Open-Source Real-Time Closed-Loop Electrical Threshold Tracking for Translational Pain Research.

Nociceptors are a class of primary afferent neurons that signal potentially harmful noxious stimuli. An increase in nociceptor excitability occurs in acute and chronic pain conditions. This produces abnormal ongoing activity or reduced activation thresholds to noxious stimuli. Identifying the cause of this increased excitability is required for the development and validation of mechanism-based treatments. Single-neuron electrical threshold tracking can quantify nociceptor excitability. Therefore, we have developed an application to allow such measurements and demonstrate its use in humans and rodents. APTrack provides real-time data visualization and action potential identification using a temporal raster plot. Algorithms detect action potentials by threshold crossing and monitor their latency after electrical stimulation. The plugin then modulates the electrical stimulation amplitude using an up-down method to estimate the electrical threshold of the nociceptors. The software was built upon the Open Ephys system (V0.54) and coded in C++ using the JUCE framework. It runs on Windows, Linux, and Mac operating systems. The open-source code is available (https://github.com/Microneurography/APTrack). The electrophysiological recordings were taken from nociceptors in both a mouse skin-nerve preparation using the teased fiber method in the saphenous nerve and in healthy human volunteers using microneurography in the superficial peroneal nerve. Nociceptors were classified by their response to thermal and mechanical stimuli, as well as by monitoring the activity-dependent slowing of the conduction velocity. The software facilitated the experiment by simplifying the action potential identification through the temporal raster plot. We demonstrate real-time closed-loop electrical threshold tracking of single-neuron action potentials during in vivo human microneurography, for the first time, and during ex vivo mouse electrophysiological recordings of C-fibers and Aδ-fibers. We establish proof of principle by showing that the electrical threshold of a human heat-sensitive C-fiber nociceptor is reduced by heating the receptive field. This plugin enables the electrical threshold tracking of single-neuron action potentials and allows the quantification of changes in nociceptor excitability.

Group- and sex-related differences in psychological and pain processing factors in people with and without patellofemoral pain: correlation with clinical outcomes.

BACKGROUND: People with patellofemoral pain (PFP) exhibit impaired psychological and pain processing factors (i.e., kinesiophobia, pain catastrophizing and pressure pain thresholds [PPTs]). However, it remains unclear whether these factors have different presentations in women and men with PFP, as well as whether their correlation with clinical outcomes differ according to sex. The aims of this study were to: (1) compare psychological and pain processing factors between women and men with and without patellofemoral pain (PFP); (2) investigate their correlation with clinical outcomes in people with PFP. METHODS: This cross-sectional study included 65 women and 38 men with PFP, 30 women and 30 men without PFP. The psychological and pain processing factors were assessed with the Tampa Scale of Kinesiophobia, Pain Catastrophizing Scale, and PPTs of shoulder and patella measured with an algometer. Clinical outcomes assessed were self-reported pain (Visual Analogue Scale), function (Anterior Knee Pain Scale), physical activity level (Baecke's Questionnaire), and physical performance (Single Leg Hop Test). Generalized linear models (GzLM) and effect sizes [Cohen's d] were calculated for group comparisons and Spearman's correlation coefficients were calculated to investigate correlations between outcomes. RESULTS: Women and men with PFP had higher kinesiophobia (d = .82, p = .001; d = .80, p = .003), pain catastrophizing (d = .84, p < .001; d = 1.27, p < .001), and lower patella PPTs (d = -.85, p = .001; d = -.60, p = .033) than women and men without PFP, respectively. Women with PFP had lower shoulder and patella PPTs than men with PFP (d = -1.24, p < .001; d = -.95, p < .001), but there were no sex differences in those with PFP for psychological factors (p > .05). For women with PFP, kinesiophobia and pain catastrophizing had moderate positive correlations with self-reported pain (rho = .44 and .53, p < .001) and moderate negative correlations with function (rho = -.55 and -.58, p < .001), respectively. For men with PFP, only pain catastrophizing had moderate positive correlations with self-reported pain (rho = .42, p = .009) and moderate negative correlations with function (rho = -.43, p = .007). CONCLUSIONS: Psychological and pain processing factors differ between people with and without PFP and between sexes, respectively. Also, correlations between psychological and pain processing factors with clinical outcomes differ among women and men with PFP. These findings should be considered when assessing and managing people with PFP.

