Increase In Pain Threshold Research Articles

The effect of stretching intensity on pain sensitivity: A randomized crossover study on healthy adults.

Stretching exercises have effects on local and widespread pain sensitivity. A dose-response relationship may exist between the analgesic effect and the intensity of stretching, such that a higher intensity of stretching may generate a larger reduction in analgesic response, but this remains to be studied. This study aimed to examine the dose-response relationship between stretching intensity and the analgesic effect. A randomized, repeated-measures crossover study was performed to examine the effect of stretching to the first point of pain onset and stretching to the point of a sensation of stretching (discomfort). The primary outcome was regional and distant pressure pain thresholds. Thirty-one participants (n = 24 female) were available for analysis. We observed a 22.2% increase in regional pressure pain thresholds (93.2 kPa, p = 0.001) and a 15.0% increase in distant pressure pain thresholds (50.9 kPa, p = 0.012) following stretching to the point of stretch. We observed a 20.0% increase in regional pressure pain thresholds (90.3 kPa, p = 0.001) and a 15.1% increase in distant pressure pain thresholds (52.1 kPa, p = 0.004) following stretching to the point of pain. The results showed that local and widespread pain sensitivity decreased following acute stretching, regardless of stretching intensity. No differences in pain sensitivity were found between stretching to the point of stretch or stretching to the first onset of pain. Thus, the results showed no evidence of a dose-response relationship between stretching intensity and the analgesic effect. The study showed a significant acute hypoalgesic effect of stretching exercises regardless of stretching intensity. This may have appropriate clinical implications for patients with musculoskeletal and nociplastic pain.

New insights into individual differences in response to chronic unpredictable mild stress (CUMS) in rats with respect to hippocampal BDNF and GSK3-β expression levels

Preclinical and clinical studies have shown a wide-range of individual differences in response to stressors or novel environments which can affect the susceptibility to develop abnormal behaviors and neuropsychiatric disorders. Both vulnerability and resiliency have been observed in animals and humans experiencing stressful events. Chronic unpredictable mild stress (CUMS) is a rodent depression model consisting of various stressors. This protocol leads to depressive- and anhedonic-like behaviors in rodents. The present study aimed to evaluate potential individual differences in response to CUMS in rats, with respect to the expression level of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinases 3-beta (GSK3-β) (proteins involved in the modulation of mood, neuroplasticity, and cognition) in the hippocampus. CUMS was performed for four consecutive weeks. Depressive-like behavior, locomotor activity, anxiety-like behavior, and pain threshold were also evaluated using forced swim test (FST), open field test (OFT), and the hot plate (HP), respectively. Real-time PCR was used to evaluate BDNF and GSK3-β expression levels. The results showed that CUMS rats can be classified as two clusters: affected and non-affected (depressed and non-depressed). Affected rats showed depressive- and anxiety-like behaviors, decreased locomotor activity, and increased pain threshold. However, non-affected rats were similar to controls. In addition, there was a downregulation of BDNF and upregulation of GSK3-β in affected rats. Spearman correlation analysis also showed a relationship between BDNF and GSK3-β expression levels with individual differences. In conclusion, the present study showed that BDNF and GSK3-β may be involved in individual differences in CUMS rats.

Resistance Training Demonstrates Acute Local Muscular Increases In Heat Pain Threshold

Resistance Training Demonstrates Acute Local Muscular Increases In Heat Pain Threshold

The Effect of a Caffeine and Nicotine Combination on Nicotine Withdrawal Syndrome in Mice.

Nicotine dependence is an important cause of excessive exposure to tobacco combustion compounds in most smokers. Nicotine replacement therapy is the main method to treat nicotine dependence, but it still has its shortcomings, such as the inability to mitigate withdrawal effects and limited applicability. It has been hypothesized that a combination of low-dose nicotine and caffeine could achieve the same psychological stimulation effect as a high dose of nicotine without causing nicotine withdrawal effects. To establish a model of nicotine dependence, male C57BL/6J mice were subcutaneously injected four times a day with nicotine (2 mg/kg) for 15 days and fed with water containing nicotine at the same time. They were randomly divided into four groups. After 24 h of withdrawal, different groups were injected with saline, nicotine (0.25 mg/kg or 0.1 mg/kg), or nicotine (0.1 mg/kg) and caffeine (20 mg/kg). Behavioral and physiological changes were evaluated by an assessment of physical signs, open field tests, elevated plus maze experiments, forced swimming tests, hot plate tests, and new-object-recognition tests. The changes in dopamine release in the prefrontal cortex (PFC) and ventral tegmental area (VTA) in the midbrain were analyzed using ELISA. The results showed that a combination of caffeine and nicotine could effectively relieve nicotine withdrawal syndrome, increase movement ability and pain thresholds, reduce anxiety and depression, enhance memory and cognitive ability, and increase the level of dopamine release in the PFC and VTA. Thus, caffeine combined with nicotine has potential as a stable and effective treatment option to help humans with smoking cessation.

