Contribution of mechanoreceptors to spinal cord injury-induced mechanical allodynia.

ABSTRACT: Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. The aim of the present study was to understand the contribution of mechanoreceptors with respect to mechanical allodynia in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B expressing mechanoreceptors before SCI, mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. Peptidergic nociceptor sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. However, skin-nerve preparations of contusion SCI mice 7 days after injury yielded hyperexcitability in nociceptors, not in mechanoreceptors, which makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors seem to be the main drivers of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early-onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.

Functional connectivity associated with attention networks differs among subgroups of fibromyalgia patients: an observational case-control study.

Fibromyalgia is a heterogenous chronic pain disorder diagnosed by symptom-based criteria. The aim of this study was to clarify different pathophysiological characteristics between subgroups of patients with fibromyalgia. We identified subgroups with distinct pain thresholds: those with a low pressure pain threshold (PL; 16 patients) and those with a normal pressure pain threshold (PN; 15 patients). Both groups experienced severe pain. We performed resting-state functional MRI analysis and detected 11 functional connectivity pairs among all 164 ROIs with distinct difference between the two groups (p < 0.001). The most distinctive one was that the PN group had significantly higher functional connectivity between the secondary somatosensory area and the dorsal attention network (p < 0.0001). Then, we investigated the transmission pathway of pain stimuli. Functional connectivity of the thalamus to the insular cortex was significantly higher in the PL group (p < 0.01 - 0.05). These results suggest that endogenous pain driven by top-down signals via the dorsal attention network may contribute to pain sensation in a subgroup of fibromyalgia patients with a normal pain threshold. Besides, external pain driven by bottom-up signals via the spinothalamic tract may contribute to pain sensations in another group of patients with a low pain threshold. Trial registration: UMIN000037712.

Influence of psychometric and sleep quality features on painful mechanical sensitivity and pain modulation in patients with temporomandibular disorders.

Investigating the collective impact of psychometric properties and sleep quality on pain sensitivity in temporomandibular disorder (TMD) patients could improve clinical management strategies. OBJECTIVE: Assessing whether combined psychometric properties and sleep quality impact painful mechanical sensitivity and pain modulation in TMD patients. MATERIALS AND METHODS: A cross-sectional study using secondary data analysis of 77 TMD patients and 101 controls. All participants completed questionnaires characterizing their psychometric profile (anxiety, depression, stress and catastrophizing) and sleep quality, alongside psychophysical tests for painful mechanical sensory (mechanical pain threshold (MPT), pressure pain threshold (PPT), and wind-up ratio (WUR)) and conditioned pain modulation (CPM). Participants were grouped into "High distress" or "Low distress" categories based on psychometric properties and sleep quality using hierarchical cluster and k-means analyses. Multiple linear regression evaluated the influence of TMD, age, and the distress cluster on MPT, WUR, PPT, and CPM in masseter and thenar muscles. Differences were statistically significant when p < 0.05. RESULTS: The presence of TMD was the strongest predictor of mechanical painful sensitivity in the trigeminal region (MPT[F(3,174) = 51.902;p < .001;R2 = .463]; TMD presence (ß = -.682) / PPT[F(3,174) = 15.573;p < .001;R2 = .198] TMD presence (ß = -.452), and extra-trigeminal (MPT[F(3,174) = 35.897;p < .001;R2 = .382] TMD (ß = -.647) / CPM [F(3,174) = 4.106;p < .05;R2 = .050] TMD presence (ß = .197). Furthermore, neither the high distress group nor the low distress group were able to significantly influence the variation of the values of any of the psychophysical variables evaluated (p > .05). CONCLUSIONS: There is not a significant influence of impairment clusters based on psychological variables and sleep quality on painful mechanical sensitivity and pain modulation, regardless of the presence of TMD. CLINICAL RELEVANCE: This outcome suggests that psychosocial factors and sleep quality may not play a decisive role in the sensory-discriminative aspect of pain, particularly concerning painful TMD.

The Relationship between Abdominal Diastasis and Lumbar Pain Pressure Threshold in Women Who Have Given Birth between the Ages of 30 and 45 Years-An Observational Pilot Study.

