be identified by pressure pain threshold (PPT) and conditioned pain modulation (CPM) tests. The purpose of the study was to examine neurophysiological characteristics and psychosocial symptoms in a subgroup of FM-positive CLBP compared with FM-negative CLBP patients. METHODS: A total of 46 participants with CLBP and 22 pain-free controls completed outcome measures of the 2011 FM survey, PPT and CPM tests, and psychosocial questionnaires. Differences between FM-positive and FM-negative CLBP participants on these measures and correlations were analyzed. RESULTS: The 2011 FM survey identified 22 (48%) participants with CLBP as FM positive. FM-positive CLBP participants showed lower PPT values of the thumbnail (P=0.011) and lower back (P=0.003), lower CPM values of the thumbnail (P=0.002), and more severe pain catastrophizing, anxiety, and depression symptoms (P<0.05) than FM-negative CLBP participants. The 2011 FM scores were significantly correlated with the PPT and CPM values of the thumbnail and with psychosocial symptoms (P<0.001). DISCUSSION: Our findings suggest a subgroup of CLBP patients exhibiting with signs and symptoms of CS. Associations between subjective and objective CS measures indicate that the 2011 FM survey can be utilized to identify the presence of CS in CLBP in clinical practice.

Volatile anesthetic sevoflurane pretreatment alleviates hypoxia-induced potentiation of excitatory inputs to striatal medium spiny neurons of mice.

Sevoflurane, a commonly used anesthetic in surgery, has drawn attention because of its preconditioning effects in hypoxic conditions. To investigate the preconditioning effects in the striatum, a common site for ischemic stroke, we collected whole-cell current-clamp recordings from striatal medium spiny neurons. In our in vitro brain slice experiments, deprivation of oxygen and glucose depolarized the striatal neurons to subthreshold potentials, and the pre-administration of sevoflurane (4%, 15 min) prolonged the time to depolarization. Furthermore, transient hypoxia induced the potentiation of excitatory postsynaptic potentials, which play a part in post-ischemic excitotoxicity. Glibenclamide, a KATP channel inhibitor, reversed the prolonged time to depolarization and the prevention of the pathological potentiation of excitatory responses, indicating that the short exposure to sevoflurane likely participates in neuroprotection against hypoxia via activation of KATP channels. A monocarboxylate transporter blocker, 4-CIN, also depolarized striatal neurons. Interestingly, the blockade of monocarboxylate transporters that supply lactate to neurons caused the pathological potentiation, even in the presence of enough oxygen and glucose. In this case, sevoflurane could not prevent the pathological potentiation, suggesting the involvement of monocarboxylate transporters in the sevoflurane-mediated effects. These results indicate that sevoflurane protects striatal neurons from hypoxic damage and alleviates the pathological potentiation. Under these conditions, sevoflurane may become an effective intervention for patients undergoing surgery.

Microglial NLRP3 inflammasome activation mediates IL-1ß release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model.

BACKGROUND: Central sensitization is an important mechanism of chronic migraine (CM) and is related to the inflammatory response of microglia. The NOD-like receptor protein 3 (NLRP3) inflammasome may regulate the inflammatory process of microglia in several neurological diseases, but its role in CM is largely unknown. Therefore, the aim of this study was to identify the precise role of microglial NLRP3 in CM. METHODS: An experimental CM mouse model was established by repeated intraperitoneal (i.p) injection with nitroglycerin (NTG). We evaluated the expression levels of NLRP3 and its downstream interleukin (IL)-1ß protein in the trigeminal nucleus caudalis (TNC; which is a central area relevant to migraine pain) at different time points. To further examine the effects of the NLRP3 inflammasome pathway on central sensitization of CM, we examined MCC950, an NLRP3 inflammasome-specific inhibitor, and IL-1ra, an IL-1ß antagonist, whether altered NTG-induced mechanical hyperalgesia of the periorbital area and hind paw. The effect of MCC950 and IL-1ra on c-Fos, phosphorylated extracellular signal-regulated kinase (p-ERK) and calcitonin gene-related peptide (CGRP) expression in the TNC were also analyzed. The cell localization of NLRP3 and IL-1ß in the TNC was evaluated by immunofluorescence staining. RESULTS: Repeated NTG administration induced acute and chronic mechanical hyperalgesia and increased expression of NLRP3 and IL-1ß. Blockade of NLRP3 or IL-1ß reduced NTG-induced hyperalgesia, and this effect was accompanied by a significant inhibition of the NTG-induced increase in p-ERK, c-Fos and CGRP levels in the TNC. Immunofluorescence staining revealed that NLRP3 and IL-1ß were mainly expressed in microglia in the TNC, and the IL-1ß receptor, IL-1R, was mainly expressed in neurons in the TNC. CONCLUSIONS: These results indicate that NLRP3 activation in the TNC participates in the microglial-neuronal signal by mediating the inflammatory response. This process contributes to the central sensitization observed in CM.

Regulation of microRNA-29c in the nucleus accumbens modulates methamphetamine -induced locomotor sensitization in mice.

Changes in microRNA (miRNA)-mediated gene expression in the nucleus accumbens (NAc) may play important roles in regulating drug addiction. MiR-29c is a highly expressed miRNA in the human and rodent nervous systems where it plays a broad regulatory role. As the first step towards investigating potential functions of miR-29c in methamphetamine (METH) addiction, we used C57BL/6 mice in a model of METH-induced locomotor sensitization. We measured miR-29c expression changes in the NAc of the mice after repeated-intermittent METH exposure and acute METH administration respectively by using quantitative real-time PCR (qPCR). We found that miR-29c expression was significantly down-regulated in the NAc of METH-sensitized mice but not in the acute METH-treated mice. Then, we tested the respective effects of miR-29c over-expression and inhibition in the NAc on METH-induced locomotor sensitization. To reach this goal, we constructed adeno-associated virus (AAV)-expressing miR-29c (AAV-miR-29c) and its corresponding inhibitor - tough decoy (AAV-anti-miR-29c TuD) to over-express and inhibit miR-29c, respectively. We found that AAV-miR-29c over-expression in the NAc enhanced METH-induced locomotor sensitization, whereas AAV inhibition of miR-29c expression in the NAc attenuated the effects of METH. Moreover, we observed the participation of Dnmt3a, Dnmt3b, and Meg3 in the effects of miR-29c on METH sensitization. Our results suggest that miR-29c is an important epigenetic regulator of METH-induced behavioural sensitization and changes in gene expression. These data further suggest a potential role of miR-29c in regulating long-term METH-induced adaptation in the brain.