Brain activity changes after high/low frequency stimulation in a nonhuman primate model of central post-stroke pain

Central post-stroke pain (CPSP) is a chronic pain resulting from a lesion in somatosensory pathways. Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) that target the primary motor cortex (M1), have shown promise for the treatment of CPSP. High-frequency (Hf) rTMS exhibits analgesic effects compared to low-frequency (Lf) rTMS; however, its analgesic mechanism is unknown. We aimed to elucidate the mechanism of rTMS-induced analgesia by evaluating alterations of tactile functional magnetic resonance imaging (fMRI) due to Hf- and Lf-rTMS in a CPSP monkey model. Consistent with the patient findings, the monkeys showed an increase in pain threshold after Hf-rTMS, which indicated an analgesic effect. However, no change after Lf-rTMS was observed. Compared to Lf-rTMS, Hf-rTMS produced enhanced tactile-evoked fMRI signals not only in M1 but also in somatosensory processing regions, such as the primary somatosensory and midcingulate cortices. However, the secondary somatosensory cortex (S2) was less active after Hf-rTMS than after Lf-rTMS, suggesting that activation of this region was involved in CPSP. Previous studies showed pharmacological inhibition of S2 reduces CPSP-related behaviors, and the present results emphasize the involvement of an S2 inhibitory system in rTMS-induced analgesia. Verification using the monkey model is important to elucidate the inhibition system.

The cumulative analgesic effect of repeated electroacupuncture is modulated by Adora3 in the SCDH of mice with neuropathic pain.

Existing remedial approaches for relieving neuropathic pain (NPP) are challenging and open the way for alternative therapeutic measures such as electroacupuncture (EA). The mechanism underlying the antinociceptive effects of repeated EA sessions, particularly concerning the regulation of the Adora3 receptor and its associated enzymes, has remained elusive. This study used a mouse model of spared nerve injury (SNI) to explore the cumulative analgesic effects of repeated EA at ST36 (Zusanli) and its impact on Adora3 regulation in the spinal cord dorsal horn (SCDH). Forty-eight male mice underwent SNI surgery for induction of neuropathic pain and were randomly assigned to the SNI, SNI + 2EA, SNI + 4EA, and SNI + 7EA groups. Spinal cord (L4-L6) was sampled for immunofluorescence, adenosine (ADO) detection and for molecular investigations following repeated EA treatment. Following spared nerve injury (SNI), there was a significant decrease in mechanical withdrawal thresholds (PWTs) and thermal nociceptive withdrawal latency (TWL) in the ipsilateral hind paw on the third day post-surgery, while the contralateral hind paw PWTs showed no significant changes. On subsequent EA treatments, the SNI + EA groups led to a significant increase in pain thresholds (p < 0.05). Repeated EA sessions in SNI mice upregulated Adenosine A3 (Adora3) and cluster of differentiation-73 (CD73) expression while downregulating adenosine deaminase (ADA) and enhancing neuronal instigation in the SCDH. Colocalization analysis of Neun-treated cells revealed increased Adora3 expression, particularly in the SNI + 7EA group. In conclusion, cumulative electroacupuncture treatment reduced neuropathic pain by regulating Adora3 and CD73 expression, inhibiting ADA and most likely increasing neuronal activation in the SCDH. This study offers a promising therapeutic option for managing neuropathic pain, paving the way for further research.