No Sufficient Evidence for an Immediate Hypoalgesic Effect of Spinal Manual Therapy on Pressure Pain Thresholds in Asymptomatic and Chronic Pain Populations: A Systematic Review and Meta-Analysis.

OBJECTIVE: Spinal manual therapy (SMT) is often used to treat patients with spinal disorders; however, the underlying mechanisms of SMT are not fully understood. This systematic review and meta-analysis investigates the effect of SMT compared with sham treatment or no intervention on local or remote (segmental or non-segmental) pressure pain thresholds (PPTs) in patients with chronic musculoskeletal conditions and people who are pain free. METHODS: A systematic search was conducted in the PubMed, Cochrane Library, Web of Science, and CINAHL databases. Randomized controlled trials investigating the effect of SMT on PPTs in patients with chronic musculoskeletal conditions and in people who were pain free were included. Quality assessment and evidence synthesis were performed according to Cochrane Handbook recommendations. A meta-analysis was performed using standardized mean difference and 95% CIs. RESULTS: Twenty-two reports were included in the present review. There were no significant results for an immediate effect of SMT on local (low certainty of evidence), remote (segmental) (low certainty of evidence), and remote (non-segmental) (low certainty of evidence) PPTs in patients with chronic pain as well as on local (moderate certainty of evidence) and remote (segmental) (low certainty of evidence) PPTs in people who were pain free. A small but significant effect (standardized mean difference = 0.26; 95% CI = 0.01 to 0.51; low certainty of evidence) was observed on remote (non-segmental) PPTs in people who were pain free, which was not considered a meaningful effect size. CONCLUSION: No immediate, consistent, or meaningful hypoalgetic effect of SMT was shown on PPTs on various body areas. Involvement of spinal or supraspinal underlying mechanisms were, therefore, not confirmed via PPTs but should still be investigated using methods designed to assess central nervous pain processing. IMPACT: No consistent and meaningful hypoalgesic effects of spinal manual therapy were demonstrated on PPTs in participants who were pain free and in patients with chronic musculoskeletal disorders.

Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated by l-Tetrahydropalmatine.

Effective pain control is an underappreciated aspect of managing opioid withdrawal, and its absence presents a significant barrier to successful opioid detoxification. Accordingly, there is an urgent need for effective non-opioid treatments to facilitate opioid detoxification. l-Tetrahydropalmatine (l-THP) possesses powerful analgesic properties and is an active ingredient in botanical formulations used in Vietnam for the treatment of opioid withdrawal syndrome. In this study, rats receiving morphine (15 mg/kg, i.p.) for 5 days per week displayed a progressive increase in pain thresholds during acute 23 h withdrawal as assessed by an automated Von Frey test. A single dose of l-THP (5 or 7.5 mg/kg, p.o.) administered during the 4th and 5th weeks of morphine treatment significantly improves pain tolerance scores. A 7-day course of l-THP treatment in animals experiencing extended withdrawal significantly attenuates hyperalgesia and reduces the number of days to recovery to baseline pain thresholds by 61% when compared to vehicle-treated controls. This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments.

Longitudinal relationships between habitual physical activity and pain tolerance in the general population.