Background and Objectives: Current evidence confirms that the magnitude of the inter-rectus distance (IRD) is associated with the severity of abdominal pain. Furthermore, evidence exists in the literature about the impact abdominal muscles have on low back pain, lumbopelvic pain, breathing and lumbar abdominal strength; however, no studies analysing the level of association between abdominal diastasis and lumbar pain pressure threshold (PPT) exist. The aim of this study was to analyse the level of association between the rectus abdominis distance and pain pressure threshold in the lumbar spinous processes in women who have given birth between the ages of 30 and 45 years. Secondly, it was to study the level of association between the time elapsed since the last delivery and low back pain in women who have given birth between 30 and 45 years of age. Material and Methods: This was a pilot observational study in which 21 females participated. The abdominal diastasis was measured by ultrasound, the pain pressure threshold was assessed by an algometer and the pain perception by the Mc Gill questionnaire. Results: There was no significant relationship between increased abdominal distance and increased lumbopelvic pain in women who gave birth between the ages of 30 and 45 years. However, there was a correlation between the time that had elapsed since the last delivery and low back pain. Conclusions: there was a correlation between the time that had elapsed since the last delivery and low back pain. Further studies analysing factors that may perpetuate the chronicity of symptoms, such as lifestyle and intrinsic factors, are needed.

Is the Central Sensitization Inventory (CSI) associated with quantitative sensory testing (QST)? A systematic review and meta-analysis.

Central sensitization (CS) involves an amplification of neural processing within the central nervous system that can result in widespread pain patterns and hypersensitivity to stimuli. The Central Sensitization Inventory (CSI) and various quantitative sensory testing (QST) methods purport to assess clinical markers of CS. The purpose of this systematic review and meta-analysis was to summarize and quantify the associations between total CSI scores and QST measures from previous studies. A systematic search identified 39 unique studies that were deemed eligible for the systematic review and 33 studies for meta-analyses (with 3314 subjects and 154 effect sizes), including five QST modalities: conditioned pain modulation, temporal summation, pressure pain threshold, heat pain threshold, and cold pain threshold. The meta-analysis yielded statistically significant CSI-QST correlations in total subject samples for all five QST modalities. The strongest associations were identified between CSI scores and pain threshold testing, especially pressure pain threshold, in which 51% of effects sizes, from 29 studies and 3071 subjects, were determined to be in a medium to large range.

Pain symptoms are associated with two-point discrimination threshold in patients with temporomandibular disorders.

OBJECTIVE: This study aimed to explore the associations of orofacial two-point discrimination (2-PD) test result with pain symptoms and psychological factors in patients with Temporomandibular Disorders (TMDs). METHODS: 193 patients with TMDs were included in this study. Patients' demographics, pain intensity, and psychological status were recorded. The 2-PDs in the bilateral temporal, zygomatic, mandibular, and temporomandibular joint (TMJ) regions of the patients were measured. Statistical analyses were conducted to observe the associations between variables. RESULTS: For Pain-related TMDs (PT) patients, Monthly Visual Analogue Scale (VAS-M) and Current Analogue Scale (VAS-C) were correlated with TMJ, zygomatic and temporal 2-PDs. Patients with PT tended to have higher TMJ 2-PDs[Right: ß = 1.827 mm, 95%CI(0.107, 3.548), P = 0.038], zygomatic 2-PDs[Right: ß = 1.696 mm, 95%CI(0.344, 3.048), P = 0.014], temporal 2-PDs[Left: ß = 2.138 mm, 95%CI(0.127, 4.149), P = 0.037; Right: ß = 1.893 mm, 95%CI(0.011, 3.775), P = 0.049]. Associations were also observed between VAS-C and TMJ 2-PDs[Left: ß = 0.780, 95%CI(0.190, 1.370), P = 0.01; Right: ß = 0.885, 95%CI(0.406, 1.364), P = 0.001], Zygomatic 2-PDs[Right: ß = 0.555, 95%CI(0.172, 0.938), P = 0.005]; VAS-M and TMJ 2-PDs[Left: ß = 0.812, 95%CI(0.313, 1.311), P = 0.002; Right: ß = 0.567, 95%CI(0.152, 0.983), P = 0.008], zygomatic 2-PDs[Left: ß = 0.405, 95%CI(0.075, 0.735), P = 0.016; Right: ß = 0.545, 95%CI(0.221, 0.870), P = 0.001], and temporal 2-PDs [Left: ß = 0.741, 95%CI(0.258, 1.224), P = 0.003; Right: ß = 0.519, 95%CI(0.063, 0.975), P = 0.026]. CONCLUSION: TMJ, zygomatic, and temporal 2-PDs were significantly associated with PT and pain intensity. Age, gender and psychological factors were not associated with orofacial 2-PDs. PT patients exhibited weaker tactile acuity compared to Non-PT patients. Further discussion on the underlying mechanism is needed. CLINICAL RELEVANCE: Orofacial tactile acuity of TMDs patients was associated with their pain symptoms, which researchers should take account into when performing 2-PD tests for TMDs patients. The 2-PD test can be considered as a potential tool along with the current procedures for the differentiations of PT and Non-PT.

