Muscle Pain Conditions Research Articles

Profile and Characteristics of Analgesic Use in Myalgia Cases at Soromandi Health Center

Myalgia is a common muscle pain condition that often requires pharmacological analgesic therapy for pain management. This study aims to determine the profile and characteristics of analgesic use in myalgia patients at Puskesmas Soromandi. Data were obtained through a retrospective study of patient medical records from January to December 2023, using consecutive sampling method. The data were analyzed descriptively and presented in tables and percentages. The results show that the most common demographic groups using analgesics for myalgia were patients aged 46-65 years (46.53%), female (57.4%), and farmers (48.5%). The most frequently used analgesic was ibuprofen 400 mg (40.59%), which was more often combined with supplements rather than used as monotherapy. The most common duration for analgesic administration was 5 days (56.43%). Conclusion: Myalgia patients are generally aged 46-65 years, with a predominance of females and farmers. Ibuprofen and a 5-day duration of analgesic treatment are the most frequently applied approaches in myalgia cases at Puskesmas Soromandi.

Nanomaterials as catalysts for the sensitive and selective determination of diclofenac.

Diclofenac (DCF) is a non-steroidal anti-inflammatory drug possessing analgesic and antipyretic properties. It is used for the treatment of rheumatoid arthritis pain, osteoarthritis, and acute muscle pain conditions and can be administrated orally, topically or intravenously. Because of its widespread use, hydrophilicity, stability and poor degradation (bioaccumulation in the food chain), DCF is an emerging chemical contaminant that can cause adverse effects in the ecosystems. Taking into account the consumption of DCF in pharmaceutical formulations and its negative impact on the environment, the development of new sensitive, selective, cheap, fast, and online capable analytical devices is needed for on-site applications. This brief review attempts to cover the recent developments related to the use of nanomaterials as catalysts for electrochemical determination of DCF in pharmaceutical formulations, biological fluids and environmental samples. The article aims to prove how electrochemical sensors represent reliable alternatives to conventional methods for DCF analysis. The manuscript highlights the progress in the development of electrochemical sensors for DCF detection. We have analyzed numerous recent papers (mainly since 2019) on sensors developed for the quantitative determination of DCF, indicating the limit of detection, linear range, stability, reproducibility, and analytical applications. Current challenges related to the sensor design and future perspectives are outlined.

4 Resting State Functional Connectivity Impairments Implicate CNS Mechanisms Underlying Chronic Pain and Depression in Gulf War Veterans’ Illness

Objective:Around 200,000 veterans (up to 32% of those deployed) of the 1991 Gulf War (GW) suffer from GW veterans’ illness (GWVI). GWVI is a poorly understood chronic medical condition, characterized by symptoms indicative of brain function deficits in multiple domains. Among the symptoms of brain impairment GWVI-related chronic headaches and body muscle and joint pain conditions (GWVI-HAP) are the most debilitating, affecting around 64% of the GWVI veterans. Further, depression carries a very high co-morbid rate (>50%) in patients with chronic pain, including GWVI-HAP. In this preliminary study, we examined the integrity of brain function networks in a group of GWI-HAP veterans, with resting state fMRI (rsfMRI).Participants and Methods:Data from the first twenty-two GWVI-HAP veterans from two ongoing parallel clinical trials was examined. Of these 14 subjects (GWVI-HAP-DM) had mild depression (Hamilton Rating Scale for Depression (HSRD < 13); and 8 subjects (GWVI-HAP-DS) had moderate to severe depression (HSRD > 14). Written informed consent was obtained from all participants in the protocol approved by the local Institutional Review Board. RsfMRI data was acquired on a Siemens 3T Prisma-Fit MRI scanner using a 10-minute whole-brain high resolution simultaneous multi-slice (SMS) gradient echo echo-planar imaging (EPI) sequence: TR/TE/FA = 2.2 sec/ 27 msec/80°, and analyzed with well-established image processing pipelines. Functional connectivity (FC) to different regions implicated in depression and chronic pain was assessed with seed-based correlation analysis. Between group differences in FC were obtained with 2-sample t-tests.Results:GWVI-HAP-DS group exhibited significantly (p < 0.05) reduced FC compared to GWVI-HAP-DM between frontal lobe (medial (mPFC), and dorsolateral (dlPFC) prefrontal cortex) and the striatum. This indicates that malfunction of fronto-striatal circuits could be a source of the increased chronic pain and depression seen in veterans with GWVI- HAP-DS. Dysregulation of fronto-striatal networks has been implicated in major depressive disorder as well as many chronic pain conditions. In addition, FC between mPFC, and salience network (SN; anterior insula and dorsal anterior cingulate) and limbic (subgenual and ventral anterior cingulate) regions were also reduced in GWVI-HAP-DS. Similarly, mPFC and SN also exhibited reduced FC to pain processing regions (posterior insula, centromedian thalamus and cerebellum). These FC impairments could reflect greater deficits in regulation of and salience attribution to emotions and nociception in the GWVI-HAP-DS group. Finally, GWVI-HAP-DS also exhibited reduced FC between nodes of the default mode network. DMN impairments also have been observed in many depressive and chronic pain conditions.Conclusions:The results of this preliminary analysis implicate impairments in cognitive control of emotion and nociception as a mechanism underlying the enhanced chronic pain and depression observed in GWVI-HAP veterans, especially those with moderate to severe depression. A fuller picture of deficits in FC in brain function networks is expected to emerge as more GWI-HAP subjects of both groups along with age matched healthy controls are examined in this ongoing project. Better understanding of impairments in these networks in GWI-HAP will benefit the rehabilitation of veterans with GWI-HAP.