Physical activity (PA) might influence the risk or progression of chronic pain through pain tolerance. Hence, we aimed to assess whether habitual leisure-time PA level and PA change affects pain tolerance longitudinally in the population. Our sample (n = 10,732; 51% women) was gathered from the sixth (Tromsø6, 2007-08) and seventh (Tromsø7, 2015-16) waves of the prospective population-based Tromsø Study, Norway. Level of leisure-time PA (sedentary, light, moderate, or vigorous) was derived from questionnaires; experimental pain tolerance was measured by the cold-pressor test (CPT). We used ordinary, and multiple-adjusted mixed, Tobit regression to assess 1) the effect of longitudinal PA change on CPT tolerance at follow-up, and 2) whether a change in pain tolerance over time varied with level of LTPA. We found that participants with high consistent PA levels over the two surveys (Tromsø6 and Tromsø7) had significantly higher tolerance than those staying sedentary (20.4 s. (95% CI: 13.7, 27.1)). Repeated measurements show that light (6.7 s. (CI 3.4, 10.0)), moderate (CI 14.1 s. (9.9, 18.3)), and vigorous (16.3 s. (CI 6.0, 26.5)) PA groups had higher pain tolerance than sedentary, with non-significant interaction showed slightly falling effects of PA over time. In conclusion, being physically active at either of two time points measured 7-8 years apart was associated with higher pain tolerance compared to being sedentary at both time-points. Pain tolerance increased with higher total activity levels, and more for those who increased their activity level during follow-up. This indicates that not only total PA amount matters but also the direction of change. PA did not significantly moderate pain tolerance change over time, though estimates suggested a slightly falling effect possibly due to ageing. These results support increased PA levels as a possible non-pharmacological pathway towards reducing or preventing chronic pain.

Role of macrophage autophagy in postoperative pain and inflammation in mice.

BACKGROUND: Postoperative pain and inflammation are significant complications following surgery. Strategies that aim to prevent excessive inflammation without hampering natural wound-healing are required for the management of postoperative pain and inflammation. However, the knowledge of the mechanisms and target pathways involved in these processes is lacking. Recent studies have revealed that autophagy in macrophages sequesters pro-inflammatory mediators, and it is therefore being recognized as a crucial process involved in regulating inflammation. In this study, we tested the hypothesis that autophagy in macrophages plays protective roles against postoperative pain and inflammation and investigated the underlying mechanisms. METHODS: Postoperative pain was induced by plantar incision under isoflurane anesthesia in mice lacking macrophage autophagy (Atg5flox/flox LysMCre +) and their control littermates (Atg5flox/flox). Mechanical and thermal pain sensitivity, changes in weight distribution, spontaneous locomotor activity, tissue inflammation, and body weight were assessed at baseline and 1, 3, and 7 days after surgery. Monocyte/macrophage infiltration at the surgical site and inflammatory mediator expression levels were evaluated. RESULTS: Atg5flox/flox LysMCre + mice compared with the control mice exhibited lower mechanical and thermal pain thresholds and surgical/non-surgical hindlimb weight-bearing ratios. The augmented neurobehavioral symptoms observed in the Atg5flox/flox LysMCre + mice were associated with more severe paw inflammation, higher pro-inflammatory mediator mRNA expression, and more monocytes/macrophages at the surgical site. CONCLUSION: The lack of macrophage autophagy augmented postoperative pain and inflammation, which were accompanied by enhanced pro-inflammatory cytokine secretion and surgical-site monocyte/macrophage infiltration. Macrophage autophagy plays a protective role in postoperative pain and inflammation and can be a novel therapeutic target.

Kilohertz-frequency interferential current induces hypoalgesic effects more comfortably than TENS.

Recent research on transcutaneous electrical stimulation has shown that inhibiting nerve conduction with a kilohertz frequency is both effective and safe. This study primarily aims to demonstrate the hypoalgesic effect on the tibial nerve using transcutaneous interferential-current nerve inhibition (TINI), which injects the kilohertz frequency produced by the interferential currents. Additionally, the secondary objective was to compare the analgesic effect and comfort of TINI and transcutaneous electrical nerve stimulation (TENS). Thirty-one healthy adults participated in this cross-over repeated measures study. The washout period was set to 24 h or more. Stimulus intensity was set just below the pain threshold level. TINI and TENS were applied for 20 min each. The ankle passive dorsiflexion range of motion, pressure pain threshold (PPT), and tactile threshold were measured at the baseline, pre-test, test (immediately before ceasing intervention), and post-test (30 min after ceasing intervention) sessions. After the interventions, the participants evaluated the level of discomfort for TINI and TENS on a 10 cm visual analog scale (VAS). As the results, PPT significantly increased compared to baseline in test and posttest sessions of TINI, but not in those of TENS. Also, participants reported that TENS was 36% more discomfort than TINI. The hypoalgesic effect was not significantly different between TINI and TENS. In conclusion, we found that TINI inhibited mechanical pain sensitivity and that the inhibitory effect persisted long after electrical stimulation ceased. Our study also shows that TINI provides the hypoalgesic effect more comfortably than TENS.