Exercise induced hypoalgesia during different intensities of a dynamic resistance exercise: A randomized controlled trial.

INTRODUCTION: Exercise produces an immediate lessening of pain sensitivity (Exercise-Induced Hypoalgesia (EIH)) in healthy individuals at local and distant sites, possibly through a shared mechanism with conditioned pain modulation (CPM). Dynamic resistance exercise is a recommended type of exercise to reduce pain, yet limited research has examined the effects of intensity on EIH during this type of exercise. Therefore, the primary purpose of this study is to compare changes in PPT at a local and distant site during a leg extension exercise at a high intensity, a low intensity, or a quiet rest condition. A secondary purpose is to examine if CPM changes after each intervention. The final purpose is to examine if baseline pain sensitivity measures are correlated with response to each intervention. METHODS: In a randomized controlled trial of 60 healthy participants, participants completed baseline pain sensitivity testing (heat pain threshold, temporal summation, a cold pressor test as measure of CPM) and were randomly assigned to complete a knee extension exercise at: 1) high intensity (75% of a 1 Repetition Maximum (RM), 2) low intensity (30% 1RM), or 3) Quiet Rest. PPT was measured between each set at a local (quadriceps) and distant (trapezius) site during the intervention. CPM was then repeated after the intervention. To test the first purpose of the study, a three-way ANOVA examined for time x site x intervention interaction effects. To examine for changes in CPM by group, a mixed-model ANOVA was performed. Finally, a Pearson Correlation examined the association between baseline pain sensitivity and response to each intervention. RESULTS: Time x site x intervention interaction effects were not significant (F(5.3, 150.97) = 0.87, p = 0.51, partial eta2 = 0.03). CPM did not significantly change after the interventions (time x intervention F(1,38) = 0.81, p = 0.37, partial eta2 = 0.02. EIH effects at the quadriceps displayed a significant, positive moderate association with baseline HPT applied over the trapezius (r = 0.61, p<0.01) and TS (r = 0.46, p = 0.04). DISCUSSION: In healthy participants, PPT and CPM did not significantly differ after a leg extension exercise performed at a high intensity, low intensity, or quiet rest condition. It is possible pre-intervention CPM testing with a noxious stimuli may have impaired inhibitory effects frequently observed during exercise but future research would need to examine this hypothesis.

Sex Dimorphism in Pain Threshold and Neuroinflammatory Response: The Protective Effect of Female Sexual Hormones on Behavior and Seizures in an Allergic Rhinitis Model.

Our previous research demonstrated that allergic rhinitis could impact behavior and seizure threshold in male mice. However, due to the complex hormonal cycles and hormonal influences on behavior in female mice, male mice are more commonly used for behavioral tests. In this study, we aimed to determine whether these findings were replicable in female mice and to explore the potential involvement of sexual hormones in regulating neuroinflammation in an allergic model. Our results indicate that pain threshold was decreased in female mice with allergic rhinitis and the levels of IL-23/IL-17A/IL-17R were increased in their Dorsal root ganglia. However, unlike males, female mice with AR did not display neuropsychological symptoms such as learning and memory deficits, depression, and anxiety-like behavior. This was along with decreased levels of DNA methyl transferase 1 (DNMT1) and inflammatory cytokines in their hippocampus. Ovariectomized mice were used to mitigate hormonal effects, and the results showed that they had behavioral changes and neuroinflammation in their hippocampus similar to male mice, as well as increased levels of DNMT1. These findings demonstrate sex differences in how allergic rhinitis affects behavior, pain sensitivity, and seizure thresholds. Furthermore, our data suggest that DNMT1 may be influenced by sexual hormones, which could play a role in modulating inflammation in allergic conditions.

Conditioned pain modulation (CPM) paradigm type affects its sensitivity as a biomarker of fibromyalgia.