Polyphenol-rich Sorghum bicolor supplement exhibits anti-nociceptive activity and protective effects against pathological changes associated with complete Freund's adjuvant induced arthritis in rodents

IntroductionArthritis is a common inflammatory joint disease; causing severe pain, anxiety, and depression. Sorghum bicolor L. Moench (Pocaeae) is used for treating cough, asthma, and arthritic pain in Traditional Chinese Medicine (TCM). This study evaluates the anti-nociceptive and anti-arthritic effects of the polyphenol-rich Sorghum bicolor supplement (SBS) in rodents. MethodsThe anti-nociceptive activity of SBS was assessed using hot plate, acetic acid mouse writhing, and formalin-induced paw licking tests in mice. In the arthritis study, rats received SBS (50, 100, and 200 mg/kg p.o) for 28 days. Thirty minutes after treatment on days, 1 and 20, rats received intra-articular injection of Complete Freund's adjuvant (CFA) for arthritis induction. Arthritic scores and paw edema were determined before assessing motor function, anxiety, depression, hyperalgesia and allodynia on day 28. Lipid profiles were determined, and ankle and brain tissues were analyzed for oxidative stress and inflammatory biomarkers, alongside histopathological studies. ResultsSBS reduced nociceptive responses induced by noxious heat, acetic acid and formalin in mice. In CFA-injected rats, SBS decreased paw volume and arthritic scores, and increased pain thresholds to thermal, cold, and mechanical stimuli. The SBS reduced motor activity, anxiety and depression, and improved serum lipid profiles in arthritic rats. It further modulated oxidative stress, pro-inflammatory cytokines, nuclear factor kappa (NF-kB), apoptotic markers, nuclear factor erythroid 2-related factor 2 (NRF2), glutamic acid decarboxylase (GAD) and brain-derived neurotrophic factor (BDNF) in CFA-treated rats. SBS produced histopathological improvements in joint tissues of arthritic rats. DiscussionThis study revealed that SBS exhibited anti-nociceptive activity in mice and reduces inflammation, hyperalgesia, anxiety and depression in CFA-arthritic rats. The ability of SBS to modulate key biomarkers such as pro-inflammatory cytokines, NF-κB, caspases, Nrf2, BDNF, and GAD highlights its multifaceted approach in addressing both the physical and psychological aspects of arthritis, providing a comprehensive therapeutic strategy, justifying its use in TCM for this debilitating condition.

Effectiveness of photobiomodulation and orofacial myofunctional therapy in orofacial pain disorders. A systematic review of randomized control trials.

Orofacial pain can significantly affect physical, psychological, and overall quality of life. This study aimed to compare the effectiveness of combining photobiomodulation (PBM) with orofacial myofunctional therapy (OMT) in managing orofacial pain disorders. An electronic search of randomized controlled trials in electronic databases was performed until March 2024. Randomized controlled trials (RCTs) focusing on PBM and OMT for the management of orofacial pain were included. Risk of bias across individual studies was performed using the Cochrane risk of bias tool for interventions. A total of 10 RCTs were included, out of which 7 RCTs revealed that the combined approach of PBM and OMT had a more pronounced impact on diminishing pain and enhancing functional activity in patients with orofacial disorders. One study reported significant increases in pressure pain threshold for TMJ, masseter, and anterior temporalis muscles at both sides in the post-treatment compared with the pre-treatment in both groups. The risk of bias was low in 7, moderate in 2, and high in 1 study. The efficacy of a combined modality treatment of PBM with OMT for orofacial pain disorder shows promising results. However, further randomized controlled trials with extended follow-up periods standardized PBM and OMT parameters are warranted to obtain firm conclusions.

GABA transporter mGat4 is involved in multiple neural functions in mice

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. The termination of GABA transmission is through the action of GABA transporters (GATs). mGAT4 (encoded by Slc6a11) is another GAT besides GAT1 (encoded by Slc6a1) that functions in GABA reuptake in CNS. Research on the function of mGAT4 is still in its infancy. We developed an mGat4 knockout mouse model (mGat4−/− mice) and performed a series of behavioral analyses for the first time to study the effect of mGat4 on biological processes in CNS. Our results indicated that homozygous mGat4−/− mice had less depression, anxiety-like behavior and more social activities than their wild-type littermate controls. However, they had weight loss and showed motor incoordination and imbalance. Meanwhile, mGat4−/− mice showed increased pain threshold and hypoalgesia behavior in nociceptive stimulus and learning and memory impairments. The expression of multiple components of the GABAergic system including GAD67, GABAA and KCC2 was altered. There is little or no compensatory change in mGat1. In a word, mGat4 may play a key role in normal motor coordination, sensation, emotion, learning and memory and could be the potential target of neurological disorders.

Electroacupuncture improves peripheral neuropathy by up-regulating Sirt1/PGC-1α/TFAM pathway in type 2 diabetes rats with peripheral neuropathy.