Machine learning analysis predicts a person's sex based on mechanical but not thermal pain thresholds.

Sex differences in pain perception have been extensively studied, but precision medicine applications such as sex-specific pain pharmacology have barely progressed beyond proof-of-concept. A data set of pain thresholds to mechanical (blunt and punctate pressure) and thermal (heat and cold) stimuli applied to non-sensitized and sensitized (capsaicin, menthol) forearm skin of 69 male and 56 female healthy volunteers was analyzed for data structures contingent with the prior sex structure using unsupervised and supervised approaches. A working hypothesis that the relevance of sex differences could be approached via reversibility of the association, i.e., sex should be identifiable from pain thresholds, was verified with trained machine learning algorithms that could infer a person's sex in a 20% validation sample not seen to the algorithms during training, with balanced accuracy of up to 79%. This was only possible with thresholds for mechanical stimuli, but not for thermal stimuli or sensitization responses, which were not sufficient to train an algorithm that could assign sex better than by guessing or when trained with nonsense (permuted) information. This enabled the translation to the molecular level of nociceptive targets that convert mechanical but not thermal information into signals interpreted as pain, which could eventually be used for pharmacological precision medicine approaches to pain. By exploiting a key feature of machine learning, which allows for the recognition of data structures and the reduction of information to the minimum relevant, experimental human pain data could be characterized in a way that incorporates "non" logic that could be translated directly to the molecular pharmacological level, pointing toward sex-specific precision medicine for pain.

High intensity-transcutaneous electrical nerve stimulation does not inhibit temporal summation of the nociceptive flexion reflex.

Pain facilitation contributes to chronic pain conditions. Transcutaneous electrical nerve stimulation (TENS) is used to alleviate pain. The effects of conventional TENS on chronic pain have been limited, and its effects on pain facilitation are controversial. Because the analgesic effects of TENS depend on the setting parameters (e.g., pulse intensities or treatment time), the optimal TENS settings to maximize analgesic effects under various pain conditions have been investigated. High-intensity TENS (HI-TENS), which involves tolerable-level pulse intensities for a short duration, is another conventional TENS method that used to alleviate pain. However, the effects of HI-TENS on pain facilitation remain unclear. The temporal summation of pain is widely used to evaluate pain facilitation, and the temporal summation-nociceptive flexion reflex (TS-NFR) is a neuropsychological parameter that can be used to evaluate pain facilitation. We aimed to investigate the effects of HI-TENS on the TS-NFR in healthy participants. Participants were randomly allocated into HI-TENS (n = 15) and control groups (n = 16). HI-TENS was administered at the left lateral lower leg for 1 min. The TS-NFR elicited by three noxious stimuluses at the left sural nerve was obtained from electromyography of the left biceps femoris. The nociceptive flexion reflex (NFR) was obtained by a single noxious stimulus. We measured the thresholds of the NFR and the TS-NFR at baseline and post-intervention. The application of HI-TENS significantly increased the NFR threshold (p = 0.013) but not the TS-NFR threshold (p > 0.05). These results suggest that HI-TENS does not inhibit pain facilitation.

Evidence for Improvement in Local but Not Diffuse Pressure Pain Thresholds Following Physical Therapist Interventions for Tendinopathy: A Systematic Review.

OBJECTIVES: The objectives of this study were to investigate whether quantitative sensory testing proxy measures for peripheral and central sensitization change following physical therapist interventions for tendinopathy and whether changes occur in parallel to changes in self-reported pain. METHODS: Four databases-Ovid EMBASE, Ovid MEDLINE, CINAHL Plus, and CENTRAL-were searched from inception to October 2021. Three reviewers extracted data for the population, tendinopathy, sample size, outcome, and physical therapist intervention. Studies that reported quantitative sensory testing proxy measures and pain at baseline and another time point following a physical therapist intervention were included. Risk of bias was assessed using the Cochrane Collaboration's tools and the Joanna Briggs Institute checklist. Levels of evidence were assessed using the Grading of Recommendations Assessment, Development and Evaluation. RESULTS: Twenty-one studies were included and all investigated changes in pressure pain threshold (PPT) at either local and/or diffuse sites. Change in other proxy measures of peripheral and central sensitization were not investigated among any studies. Diffuse PPT did not demonstrate significant change in all trial arms that reported this outcome. Local PPT improved for 52% of trial arms, and it was more likely to change at the medium (63%) and longer (100%) compared with the immediate (36%) and short (50%) timepoints. On average, 48% of trial arms demonstrated parallel changes in either outcome. Pain improvement was more frequent than local PPT improvement at all timepoints except for the longest. CONCLUSION: Local PPT may improve among people receiving physical therapist interventions for tendinopathy, but these changes appear to lag behind changes in pain. Change in diffuse PPT among people with tendinopathy has been infrequently investigated in the literature. IMPACT: The findings of the review contribute to knowledge of how tendinopathy pain and PPT change with treatments.