Fibromyalgia (FM) is a widespread chronic pain syndrome, possibly associated with the presence of central dysfunction in descending pain inhibition pathways. Conditioned Pain Modulation (CPM) has been proposed as a biomarker of FM. Nonetheless, the wide variety of methods used to measure CPM has hampered robust conclusions being reached. To clarify the validity of CPM as a biomarker of FM, we tested two CPM paradigms (parallel and sequential) in a sample of 23 female patients and 23 healthy women by applying test (mechanical) stimuli and conditioning (pressure cuff) stimuli. We evaluated whether CPM indices could correctly classify patients and controls, and we also determined the correlations between the indices and clinical variables such as symptomatology, disease impact, depression, quality of life, pain intensity, pain interference, fatigue and numbness. In addition, we compared the clinical status of CPM responders (efficient pain inhibitory mechanism) and non-responders. We observed that only parallel CPM testing correctly classified about 70% of patients with FM. In addition, more than 80% of healthy participants were found to be responders, while the rate was about 50% in the FM patients. The sequential CPM test was not as sensitive, with a decrease of up to 40% in the response rate for both groups. On the other hand, we did not observe any correlation between CPM measures and clinical symptoms. In summary, our findings demonstrate the influence of the CPM paradigm used and confirm that CPM may be a useful marker to complement FM diagnosis. However, the findings also cast doubts on the sensitivity of CPM as a marker of pain severity in FM.

The normative values of pain thresholds in healthy Taiwanese.

OBJECTIVE: Quantitative sensory testing is widely used in clinical and research settings to assess the sensory functions of healthy subjects and patients. It is of importance to establish normative values in a healthy population to provide reference for studies involving patients. Given the absence of normative values for pain thresholds in Taiwan, the aim of this study was to report the normative values for future reference in the Taiwanese population and compare the differences between male and female participants. METHODS: Healthy adults without any chronic or acute pain condition were recruited. The pain thresholds were assessed over the cephalic (supraorbital area and masseter muscle) and extracephalic (medio-volar forearm and thenar eminence) areas. The heat, cold, mechanical punctate, and pressure pain thresholds were measured with a standardized protocol. Comparisons between male and female participants were performed. RESULTS: One hundred and thirty healthy participants (55 males: 30.4 ± 7.4 years; 75 females: 30.5 ± 8.1 years) finished the assessments. Male participants were less sensitive to mechanical stimuli, including pressure over masseter muscle (male vs. female: 178.5 ± 56.7 vs. 156.6 ± 58.4 kPa, p = .034) and punctate over medio-volar forearm (male vs. female: 116.4 ± 45.2 vs. 98.7 ± 65.4 g, p = .011), compared to female participants. However, female participants were less sensitive to cold stimuli, indicated by lower cold pain thresholds over the supraorbital area (male vs. female: 18.6 ± 8.4 vs. 13.6 ± 9.3°C, p = .004), compared to male participants. No significant differences were found between sexes in other pain threshold parameters. CONCLUSIONS: We provided the normative values of healthy male and female adults in Taiwan. This information is crucial for comparison in future pain-related studies to identify potential hypoalgesia or hyperalgesia of tested subjects.

Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, ß1, and ß2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased ß1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and ß band oscillations and may have relevance for pain therapies.

Pain tolerance as a 'barrier' to nonsuicidal self-injury: A longitudinal study.

Theoretical perspectives underscore that low pain tolerance may be a relevant 'barrier' to non-suicidal self-injury (NSSI). However, there is limited longitudinal work on the link between pain tolerance and NSSI, which is needed to assess if pain tolerance precedes NSSI engagement, and/or if NSSI precedes altered pain tolerance. Further, assessing both NSSI frequency and versatility (or number of NSSI methods), in addition to engagement, can provide a more nuanced understanding of the influence of pain on NSSI severity. In the present study, 1125 undergraduate students at a large university (72 % female, Mage = 17.96) reported on their NSSI frequency, NSSI versatility, and perceived pain tolerance. Four individual regressions were run to examine the potential bidirectional nature of the association between NSSI frequency and pain tolerance, and NSSI versatility and pain tolerance. Pain tolerance predicted both NSSI frequency and versatility over time. Neither NSSI frequency nor versatility predicted pain tolerance. Results suggest that high pain tolerance may be a risk factor for severe NSSI engagement.