To observe the effect of electroacupuncture (EA) on activation of silent information regulator 1 (Sirt1)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/mitochondrial transcription factor A (TFAM) pathway in type 2 diabetes (T2DM) rats with peripheral neuropathy (DPN) , so as to explore its possible mechanisms underlying improvement of DPN. Thirty male SD rats were randomly divided into blank control group (n=8) and DPN model group (n=22) which were further divided into model group (n=8) and EA group (n=8) after successful modeling. The model of T2DM was established by high-fat diet and low-dose intraperitoneal injection of streptozocin (35 mg/kg). For rats of the EA group (anesthetized with isoflurane), EA stimulation (2 Hz/15 Hz, 2 mA) was applied to "Tianshu"(ST25) for 20 min, once daily, 6 times a week for 6 weeks. The blood glucose level, body weight, area under curve (AUC) of glucose tolerance test, and hind-paw mechanical pain threshold and thermal pain threshold were observed. The intra-epidermal nerve fiber density (IENFD) of the hind-foot pad was observed by immunofluorescence staining. The motor nerve conduction velocity (MNCV) of the sciatic nerve was measured by using electrophysiological method. H.E. staining was used to observe the histopathological changes of the sciatic nerve after modeling. Transmission electron microscopy (TEM) was used to observe the ultrastructural changes of the sciatic nerve. The protein expressions of energy-related Sirt1, PGC-1α and TFAM in the sciatic nerve was detected by Western blot. Compared with the blank control group, the model group had a higher blood glucose contents and AUC (P<0.001), a slower MNCV (P<0.01), and a decrease in the body weight and in the mechanical and thermal pain thresholds (P<0.001) and IENFD (P<0.001), and in the expression levels of Sirt1, PGC-1α and TFAM (P<0.05, P<0.01). In contrast to the model group, the EA group had a decrease in the blood glucose contents and AUC (P<0.05, P<0.01), and an increase in mechanical and thermal pain thresholds, MNCV, IENFD, and expression levels of Sirt1, PGC-1α and TFAM proteins (P<0.01, P<0.05). In addition, results of histopathological and ultrastructural changes of the sciatic nerve showed more fragmented and disordered distribution of axons on the transverse section, and extensive separation of myelin and axons, uneven myelin thickness, axonal degeneration and irregular shape in the model group, whereas in the EA group, the axons on the transverse section were relatively more dense and more complete, the myelin sheath of the sciatic nerve was relatively uniform, and the axonal shape was relatively regular with relatively milder lesions. EA up-regulates the expressions of Sirt1, PGC-1α, TFAM in T2DM rats with DPN, which may be associated with its functions in improving and repairing the injured peripheral nerves in rats with DPN.

125 Contribution of Sensory Neuron-associated Macrophages to Neuropathic Pain via Up-regulation of Calcium Channel in C Fiber Sensory Neurons in Dorsal Root Ganglion: An Animal Model Study

INTRODUCTION: Animal models have demonstrated that sensory neuron-associated macrophages (sNAMs) play a key role in the initiation and persistence of neuropathic pain. The Cav3.2 calcium channel (Cav3.2) is also known to be involved in modulating neuropathic pain in peripheral sensory neurons. METHODS: Male Sprague-Dawley rats underwent unilateral tight ligation of the lumbar 5 spinal nerve and were divided into three groups: a control group (SHAM), a group that underwent ligation without, and with minocycline (SNL and SNL+Mino). The mechanical pain threshold of the hind paw was assessed with von-Frey filament application. Immunohistochemical staining techniques were used to evaluate the levels of sNAM, Cav3.2, and C-fiber sensory neurons with anti-Iba1, anti-Cav3.2, and IB4 antibodies, respectively. Cytokine levels were analyzed using cytokine arrays and western blotting. RESULTS: The SNL group had a significantly lower pain threshold compared to the control group (p &lt; 0.001). In the DRG, neuropathic pain led to an accumulation of macrophages and increased their ability to attach to Cav 3.2. The expression of Cav 3.2 then triggered the activation of IB4 cells in the DRG. Additionally, cytokine array and western blot analyses revealed a higher expression rate of TNF-α in the SNL group compared to the control group (p = 0.048). Treatment with minocycline resulted in increased pain threshold, decreased number of macrophages in the DRG, and interruption of the attachment between macrophages and Cav 3.2, leading to lower expression of TNF-α. CONCLUSIONS: In conclusion, the results of this study suggest that sNAMs may play a role in the development of neuropathic pain by increasing the expression of Cav3.2 through the upregulation of TNF-α release in peripheral sensory nociceptive neurons.