Evaluating pain behaviours: Widely used mechanical and thermal methods in rodents.

Globally, over 300 million surgical procedures are performed annually, with pain being one of the most common post-operative side effects. During the onset of injury, acute pain plays a protective role in alerting the individual to remove noxious stimuli, while long-lasting chronic pain without any physiological reason is detrimental to the recovery process. Hence, it created an urgent need to better understand the pain mechanism and explore therapeutic targets. Despite the hardship in performing human pain studies due to ethical considerations, clinically relevant rodent pain models provide an excellent opportunity to perform pain studies. Several neurobehavioural tests are used to assess the drug efficacy in rodents to determine avoidance behaviour latency and threshold. This review article provides a methodological overview of mechanical (i.e. von Frey, Mechanical Conflict System) and thermal (i.e. Hargreaves Assay, Hot and Cold Plate, Temperature Place Preference) tests to assess pain in clinically relevant pain rodent models. We further discussed the current modifications of those tests along with their use in literature, the impact of confounding variables, advantages and disadvantages.

Investigating the hypoalgesic effects of spinal manipulative therapy using hidden pain conditioning and positive expectation in patients with chronic low back pain: protocol for a randomised controlled trial.

INTRODUCTION: Placebo effects are responses capable of modulating pain and influencing treatment response. Two mechanisms are commonly related to placebo effects: expectations and conditioning. However, the research in this field is focused on laboratory studies with healthy participants. This study aims to identify whether a conditioning procedure with positive induced expectations about spinal manipulative therapy (SMT) will result in greater hypoalgesic effects in adults with chronic low back pain (CLBP) in a clinical trial design. METHODS AND ANALYSIS: This trial will enrol 264 patients with non-specific CLBP, aged 18-60 years. Patients will undergo a calibration test to determine the thermal pain threshold for the hidden pain conditioning procedure. Afterward, they will be randomised to one of the three groups: hidden pain conditioning with positive induced expectations-group one (G1); positive expectations-group two (G2) and neutral expectations-group three (G3). Patients will receive instructions to manipulate the expectations. The pretreatment heat pain test will be performed before the SMT and after the intervention patients will undergo again the heat pain intensity test. However, only patients in G1 will receive hidden pain conditioning to reinforce the association between SMT and pain intensity reduction. All patients will undergo five sessions of SMT. The outcomes will be assessed immediately after the last session and at the 6 weeks and 3-month follow-ups. All statistical analyses will be conducted following intention-to-treat principles, and the treatment effects will be determined with linear mixed models. ETHICS AND DISSEMINATION: The Federal University of São Carlos approved this research (Process n° 52359521.1.0000.5504). All participants will give written informed consent. Dissemination of the results will include publications in peer-reviewed journals and presentations at conferences. If positive expectations and classical conditioning improve outcomes, it may support the administration of such intervention. TRIAL REGISTRATION NUMBER: NCT05202704.

Effects of intrathecally administered interferon α on chronic constriction injury model rats' mechanical pain threshold and G protein expression in the spinal cord.