Acute hypoalgesic, neurophysiological and perceptual responses to low-load blood flow restriction exercise and high-load resistance exercise.

This study compared the acute hypoalgesic and neurophysiological responses to low-load resistance exercise with and without blood flow restriction (BFR), and free-flow, high-load exercise. Participants performed four experimental conditions where they completed baseline measures of pain pressure threshold (PPT), maximum voluntary force (MVF) with peripheral nerve stimulation to determine central and peripheral fatigue. Corticospinal excitability (CSE), corticospinal inhibition and short interval intracortical inhibition (SICI) were estimated with transcranial magnetic stimulation. Participants then performed low-load leg press exercise at 30% of one-repetition maximum (LL); low-load leg press with BFR at 40% (BFR40) or 80% (BFR80) of limb occlusion pressure; or high-load leg press of four sets of 10 repetitions at 70% one-repetition maximum (HL). Measurements were repeated at 5, 45 min and 24 h post-exercise. There were no differences in CSE or SICI between conditions (all P > 0.05); however, corticospinal inhibition was reduced to a greater extent (11%-14%) in all low-load conditions compared to HL (P < 0.005). PPTs were 12%-16% greater at 5 min post-exercise in BFR40, BFR80 and HL compared to LL (P ≤ 0.016). Neuromuscular fatigue displayed no clear difference in the magnitude or time course between conditions (all P > 0.05). In summary, low-load BFR resistance exercise does not induce different acute neurophysiological responses to low-load, free-flow exercise but it does promote a greater degree of hypoalgesia and reduces corticospinal inhibition more than high-load exercise, making it a useful rehabilitation tool. The changes in neurophysiology following exercise were not related to changes in PPT.

Reduced reactivity to fear conditioning and pain tests in persons involved in violent video gaming is influenced by adverse childhood experiences.

Video gaming, including violent video gaming, has become very common and lockdown measures of the COVID-19 pandemic even increased the prevalence rates. In this study, we examined if violent video gaming is associated with more adverse childhood experiences (ACE) and if it impairs pain processing and fear conditioning. We tested three groups of participants (violent video gamers, nonviolent video gamers, and non-gamers) and examined fear conditioning as well as pain perception during functional magnetic resonance imaging (fMRI). Violent video gamers displayed significantly higher pain thresholds as well as pain tolerance for electric stimulation, pressure pain stimulation, and cold pressor pain measurements than nonviolent video gamers and non-gamers. This relationship was moderated by adverse childhood experiences, especially physical neglect. Brain images acquired during the fear conditioning fMRI task showed that violent video gamers display significantly less differential brain activation to stimuli signaling pain versus no pain in the anterior cingulate cortex, the juxtapositional lobule cortex, and the paracingulate gyrus compared to non-gamers. There was also a significant negative correlation between adverse childhood experiences and activation in the precuneus and the intracalcarine cortex for signals of pain versus safety. The results of this study imply that violent video gaming is related to reduced processing of pain and signals of pain in a fear learning task, dependent of adverse childhood experiences. These mechanisms need to be examined in more detail and these data could be helpful in preventing the onset and adverse consequences of violent video gaming.

Concurrent validity of dynamic bedside quantitative sensory testing paradigms in breast cancer survivors with persistent pain.

BACKGROUND: Studies on the concurrent validity of clinically applicable testing protocols for conditioned pain modulation (CPM) and temporal summation of pain (TSP) in breast cancer survivors (BCS) with persistent pain are lacking. OBJECTIVES: This study investigated the concurrent validity of two bedside protocols for CPM and TSP in comparison to a respective reference protocol. The participants' preferences for bedside CPM and TSP protocols were assessed. METHODS: Thirty BCS experiencing persistent pain were included in this study. Each participant underwent a reference test along with two bedside alternatives for assessing both TSP and CPM. For CPM, a cold pressor test (CPT) and blood pressure cuff (BPC) were used as conditioning stimulus. The test stimulus was elicited in parallel by pressure pain threshold after 45 and 90 s of conditioning at the lower limb. The CPM reference test consisted of parallel heat stimuli at the forearms using a two-thermode system. TSP was elicited using a von Frey monofilament (256 mN) and an algometer (98 kPa) at the affected site and opposite lower limb. The TSP reference test consisted of heat stimuli at the affected site and opposite lower limb. Participants' testing preference was examined using a purpose-designed questionnaire. Spearman's rank test examined the correlation between protocols. RESULTS: The two bedside CPM protocols were strongly correlated (r = 0.787-0.939, p < 0.005). A strong correlation was found between the BPC protocol and reference test using the relative effect magnitude (r = 0.541-0.555, p < 0.005). The bedside TSP protocols were moderately correlated with each other only at the lower limb using absolute change scores (r = 0.455, p = 0.012). No significant correlation was found between the bedside and reference TSP protocols. CONCLUSION: The significantly moderate to very strong correlations between the bedside protocols validate their interchangeability. Researchers and clinicians should be able to choose which bedside protocol they utilize; however, participants favored the use of a BPC and algometer for the evaluation of CPM and TSP, respectively.