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.

Bioinformatics and LC-QTOF-MS based discovery of pharmacodynamic and Q-markers of Pitongshu against functional dyspepsia

Pitongshu (PTS) is a clinically effective empirical formula for the treatment of FD. The efficacy and safety of PTS have been demonstrated in randomized, controlled, double-blind trials, but there is a lack of understanding of the systematic evaluation of the efficacy of PTS and its material basis. To investigate the efficacy of PTS in Functional dyspepsia (FD) mice and possible Q-markers. In this study, we used "irregular feeding+chronic unpredictable chronic stimulation" to establish a mice model of FD with hepatogastric disharmony. The efficacy of PTS was assessed from hair condition, behavioral, pain, gastrointestinal function, and serum 5-HT, GAS, MTL levels in mice by instillation of different doses of PTS. In addition, the composition of drugs in blood was analyzed by LC-QTOF-MS and potential Q-markers were selected by combining network pharmacology, molecular docking and actual content. Our study showed that different doses of PTS increased pain threshold and writhing latency, decreased the number of writhings, increased gastric emptying rate and small intestinal propulsion rate, decreased total acidity of gastric contents and gastric acid secretion, and increased serum levels of 5-HT, GAS, and MTL in mice to different degrees. Enrichment analysis showed that PTS may be anti-FD through multiple pathways such as Serotonergic synapse, thyroid hormone signaling pathway, cholinergic synapse, and dopaminergic synapse. In addition, potential active ingredient substances were explored by LC-QTOF-MS combined with bioinformatics. Combined with the actual contentselected six constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol, possible as Q-markers. PTS may exert its anti-FD effects through multi-component, multi-target and multi-pathway". Constituents, hesperidin, neohesperidin, naringin, paeoniflorin, magnolol and honokiol may be the Q-markers of its anti-FD effects.

The Effect of Acute Physical Fatigue on Information Processing, Pain Threshold and Muscular Performance

This study explores the multifaceted effects of acute physical fatigue on information processing, pain threshold, and muscular performance. Enrolling 28 recreational athletes, we used a high-intensity interval training (HIIT) protocol to induce fatigue and conducted pre- and post-intervention assessments. Our findings revealed significant physiological and performance adaptations following the HIIT sessions. Key observations included increased heart rate and rate of perceived exertion and an enhancement in horizontal jump performance and isometric hand strength but no significant change in cognitive processing speed. Remarkably, participants demonstrated a notable increase in pain threshold and blood lactate levels post-exercise. These results challenge traditional views of fatigue, indicating not only a physiological but also a psychological resilience to high-intensity stress. This study provides new insights into the complex interplay between physical fatigue, cognitive function, and pain perception, highlighting the comprehensive effects of HIIT on both physiological and psychological dimensions of human performance.

Regional and widespread pain sensitivity decreases following stretching in both men and women – Indications of stretch-induced hypoalgesia

IntroductionThis study aimed to investigate the effect of sex on regional and widespread pain sensitivity following acute bouts of stretching and to investigate the acute effect of stretching on regional and widespread pain sensitivity following stretching. Methods73 healthy adults (36 females; mean age 25.6 ± 6.7 years) with an age range from 19 to 62 years were recruited for this experimental study. Regional and distant pain pressure pain thresholds, passive knee extension range of motion and passive resistive torque were measured before and 30 s after four bouts of 30-s static muscle stretching of the knee flexors with 20-s rest between bouts. ResultsNo significant sex differences were found for pressure pain thresholds (p > 0.132), range of motion (p = 0.446) or passive resistive torque (p = 0.559) between pre-stretch and post-stretch measures. There were significant increases in pressure pain thresholds (p = 0.010), range of motion (p = 0.001) and passive resistive torque (p = 0.007) between pre-stretch and post-stretch measures. ConclusionMuscle stretching significantly decreased regional and widespread pain sensitivity, indicating that central pain-modulating mechanisms are engaged during muscle stretching, resulting in stretch-induced hypoalgesia. Moreover, the results showed that the effect of stretching on regional and widespread pain sensitivity is not sex-specific.