INTRODUCTION: The aim of the study was to explore the analgesic mechanism of effects of intrathecally administered interferon a (IFN-a) on chronic constriction injury (CCI) model rats. MATERIAL AND METHODS: 24 rats were divided into 6 groups, with 4 rats in each group, including the negative control group (Group N, no operation or treatment), the sham operation group (Group S, only the left sciatic nerve of the rats was exposed without ligation, 0.9% NaCl was intrathecally administered), and four experimental groups (CCI model was established first and then different drugs were intrathecally administered respectively), including 0.9% NaCl (Group C), IFN-a (Group CI), morphine (Group CM), and IFN-a combined with morphine (Group CIM). The mRNA levels of G proteins in both the spinal cord and dorsal root ganglia (DRG), as well as the content of amino acid and chemokine (C-X-C motif) ligand 6 (CXCL-6) in the cerebrospinal fluid were measured and analysed in each group. RESULTS: Intrathecal administration of IFN-a increased the mechanical pain threshold in CCI rats (33.32 ±1.36 vs. 21.08 ±1.59, p < 0.001), achieving the effect comparable to that of morphine (33.32 ±1.36 vs. 32.44 ±3.18, p > 0.05), increased the mRNA expression level of Gi protein (0.62 ±0.04 vs. 0.49 ±0.05, p = 0.006), and decreased the mRNA expression level of Gs protein in the spinal cord (1.80 ±0.16 vs. 2.06 ±0.15, p = 0.035) and DRG (2.11 ±0.10 vs. 2.79 ±0.13, p < 0.001). The intrathecal administration of both IFN-a and morphine can reduce the glutamate content in the cerebrospinal fluid (261.55 ±38.12 vs. 347.70 ±40.69, p = 0.012), but without any statistically significant difference in the content of CXCL-6 across all groups ( p > 0.05). CONCLUSIONS: Intrathecal injection of IFN-a improved the mechanical pain threshold in CCI rats, so we inferred that intrathecal administration of IFN-a had analgesic effects on neuropathic pain, possibly related to the activation of G-proteincoupled µ receptors in the spinal cord and the inhibition of glutamate release.

Effect of low-magnitude, variable-frequency vibration therapy on pain threshold levels and mobility in adults with moderate knee osteoarthritis-randomized controlled trial.

BACKGROUND: Osteoarthritis (OA) is one of the most commonly recorded diseases in clinical practice. Vibration therapy has been suggested for the treatment of knee OA. The purpose of the study was to determine the impact of vibrations of variable frequency and low amplitude on pain perception and mobility in patients suffering from knee OA. METHODS: Thirty-two participants were allocated into two groups - Group 1 (oscillatory cycloidal vibrotherapy-OCV) and Group 2-control (sham therapy). The participants were diagnosed with moderate degenerative changes in the knee (grade II based on the Kellgren-Lawrence (KL) Grading Scale). Subjects received 15 sessions of vibration therapy and sham therapy respectively. Pain, range of motion, and functional disability were assessed through Visual Analog Scale (VAS), Laitinen questionnaire, goniometer (ROM - range of motion), timed up and go test (TUG) and Knee Injury and Osteoarthritis Outcome Score (KOOS). Measurements were taken at baseline, after the last session and four weeks after the last session (follow up). T-test and U-Mann Whitney test compare baseline characteristics. The Wilcoxon and ANOVA tests compared mean VAS, Laitinen, ROM, TUG and KOOS. The significant P-value was less than 0.05. RESULTS: After 3 weeks (15 sessions) of vibration therapy, reduced the sensation of pain and improved mobility was recorded. There was a more significant improvement in the vibration therapy group than the control group in pain alleviation on VAS scale (p < 0.001), on Laitinen scale (p < 0.001), knee ROMs flexions (p < 0.001) and TUG (p < 0.001) at the last session. KOOS score with pain indicator, symptoms, activities of daily living, function in sport and recreation and knee related quality of life improved more in the vibration therapy group than the control group. Effects maintained up to 4 weeks in vibration group. No adverse events were reported. CONCLUSIONS: Our data demonstrated that the use of vibrations of variable frequency and low amplitude in patients with the knee OA is a safe and effective therapy. It is recommended to increase the number of treatments performed, primarily in patients with degeneration II° according to the KL classification. TRIAL REGISTRATION: Prospectively registered on ANZCTR ( ACTRN12619000832178 ). Registered on 11 June 2019.

Neonatal Injury Modulates Incisional Pain Sensitivity in Adulthood: An Animal Study.