ASIC3 plays a protective role in delayed-onset muscle soreness (DOMS) through muscle acid sensation during exercise.

Immediate exercise-induced pain (IEIP) and DOMS are two types of exercise-induced muscle pain and can act as barriers to exercise. The burning sensation of IEIP occurs during and immediately after intensive exercise, whereas the soreness of DOMS occurs later. Acid-sensing ion channels (ASICs) within muscle afferents are activated by H+ and other chemicals and have been shown to play a role in various chronic muscle pain conditions. Here, we further defined the role of ASICs in IEIP, and also tested if ASIC3 is required for DOMS. After undergoing exhaustive treadmill exercise, exercise-induced muscle pain was assessed in wild-type (WT) and ASIC3-/- mice at baseline via muscle withdrawal threshold (MWT), immediately, and 24 h after exercise. Locomotor movement, grip strength, and repeat exercise performance were tested at baseline and 24 h after exercise to evaluate DOMS. We found that ASIC3-/- had similar baseline muscle pain, locomotor activity, grip strength, and exercise performance as WT mice. WT showed diminished MWT immediately after exercise indicating they developed IEIP, but ASIC3-/- mice did not. At 24 h after baseline exercise, both ASIC3-/- and WT had similarly lower MWT and grip strength, however, ASIC3-/- displayed significantly lower locomotor activity and repeat exercise performance at 24 h time points compared to WT. In addition, ASIC3-/- mice had higher muscle injury as measured by serum lactate dehydrogenase and creatine kinase levels at 24 h after exercise. These results show that ASIC3 is required for IEIP, but not DOMS, and in fact might play a protective role to prevent muscle injury associated with strenuous exercise.

The importance of physical assessment in post-mastectomy rehabilitation

Abstract Introduction. The application of surgical, oncological and hormonal treatment causes the appearance of various dysfunctions at the somatic level: decreased joint mobility and muscle strength, lymphedema, pain, peripheral neuropathy, cardiovascular and gastrocecal conditions, and at the psychological level: insomnia, fear of relapse, anxiety and depression. Aim of the study. This study highlights the main methods of evaluating the sequelae of breast cancer treatment, which are of particular importance in physical recovery. As well, we want to spotlight the main physical activities that can be performed. Methods. In order to identify the adverse effects of the treatment as well as their assessment methods, we studied the national and international specialized literature. Results. The physical assessment of patients after mastectomy includes: assessment of functional level, manual muscle testing, active range of motion, evaluation of lymphedema, quality of life and pain assessment. Conclusions. Evaluation in physical therapy is of particular importance because it helps to create an appropriate recovery protocol, but also to appreciate the evolution of patients and the efficiency of the applied program.