Quantitative sensory testing in canine musculoskeletal pain: Findings from a systematic review, meta-analysis feasibility assessment, and limitations.

Quantitative sensory testing (QST) allows the study of pain mechanisms, patient phenotyping, and response to therapy. The goals of this study were to conduct a systematic review of the use of QST in dogs with musculoskeletal disease including osteoarthritis (OA), and to assess, by means of a meta-analysis, the ability of QST to differentiate affected dogs from healthy controls. The study protocol was registered; three bibliographic databases were screened. Studies involving QST in healthy dogs and those with musculoskeletal disease were included. Data were extracted using a standardized form. Assessment of quality and risk of bias were performed using the CAMARADES critical assessment tool. Twenty-nine articles met the inclusion criteria [systematic review (n = 11); meta-analysis (n = 28)]. In the systematic review, ten studies performed static QST: mechanical [punctate tactile (n = 6); mechanical pressure (n = 5)]; thermal [cold (n = 3); hot (n = 4)]; electrical (n = 1); and one study performed dynamic QST [conditioned pain modulation (n = 1)]. Most studies were of good scientific quality and showed low to moderate risk of bias. A meta-analysis was not possible due to numerous and severe issues of heterogeneity of data among studies. Methods to reduce risk of bias and use of reporting guidelines are some of the most needed improvements in QST research in dogs. Standardization of QST methodology is urgently needed in future studies to allow for data synthesis and a clear understanding of the sensory phenotype of dogs with and without chronic pain including OA.

The effectiveness of cervical rehabilitation interventions for pain in adults with myogenic temporomandibular disorders: A systematic review and meta-analysis.

OBJECTIVE: Little evidence exists for the most effective conservative treatment approach for adults with myogenic temporomandibular disorders (MTMD). We aim to assess the effectiveness of cervical rehabilitation interventions on pain intensity and sensitivity in adults with MTMD compared to comparison intervention such as placebo, sham treatment, education or no intervention. METHODS: For this systematic review and meta-analysis, we searched PubMed, EMBASE, Medline, PEDro databases, forward and backward citations and grey literature studies through PROSPERO, clinical trials and data registries without language or date restrictions between inception and 1 December 2021. We selected randomised controlled trials (RCTs) based on adult populations with MTMD who had a cervical rehabilitation intervention which was defined as any conservative intervention targeting the anatomical structures of the cervical spine. The primary outcome measures for pain were self-reported pain intensity and pain sensitivity through the pressure pain threshold (PPT) of the masseter and temporalis muscles. Secondary outcome measures of maximal mouth opening (on MMO) were included. Included studies were assessed for bias with the Cochrane risk of bias tool for randomised trials. Evidence from RCTs was synthesised to determine treatment effect size as differences between standardised mean difference (SMD) for changes in pain intensity, PPT and MMO comparing adults with MTMD who were treated with cervical rehabilitation interventions compared to a control group. This study is registered on Prospero, number CRD 42021289299. RESULTS: Our general search yielded 2647 studies where seven RCTs met eligibility criteria with low to some concerns in their risk of bias. Pain intensity (five studies, n = 223, SMD -0.98, 95% CI -1.67 to -0.28, I2 = 79%), PPT of the masseter muscle (six studies, n = 395, SMD 0.64, 95% CI 0.43 to 0.86, I2 = 90%) and the temporalis muscles (five studies, n = 295, SMD 0.76, 95% CI 0.07 to 1.45, I2 = 84%) showed large treatment effect estimates favouring cervical rehabilitation interventions compared to no treatment, sham cervical treatment, patient education or non-cervical neuromuscular techniques. Compared to control interventions, one type of cervical rehabilitation intervention, cervical manual therapy alone or in combination with a neck exercise program was associated with statistically significant, large treatment effect estimates on pain intensity (four studies, n = 203, SMD -1.52, 95% CI -2.50 to -0.55). CONCLUSIONS: This review found that in the short-term, cervical rehabilitation interventions especially upper cervical MT alone or in combination with a neck exercise program are effective in improving multiple pain outcomes in adults with MTMD. However, further research is needed to measure the long-term effects of this type of intervention.