Assessment of the Efficacy and Safety of Hyperbaric Oxygen Therapy on Pain in Patients with Fibromyalgia: A Systematic Review and Meta-analysis of Randomised Controlled Studies

Abstract Hyperbaric oxygen therapy (HBOT) is an adjunctive treatment for chronic pain. The current study aimed to perform a systematic evaluation and meta-analysis of randomised controlled trials (RCTs) to assess the clinical efficacy and safety of HBOT for pain reduction in fibromyalgia (FM) patients compared to conventional therapy. A systematic search of medical subject headings and keywords associated with HBOT for FM patients was conducted using electronic databases: MEDLINE/ PubMed, Web of Science, Cochrane Library Central Register of Controlled Trials, and Scopus. Google Scholar was also combed to detect likely non-indexed available studies. We also searched manually through reference lists of identified original articles or reviews for relevant articles. The http://www.clinicaltrial.gov was examined for all research protocols being conducted/ planned. The Cochrane Collaboration tool and Higgins and Thompson’s I2 method determined the risk of bias and heterogeneity. The primary outcome was the effect of HBOT on pain; secondary outcomes included adverse effects of HBOT, assessment of the quality of life, functional impairment, psychological symptoms, and sleep quality. The overall quality of evidence was assessed with the GRADE approach. Cochrane RevMan software (version 5.4) was used for data analysis. Results were synthesised through a general summary of the characteristics and findings of each study. We also analysed different HBOT protocols and their outcomes across the studies. Five RCTs enrolling 91 and 89 patients in FM and control groups were included in the present study. HBOT results in decreased tender points (-6.23 (95 % CI: -7.76, -4.71) P &lt; 0.0001), increased pain threshold (0.57 (95% CI: 0.3, 0.83) P &lt; 0.00001) and a decreased Visual Analog scale (VAS) score for pain (-5.31(95 % CI: -8.17, -2.45)). Quality of life, sleep, functional impairment, etc., also improved after HBOT. HBOT is effective in pain and other associated outcomes in FM patients. In FM patients, high-quality evidence in favour of HBOT to improve pain, fatigue, quality of life, sleep, psychological outcomes, etc., is required.

Sema3A secreted by sensory nerve induces bone formation under mechanical loads

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.

Development, optimization, and characterization of rhein loaded nanoemulgel for treatment of osteoarthritis

This work aimed to design a transdermal delivery of rhein loaded nanoemulgel to improve the bioavailability and efficacy of rhein in the treatment of osteoarthritis and reduce its systemic side effects. Rhein loaded nanoemulsion (Rh-NE) prepared by application of ternary phase diagram and spontaneous emulsification method. Box-Behnken design (BBD) was employed to optimize formulation and preparation process of Rh-NE. The optimal formulation was 11.09% mixed oil (rhein and caproyl 90), 22.96% mixed emulsifier (kolliphor RH 40: transcutol HP, 1:1, w/w), and the preparation process was 23.08 min ultrasonic time and 179.5 W ultrasonic power. The particle size of the optimized Rh-NE was 24.5 ± 3.2 nm, PDI was 0.15 ± 0.02, and zeta potential was −18.6 ± 1.8 mV. The Rh-NE was incorporated into hydrogel consisted of 0.85% carbomer, 0.2% poloxamer 188 and 8.0% glycerol to form rhein loaded nanoemulgel (Rh-NE/Gel). In vitro transdermal flux of Rh-NE/Gel was 91.4 ± 0.9 μg/cm2·h. It was found that the inhibition rate of swelling degree of auricle caused by xylene was (54%), inhibition rate of writhing reaction was (60%), percentage increase in pain threshold was (P < 0.01), and the inhibition rate of capillary permeability was (69%). The therapeutic effect of Rh-NE/Gel on osteoarthritis in model rats was significantly improved compared with control group; the swelling degree of joint and toe were significantly reduced by 91% and 71%, respectively, and the contents of inflammatory factors IL-1β and NO were decreased 35.7% and 52.4%, respectively. The developed Rh-NE/Gel could provide anti-osteoarthritis effect and reduce the release of proinflammatory mediators in OA model rats.

Comparison of the effects of moxibustion and acupuncture of combined "Biao-Ben" acupoints on intestinal sensitivity and autonomic nervous system function in rats with diarrhea-predominant irritable bowel syndrome.