Loss of Enrichment Induces Widespread Muscle Mechanical Hypersensitivity and Enhances Pain Related Behaviors after Ischemia with Reperfusion Injury via Macrophage Dependent Mechanisms

The development of chronic musculoskeletal pain is frequently associated with the presence of high levels of psychological stress. Multiple animal studies have shown that a variety of stress paradigms are effective at inducing deep tissue hyperalgesia and enhanced behavioral responses to subthreshold stimuli or injury. Nevertheless, the mechanisms behind stress-induced hyperalgesia are not clearly understood. Many of the current paradigms induce stress in rodents using physical stimuli that are known to induce changes in sensory function, such as repeated cold exposure or electrical shock. Non-invasive strategies to induce stress in animal models may uncover new mechanisms that drive stress related hyperalgesia. To address this issue, our lab has adapted a stress paradigm that utilizes environmental enhancement and subsequent loss of enrichment (LOE) to induce stress in mice, paired with fore limb ischemia/reperfusion injury (I/R) as a model of muscle hypersensitivity. After LOE, mice developed prolonged immobility time in a forced swimming test and presented with increased weight gain, suggesting increased stress/anxiety-like behaviors. At baseline (1 week after LOE), the mice also developed a bilateral decrease in mechanical withdrawal thresholds to plantar muscle squeezing, indicating stress related hypersensitivity. Immunohistochemical analysis of the plantar muscles showed increased macrophage infiltration one week after LOE. Mice exposed to LOE and I/R injury displayed a prolonged recovery time, compared to normal housing controls. Systemic ablation of macrophages only during the stress period facilitated the recovery after I/R. Our results suggests that LOE can significantly enhance the development of muscle pain after I/R. Together with our immunocytochemical data, results suggest that macrophages could play a role in the development of pain after LOE. These findings highlight the importance of stress in the development of long-lasting pain and may shed light in potential mechanisms behind chronic widespread muscle pain conditions like fibromyalgia. Grant Support from Anesthesia Innovation and Pilot (AIP) Program at Cincinnati Children's Hospital (LFQ) R01NS113965 and R01NS105715 (MPJ).

Atorvastatin Induces Mitochondria-Dependent Ferroptosis via the Modulation of Nrf2-xCT/GPx4 Axis.

As one of the cornerstones of clinical cardiovascular disease treatment, statins have an extensive range of applications. However, statins commonly used have side reactions, especially muscle-related symptoms (SAMS), such as muscle weakness, pain, cramps, and severe condition of rhabdomyolysis. This undesirable muscular effect is one of the chief reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. Moreover, the underlying mechanism of muscle cell damage is still unclear. Here, we discovered that ferroptosis, a programmed iron-dependent cell death, serves as a mechanism in statin-induced myopathy. Among four candidates including atorvastatin, lovastatin, rosuvastatin, and pravastatin, only atorvastatin could lead to ferroptosis in human cardiomyocytes (HCM) and murine skeletal muscle cells (C2C12), instead of human umbilical vein endothelial cell (HUVEC). Atorvastatin inhibits HCM and C2C12 cell viability in a dose-dependent manner, accompanying with significant augmentation in intracellular iron ions, reactive oxygen species (ROS), and lipid peroxidation. A noteworthy investigation found that those alterations particularly occurred in mitochondria and resulted in mitochondrial dysfunction. Biomarkers of myocardial injury increase significantly during atorvastatin intervention. However, all of the aforementioned enhancement could be restrained by ferroptosis inhibitors. Mechanistically, GSH depletion and the decrease in nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPx4), and xCT cystine–glutamate antiporter (the main component is SLC7A11) are involved in atorvastatin-induced muscular cell ferroptosis and damage. The downregulation of GPx4 in mitochondria-mediated ferroptosis signaling may be the core of it. In conclusion, our findings explore an innovative underlying pathophysiological mechanism of atorvastatin-induced myopathy and highlight that targeting ferroptosis serves as a protective strategy for clinical application.