Neonatal nociceptive stimulation results in pain sensitization, reduction of hippocampal 5-HT1A receptor, and p-CREB expression in adult female rats.

Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.

Effects of swimming exercise on neuropathic pain in a rat model: role of glutamate.

OBJECTIVE: The pain-reducing effects of the exercise were exerted through different mechanisms. Knowing more clear mechanisms helps to find more approach that is therapeutic. The objective of the present study is the evaluation of cerebrospinal fluid (CSF) glutamate level alteration in neuropathic pain rats and whether physical activity could modulate it. METHODS: In the present study 104 male Wistar rats weighing 180-220 g were randomly divided into 4 groups (Sham, Sham + Exe, Neuropathy, and Neuropathy + Exe) which in turn each group subdivided into 4 groups according to time points for behavioral testing and CSF sampling (Baseline, 2 weeks, 3 weeks, and 4 weeks). To induction of neuropathy (by chronic constriction injury,), after anesthetizing with a mixture of ketamine (80 mg/kg) and xylazine (10 mg/kg), the animal's right sciatic nerve was exposed and was ligated using four movable catgut chromic suture 4/0. The exercise protocol included 25 min of daily swimming, 5 days a week for 4 weeks. Thermal hyperalgesia and mechanical tactile threshold were detected using the plantar test and Von Frey filaments, respectively. CSF glutamate level was determined using high-performance liquid chromatography. RESULTS: Findings indicated that mechanical and thermal thresholds significantly (p < 0.01, p < 0.05 respectively) decreased in the neuropathy group against that in sham groups. On the other hand, exercise significantly increased mechanical tactile threshold (p < 0.0012) and thermal threshold (p < 0.05) compared to the neuropathy group. Moreover, CSF glutamate level prominently (p < 0.01) was increased in the neuropathy group compared to the sham group, and swimming exercise significantly (p < 0.001) reduced it. IN CONCLUSION: The present findings provide new evidence showing that medium-intensity swimming exercise attenuates pain-like behaviors in neuropathic pain animals, which is possibly due to decreasing CSF glutamate level and its neurotransmission.

Somatosensory and psychosocial profile of migraine patients: A cross-sectional study.

BACKGROUND: Migraine is a chronic neurological disorder that involves the brain, characterized by a series of abnormal neuronal networks interacting at different levels of the central and peripheral nervous system. Furthermore, it is known that psychosocial features contribute to the exacerbation and chronicity of symptoms. OBJECTIVE: To compare the somatosensory and psychosocial profiles of migraine patients with a control group. METHODS: We conducted a cross-sectional study comparing the somatosensory and psychosocial profiles of patients with migraine and healthy volunteers. A total of 52 women were included. For the somatosensory profile, Mechanical Detection Threshold (MDT), Pressure Pain Threshold (PPT), Temporal Summation (TS), and Conditioned Pain Modulation (CPM) in the trigeminal and extra-trigeminal areas were evaluated. Psychosocial profiles were assessed using questionnaires, the Central Sensitization Inventory, the Generalized Anxiety Disorders, the Pain Catastrophizing Scale, and the Tampa Scale of Kinesiophobia. Mann-Whitney U test was used to compare differences in the profiles between groups. The significance level was set at 5%. RESULTS: Migraine patients showed a loss of somatosensory function in the trigeminal area for MDT (p = 0.019, r = 0.34 and p = 0.011, r = 0.37 for the ophthalmic nerve and masseter muscle respectively), lower PPT in trigeminal and extra-trigeminal areas (p < 0.001, r=>0.60) and less efficient CPM (p < 0.001, r=>0.60). No statistically significant differences were found in the TS (p=>0.05). Statistically significant differences were found in all psychosocial variables (p = <0.001 r=>0.60). CONCLUSION: Migraine patients showed loss of somatosensory function, lower pressure pain threshold, and an inhibitory pro-nociceptive profile with high scores on central sensitization and fear of movement compared to the control group.