Neonatal pain experiences including traumatic injury influence negatively on development of nociceptive circuits, resulting in persistent pain hypersensitivity in adults. However, the detailed mechanism is not yet well understood. In the present study, to clarify the pathogenesis of orofacial pain hypersensitivity associated with neonatal injury, the involvement of the voltage-gated sodium channel (Nav) 1.8 and the C-C chemokine ligand 2 (CCL2)/C-C chemokine receptor 2 (CCR2) signaling in the trigeminal ganglion (TG) in facial skin incisional pain hypersensitivity was examined in 190 neonatal facial-injured and sham male rats. The whisker pad skin was incised on postnatal day 4 and week 7 (Incision-Incision group). Compared to the group without neonatal incision (Sham-Incision group), mechanical hypersensitivity in the whisker pad skin was enhanced in Incision-Incision group. The number of Nav1.8-immunoreactive TG neurons and the amount of CCL2 expressed in the macrophages and satellite glial cells in the TG were increased on day 14 after re-incision in the Incision-Incision group, compared with Sham-Incision group. Blockages of Nav1.8 in the incised region and CCR2 in the TG suppressed the enhancement of mechanical hypersensitivity in the Incision-Incision group. Administration of CCL2 into the TG enhanced mechanical hypersensitivity in the Sham-Sham, Incision-Sham and Sham-Incision group. Our results suggest that neonatal facial injury accelerates the TG neuronal hyperexcitability following orofacial skin injury in adult in association with Nav1.8 overexpression via CCL2 signaling, resulting in the enhancement of orofacial incisional pain hypersensitivity in the adulthood.

Within-Session Test-Retest Reliability of Pressure Pain Threshold and Mechanical Temporal Summation in Chronic Low Back Pain.

OBJECTIVES: To determine the absolute and relative within-session test-retest reliability of pressure pain threshold (PPT) and temporal summation of pain (TSP) at the low back and the forearm in individuals with chronic low back pain (CLBP) and to test the impact of different sequences of measurements on reliability metrics. MATERIALS AND METHODS: Twenty-eight adults with CLBP were recruited. Relative (intraclass correlation coefficient [ICC] and coefficient of variation) and absolute reliability (standard error of measurement and minimal detectable changes) were quantified at 4 sites (back: sacrum and lumbar erector spinae; wrist: hand dorsum and wrist flexors) for PPT and 2 sites (hand and low back) for TSP, for various sequences of measurements. RESULTS: Systematic differences were found between within test and retest for most PPT sequences at the lumbar erector spinae site and 1 TSP sequence (1-2-3) at back and hand sites, precluding reliability analyses for these data. Within-session PPT relative reliability was excellent at low back (ICC = 0.83 to 0.94) and wrist (ICC = 0.88 to 0.97) sites, whereas TSP showed good to excellent reliability at hand (ICC = 0.80 to 0.90) and low back (ICC = 0.73 to 0.89). In general, 2 and 3 measurements optimized absolute and relative reliability for TSP and PPT, respectively. DISCUSSION: Within-session reliability was generally excellent for PPT and TSP at the low back and hand sites among individuals with CLBP. We recommend using 3 measurements for PPT and 2 for TSP to optimize reliability. Caution is recommended when testing PPT of the painful lower back area since a systematic difference was present between the test and retest.

Effect of exercise on chronic neck pain and central sensitization: A protocol for a randomized crossover trial.

Exercise-induced hypoalgesia (EIH) has been found to vary widely within individuals with chronic neck pain (NP). Research has suggested that the presence of central sensitization within a subgroup of individuals with chronic NP might be a mediating factor to explain the relationship between exercise and improvements in patient-reported outcomes. Furthermore, recent work has found that lactate might play a role in the development and maintenance of chronic pain. The immediate effect of a single bout of physical exercise on central sensitization in individuals with chronic NP and the relationship between lactate concentration, central sensitization and pain sensitivity are to be investigated. Eighty adult participants with chronic NP will be recruited for this randomized crossover trial. Outcome measures, including temporal summation, conditioned pain modulation, EIH and lactate concentration, will be assessed before and after low- and high-intensity bicycling exercise. The outcomes of this study will provide new insights into the mechanistic effect of exercise on central sensitization in individuals with chronic NP and have the potential to add important information to the current exercise prescription guidelines for individuals with chronic NP. This study has been approved by the Human Research Ethics Committee, The University of Adelaide (H-2022-082) and registered in the Australian New Zealand Clinical Trials Registry (ACTRN12622000642785p).