Effectiveness of Acupuncture Therapy to Reduce Pain in Patients with Upper Trapezius Myofascial Pain Syndrome: A Meta-Analysis

Background: Upper trapezius myofascial pain syndrome is a muscle pain condition associated with sensory, motoric, or autonomic functions and generated by trigger point arising from hardened and stiff taut band of muscle fiber while being touched as well as palpated. One of the interventions to reduce the pain is by using acupuncture therapy. The study aims to analyze and estimate the effectiveness magnitude of acupuncture therapy toward the pain reduction in patients with upper trapezius myofascial pain syndrome. Subjects and Method: This was a systematic review and meta-analysis study using PRISMA diagrams. The article search was conducted based on the eligibility criteria using the PICO Model. population: patients with upper trapezius myofascial pain syndrome. Intervention: acupuncture therapy. Comparison: placebo acupuncture. Outcome: reduced pain. The articles used were from 6 databases, namely Pubmed, Google Scholar, Science Direct, Scopus, Spinger Link, and Hindawi Key words for article search were “acupuncture” OR “acupuncture therapy” AND “upper trapezius pain” OR “upper trapezius myofascial pain syndrome” OR “upper trapezius MPS” AND “Randomized Con¬trolled Trial” OR “RCT”. Inclusion criteria used of the study were full text articles with Randomized Controlled Trial study design, measure of association used was Mean SD. Articles were analyzed using the Review Manager 5.3 application. Results: The 9 articles reviewed were from Taiwan, China, UK, Turkey, Brazil, and Iran. The study result indicated that acupuncture therapy was effective in reducing pain in upper trapezius myofascial pain syndrome. Upper trapezius myofascial pain syndrome that obtained acupuncture therapy had average score of pain -1.16 units lower than placebo acupuncture (SMD= -1.16; CI 95%= -1.93 to -0.39; p= 0.003). Conclusion: Acupuncture therapy was effective in reducing pain in upper trapezius myofascial pain syndrome. Keywords: acupuncture, pain, upper trapezius myofascial pain syndrome, randomized controlled trial, meta-analysis. Correspondence: Niken Putri Eka Saraspuri. Masters Program in Public Health, Universitas Sebelas Maret. Jl. Ir. Sutami 36A, Surakarta 57126, Central Java. Email: nikenputri54@gmail.com. Mobile: 081327372766. Indonesian Journal of Medicine (2022), 07(03): 326-336 https://doi.org/10.26911/theijmed.2022.07.03.09

Musculoskeletal orofacial pains - overlap between tension type headache and temporomandibular disorder

A number of pain conditions in the head share clinical presentations such as being dull, diffuse, pressing, bilateral and longer-lasting with moderate intensity, often with pain referrals to the neck-shoulder regions, higher prevalence in women before menopause, aggravated by oral functions and stress and associated with considerable psycho-social distress and reduced quality of life. The International Classification of Headache Disorders (ICHD) have well-established criteria for tension-type headache and Headaches attributed to Temporomandbular Disorders (HA-TMD). The Diagnostic Criteria for TMD has set the standards for operationalized, reliable and valid diagnosis of myalgia and myofascial pain related to the jaw muscles and a variant of the HA-TMD diagnosis. Recently also International Classification for Orofacial Pain (ICOP) has proposed subtyping of the muscle pain conditions based on temporal characteristics: acute, infrequent, frequent and chronic occurrence. Nevertheless, the overarching question should be to what extent may underlying pathophysiology vary between these entities and what would the therapeutic implications be? The talk will attempt to review the musculoskeletal orofacial pain conditions, present new findings about the potential overlap and further phenotyping, and critically discuss the clinical ramifications.

P2X3 receptors contribute to transition from acute to chronic muscle pain.

This study aimed to evaluate whether the development and/or maintenance of chronic-latent muscle hyperalgesia is modulated by P2X3 receptors. We also evaluate the expression of P2X3 receptors and PKCε of dorsal root ganglions during these processes. A mouse model of chronic-latent muscle hyperalgesia, induced by carrageenan and evidenced by PGE2, was used. Mechanical muscle hyperalgesia was measured by Randall-Selitto analgesimeter. The involvement of P2X3 receptors was analyzed by using the selective P2X3 receptors antagonist A-317491 by intramuscular or intrathecal injections. Expression of P2X3 and PKCε in dorsal root ganglion (L4-S1) were evaluated by Western blotting. Intrathecal blockade of P2X3 receptors previously to carrageenan prevented the development and maintenance of acute and chronic-latent muscle hyperalgesia, while intramuscular blockade of P2X3 receptors previously to carrageenan only reduced the acute muscle hyperalgesia and had no effect on chronic-latent muscle hyperalgesia. Intrathecal, but not intramuscular, blockade of P2X3 receptors immediately before PGE2, in animals previously sensitized by carrageenan, reversed the chronic-latent muscle hyperalgesia. There was an increase in total and phosphorylated PKCε 48h after the beginning of acute muscle hyperalgesia, and in P2X3 receptors at the period of chronic muscle hyperalgesia. P2X3 receptors expressed on spinal cord dorsal horn contribute to transition from acute to chronic muscle pain. We also suggest an interaction of PKCε and P2X3 receptors in this process. Therefore, we point out P2X3 receptors of the spinal cord dorsal horn as a pharmacological target to prevent the development or reverse the chronic muscle pain conditions.