To compare the effects of moxibustion and acupuncture of combined "Biao-Ben" acupoints (Biao indicates pathogenic factors of disease, Ben refers to body constitution) on a rat model of irritable bowel syndrome with diarrhea (IBS-D). Forty female SD rats were randomly divided into 4 groups：normal group, model group, moxibustion group, and acupuncture group, with 10 rats in each group. The IBS-D rat model was established by administering acute-chronic stress combined with folium sennae gavage for 28 days. Rats in the moxibustion group received moxibustion at bilateral "Zusanli"(ST36), "Guanyuan"(CV4), and "Neiguan"(PC6), while those in the acupuncture group received acupuncture at the same acupoints, both for 15 min every time, once a day. The treatments were administered for 21 days. The loose stool rate was observed. Colonic pain threshold and colonic distension threshold were measured by a self-made balloon catheter. Total distance traveled and grid crossing numbers were observed by open field test. Heart rate variability(HRV) time domain indexes SDANN and PNN50 were acguired by using electrophysiological recorder. Histopathological changes in the colon tissue were observed after HE staining. Contents of interleukin-6(IL-6), IL-8, and tumor necrosis factor-alpha(TNF-α) in serum were detected by ELISA. Compared with the normal group, rats in the model group showed increased loose stool rate(P<0.05), decreased pain threshold and distension threshold(P<0.05), reduced total distance traveled and grid crossing numbers in the open field test(P<0.05), decreased HRV time domain indexes SDANN and PNN50(P<0.01, P<0.05), and elevated levels of serum IL-6, IL-8, and TNF-α contents(P<0.05). Compared with the model group, the moxibustion group and acupuncture group showed decreased loose stool rate(P<0.05), increased total distance traveled and grid crossing numbers in the open field test(P<0.05), increased pain threshold and distension threshold(P<0.05), increased SDANN and PNN50 (P<0.05), and decreased levels of serum IL-6, IL-8, and TNF-α contents(P<0.05). Compared with the acupuncture group, the moxibustion group showed further decreased loose stool rate(P<0.05), increased total distance traveled and grid crossing numbers in the open field test(P<0.05), increased pain threshold and distension threshold(P<0.05), increased SDANN and PNN50(P<0.05), and decreased levels of serum IL-6, IL-8, and TNF-α contents(P<0.05). No significant pathological changes were observed in the colon tissue of rats in each group. Moxibustion of combined "Biao-Ben" acupoints is more effective in regulating HRV and serum IL-6, IL-8, and TNF-α contents in the IBS-D rat model. Based on the combined "Biao-Ben" acupoints method, moxibustion has better therapeutic effects on IBS-D than acupuncture.

Examination of Conditioned Pain Modulation in Myofascial TMD With Consideration of Temporal Summation

Research on myofascial temporomandibular disorder (mTMD) has often focused on potential dysfunction in endogenous pain modulation. However, studies on the specific inhibitory and facilitatory components of endogenous pain modulation using conditioned pain modulation (CPM) and temporal summation of second pain (TSSP) have shown mixed results. This study aimed to 1) examine whether women with mTMD demonstrated efficient CPM compared to controls; 2) explore the association between independent measures of CPM and TSSP in women with mTMD relative to controls; and 3) determine whether resulting modulatory profiles differentially predicted pain intensity among cases. All participants were recruited from dental clinics. Cases were women who met the research diagnostic criteria for mTMD. Controls did not have facial pain on exam and were selected to be sociodemographically similar to cases. CPM and TSSP were assessed via independent psychophysical protocols. CPM was examined in linear mixed models predicting pain thresholds adjusted for age and stratified by TSSP. Mean CPM was estimated at a 2.2 (SD = 2.8) degree increase in pain thresholds (P ≤ .001), similar in cases and controls (P = .67). CPM was less efficient in cases with enhanced TSSP (P = .031), but not in controls. Although the double-pronociceptive profile of both low CPM and high TSSP trended higher among cases than controls, it did not predict higher levels of pain intensity among cases. This study does not support deficient inhibitory endogenous pain modulation in mTMD, but results suggest that inhibitory and facilitatory pain modulation should be examined concomitantly in the study of endogenous pain modulation. PerspectiveThis manuscript presents a novel examination of inhibitory modulation by the level of facilitatory modulation in mTMD. The findings and approach may prove useful for mechanistic researchers studying endogenous pain modulation and clinical researchers seeking to jointly examine conditioned pain modulation and temporal summation in future research on chronic pain.