SCN9A rs6746030 Polymorphism and Pain Perception in Combat Athletes and Non-Athletes.

One of the genes associated with pain perception is SCN9A, which encodes an α-subunit of the voltage gated sodium channel, NaV1.7, a crucial player in peripheral pain sensation. It has been suggested that a common missense polymorphism within SCN9A (rs6746030; G>A; R1150W) may affect nociception in the general population, but its effects of pain perception in athletes remain unknown. Therefore, the aim of the study was to investigate the association between a polymorphism within SCN9A (rs6746030) and pain perception (pain threshold and pain tolerance) in the group of combat athletes (n = 214) and students (n = 92) who did not participate in sports at a professional level. Genotyping was carried out using TaqMan Real-Time PCR method. No significant differences were found between the SCN9A genotype distributions with respect to the pain threshold. However, the probability of having a high pain threshold was higher in the combat sports group than in the control group. The probability of having a decreased pain tolerance was higher in the carriers of the GA and AA genotype than in the homozygotes of the GG genotype. Moreover, the possibility of having a high pain threshold was higher in the combat athlete group than in the control group. The results of our study suggest that the SCN9A rs6746030 polymorphism may affect pain perception. However, the additional effect of the experimental group may suggest that pain tolerance is significantly modulated by other factors, such as the systematic exposure of the athletes' bodies to short-term high-intensity stimuli during training sessions.

Psychometric properties of quantitative sensory testing in healthy and patients with shoulder pain: A systematic review.

Quantitative Sensory Testing (QST) is a psychophysical battery of various tests developed to quantify the subjects' self-reported sensory experience. Although the use of QST is valuable for the clinical assessment of pain, standard evaluation protocols have not yet been established. This systematic review aimed to investigate the level of evidence for the psychometric properties of QST in healthy and patients with shoulder pain. Eight databases were searched for peer-reviewed studies published until August 2021. The methodological quality of studies was evaluated using the COSMIN checklist. Twelve studies were included for qualitative synthesis, which included three different tests (Pressure Pain Threshold (PPT), Conditioned Pain Modulation (CPM) and Temporal Summation (TS)). As the body of evidence consisted of studies of low methodological quality, the psychometric properties of PPT, CPM, and TS in healthy and patients with shoulder pain were classified as unknown. Although there is a risk that the conclusions may be 'superficial' in nature, the reliability seems to be nearly excellent for the PPT, however, the protocols' variation and the low methodological quality of the studies do not allow for clear conclusions. Further studies are required for the CPM and TS in patients with shoulder pain.

Effects of diacutaneous fibrolysis in patients with tension-type headache: A randomized controlled trial.

BACKGROUND: Manual therapy appears to be effective for the relief of tension-type headache (TTH), just as diacutaneous fibrolysis (DF) has shown to be a beneficial technique for the relief of symptoms in other dysfunctions. However, no studies have evaluated the potential beneficial effect of DF in TTH. The aim of this study is to analyze the effect of three sessions of DF in patients with TTH. METHODS: Randomized controlled trial in 86 subjects (43 intervention/ 43 control group). The headache frequency, the headache intensity, the pressure pain thresholds (PPTs) at trapeziometacarpal joint, upper trapezius, suboccipital, frontal and temporal muscles, parietal sutures and the cervical mobility were measured at baseline, at the end of the third intervention and one-month after the last intervention. RESULTS: Statistically significant differences with p values <0.05 were observed between groups in favor of the intervention group in the one-month follow-up in the following variables: headache frequency, headache intensity, flexion, extension, right and left side-bending, right and left rotation, PPTs in left trapeziometacarpal joint, right suboccipital muscle, right and left temporal muscle, left frontal muscle and right and left parietal. CONCLUSIONS: DF provides a beneficial effect in reducing headache frequency, relieving pain, and improving cervical mobility in patients with TTH.