Pain Sensitivity And Psychological Variables Affect Delayed Onset Muscle Soreness (DOMS)

Delayed onset muscle soreness (DOMS) is an acute muscle pain condition occurring after eccentric muscular activity in some but not all people. Physiological and psychological factors may affect DOMS. PURPOSE: To investigate whether individual pain sensitivity and psychological variables levels predict DOMS. METHODS: Thirty two participants completed pain-related psychological questionnaires and quantitative sensory testing (QST) and thereafter the DOMS protocol was carried out for the upper extremity. The second session was held 24 h later, participants completed the DOMS-related interference questionnaire and QST was then reapplied. To compare QST parameters and psychological variables between those developing DOMS and those who did not, independent sample t-tests were conducted. Multiple regression analyses were used to determine the predictive role of QST and psychological variables on DOMS intensity. RESULTS: Out of the 32 participants, 17 showed a DOMS response. Participants who developed DOMS had higher trait anxiety (p=0.010), depression (p=0.025), and stress (p=0.034) scores, compared to those who did not develop DOMS. Trait anxiety predicted the intensity of DOMS (r=0.63, P<0.000). Additionally, those who developed DOMS demonstrated a higher systemic pain sensitivity at baseline, expressed by a lower pressure pain threshold in the muscle that was exercised and in a remote muscle, and by a lower pain inhibition efficiency (P<0.02). No correlation was found between the level of pain sensitivity at baseline and the intensity of DOMS. CONCLUSIONS: The endogenous ability to regulate pain has a significant impact on pain development in DOMS. Development of DOMS is affected by baseline systemic pain sensitivity as well as psychological and personality traits. Our findings highlight the contribution of physiological and psychological factors to the development of DOMS.

Nephroprotective effect of silymarin against diclofenac induced renal damage and oxidative stress in male rats

Introduction: Diclofenac (DIC), a phenylacetic acid compound which belongs to nonsteroidal anti-inflammatory drugs (NSAIDs), is generally used for the treatment of various diseases such as rheumatoid arthritis, ankylosing spondylitis, acute muscle pain conditions and osteoarthritis. Overdose of DIC can lead to renal injuries in both experimental animal and human. Our research was done to assess the protective role of silymarin on renal damage induced by DIC in rats. Methods: Thirty-two Wistar rats were assigned to four groups (n=8/group). Group 1 was control group; animals in group 2 were administrated DIC; Groups 3 and 4 administrated DIC plus silymarin with doses of 100 mg/kg and 200 mg/kg, orally (p.o), respectively. Various biochemical, molecular, and histological parameters were evaluated in serum and tissue homogenate. Results: In the second group, the levels of kidney catalase (CAT), vitamin C and superoxide dismutase (SOD) remarkably reduced (P &lt; 0.05) relative to the control group. Also, urea, creatinine (Cr), malondialdehyde (MDA), serum tumor necrosis factor-α (TNF-α) and gene expression of TNF-α in this group were noticeably elevated (P &lt; 0.05) relative to the control group. Treatment with silymarin caused a remarkable elevation (P &lt; 0.05) in vitamin C, SOD, CAT and a remarkable reduction (P &lt; 0.05) in the content of MDA, urea, Cr, TNF-α gene expression and serum TNF-α in comparison with second group. Histological injuries were also ameliorated by silymarin administration. Conclusion: The results confirm that silymarin has an ameliorative role against renal damage and oxidative stress induced by DIC in male rats.

Diclofenac-Induced Kidney Damage in Wistar Rats: Involvement of Antioxidant Mechanism

Kidney damage has been associated with administration diclofenac, a phenylacetic acid derivative belonging to the nonsteroidal anti-inflammatory drugs (NSAIDs), which is commonly used for the treatment of various diseases such as rheumatoid arthritis, ankylosing spondylitis, acute muscle pain conditions and osteoarthritis. This study investigated the exact mechanism of diclofenac in renal toxicity by determining the involvement of oxidative stress in rats. Adult male Wistar rats were divided into two groups of eight rats in each group and orogastrically treated for three days. Group 1 served as the normal control and received normal saline (0.9% w/v) and group 2 received 40 mg/kg body weight of diclofenac for three days. Administration of diclofenac caused degeneration of the kidney of rats as evidenced by significant elevation in the serum levels of creatinine, urea, albumin, uric acid, protein and electrolytes and the activities of renal-5’-nucleotidase and glucose-6-phosphate-dehydrogenase (G6PDH) compared with control. Furthermore, administration of diclofenac decreased the activities of superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione-S-transferase (GST) and the level of glutathione with concomitant increase in hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels in the kidney of the diclofenac treated groups compared with control. These findings reveal that administration of diclofenac may impair kidney functions through induction of oxidative stress.

Enlarged Areas of Pain and Pressure Hypersensitivityby Spatially Distributed Intramuscular Injections ofLow-Dose Nerve Growth Factor

Intramuscular injection of nerve growth factor (NGF) causes muscle hyperalgesia without immediate pain. This double-blinded, randomized study assessed pain and muscle hypersensitivity after a single-site bolus NGF injection (5 µg) compared with 5 spatially distributed, low-dose NGF injections (1 µg, 4 cm distance) into the tibialis anterior (TA) muscles in 20 healthy subjects. Injection pain was rated on a visual analog scale. Reports of muscle pain with functional tasks (Likert scale score) and the presence of spontaneous pain were collected daily by using a diary. Pressure pain threshold (PPT), overall pain intensity (numerical rating scale), and pain areas following the TA contraction were collected at baseline; 3 hours; and 1, 3, 7, 14, and 21 days postinjection. Low immediate visual analog scale scores were associated with both injection protocols. Likert scale scores showed moderate pain intensities but no spontaneous pain, until day 12, for both injection protocols (P < .05). Reduced PPTs at the 5- and 1-µg injection sites were found after 3 hours, lasting until day 7 (P < .05). The 1-µg injection provoked decreased PPTs at day 1 (P = .036) at the proximal injection site and at day 1 (P = .02) and day 3 (P = .01) at the distal injection site. The TA muscle contraction resulted in larger pain areas and higher numerical rating scale scores at day 3 for the distributed injections compared with the single-site injection (P < .001).Perspective: Spatially distributed low-dose NGF injections induced prolonged pain, mechanical muscle hypersensitivity, and enlarged contraction-evoked pain areas. These features mirror some clinical muscle pain conditions in which diffuse pain areas and muscle hypersensitivity are present during the activities of daily living. Low-dose NGF injections may be useful for further studies of prolonged pain conditions.

Mouse preferential incising force orientation changes during jaw closing muscle hyperalgesia and is sex dependent

IntroductionMouse incising is controlled by a central pattern generator and this activity can change in the presence of pain. The incising frequency and maximum force generation decreases with pain. In this study, we used repetitive acidic injections in the left masseter muscle of male and female mice to determine differences between baseline and jaw muscle pain conditions and the effect of sex on preferential incising direction. MethodsA within subject design was used to evaluate data previously acquired using multi-axis force data (X, Y and Z) from the 4th baseline recording day and day 7 post-injection (day of maximal pain response) for each mouse of each sex. A total of 34 female and male (age 3–9months) CD-1 mice were evaluated. After mathematically rotating the X and Y axes to align the Y axis to be parallel to the wire struts of the cage top, data were analyzed to determine incising direction preference during baseline (non-pain) and pain (day 7) conditions and between sex. Radar plots of X-Y, X-Z and Y-Z axes depicted the average direction of incising preference between baseline and pain conditions for each sex. Statistical differences among groups were tested using a mixed model ANOVA. ResultsSimilar to previous findings, female mice had a more robust difference in incising direction preference when comparing male and female pain conditions and this was most evident in the X-Z axes. The incising frequencies most commonly affected were 5.3, 6.2 and 7.6Hz. Male mice varied little in their incising direction preference between the baseline and pain conditions. In addition, statistical comparison of ratios of the percent of time spent incising in the Z versus X axes for each incising frequency found that the incising preference was not different when comparing 5.3 and 7.6Hz frequencies. Finally, female mice used a novel approach to minimize pain while incising by rotating their head and body nearly 180 degrees while males did not use this strategy as frequently. ConclusionsThe preferred incising direction changes in a jaw muscle pain condition and this information can be used to further characterize functional pain in the masticatory muscle system. The changes were dependent on the incising frequency generated by the central pattern generator for incising.

Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice.

The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise.

Placebo Analgesia Changes Alpha Oscillations Induced by Tonic Muscle Pain: EEG Frequency Analysis Including Data during Pain Evaluation.

Placebo exhibits beneficial effects on pain perception in human experimental studies. Most of these studies demonstrate that placebo significantly decreased neural activities in pain modulatory brain regions and pain-evoked potentials. This study examined placebo analgesia-related effects on spontaneous brain oscillations. We examined placebo effects on four order-fixed 20-min conditions in two sessions: isotonic saline-induced control conditions (with/without placebo) followed by hypertonic saline-induced tonic muscle pain conditions (with/without placebo) in 19 subjects using continuous electroencephalography (EEG) recording. Placebo treatment exerted significant analgesic effects in 14 placebo responders, as subjective intensity of pain perception decreased. Frequency analyses were performed on whole continuous EEG data, data during pain perception rating and data after rating. The results in the first two cases revealed that placebo induced significant increases and a trend toward significant increases in the amplitude of alpha oscillation during tonic muscle pain compared to control conditions in frontal-central regions of the brain, respectively. Placebo-induced decreases in the subjective intensity of pain perception significantly and positively correlated with the increases in the amplitude of alpha oscillations during pain conditions. In conclusion, the modulation effect of placebo treatment was captured when the pain perception evaluating period was included. The strong correlation between the placebo effect on reported pain perception and alpha amplitude suggest that alpha oscillations in frontal-central regions serve as a cortical oscillatory basis of the placebo effect on tonic muscle pain. These results provide important evidence for the investigation of objective indicators of the placebo effect.

Transcriptome analysis of trigeminal ganglia following masseter muscle inflammation in rats.

BackgroundChronic pain in masticatory muscles is a major medical problem. Although mechanisms underlying persistent pain in masticatory muscles are not fully understood, sensitization of nociceptive primary afferents following muscle inflammation or injury contributes to muscle hyperalgesia. It is well known that craniofacial muscle injury or inflammation induces regulation of multiple genes in trigeminal ganglia, which is associated with muscle hyperalgesia. However, overall transcriptional profiles within trigeminal ganglia following masseter inflammation have not yet been determined. In the present study, we performed RNA sequencing assay in rat trigeminal ganglia to identify transcriptome profiles of genes relevant to hyperalgesia following inflammation of the rat masseter muscle.ResultsMasseter inflammation differentially regulated >3500 genes in trigeminal ganglia. Predominant biological pathways were predicted to be related with activation of resident non-neuronal cells within trigeminal ganglia or recruitment of immune cells. To focus our analysis on the genes more relevant to nociceptors, we selected genes implicated in pain mechanisms, genes enriched in small- to medium-sized sensory neurons, and genes enriched in TRPV1-lineage nociceptors. Among the 2320 candidate genes, 622 genes showed differential expression following masseter inflammation. When the analysis was limited to these candidate genes, pathways related with G protein-coupled signaling and synaptic plasticity were predicted to be enriched. Inspection of individual gene expression changes confirmed the transcriptional changes of multiple nociceptor genes associated with masseter hyperalgesia (e.g., Trpv1, Trpa1, P2rx3, Tac1, and Bdnf) and also suggested a number of novel probable contributors (e.g., Piezo2, Tmem100, and Hdac9).ConclusionThese findings should further advance our understanding of peripheral mechanisms involved in persistent craniofacial muscle pain conditions and provide a rational basis for identifying novel genes or sets of genes that can be potentially targeted for treating such conditions.

The role of TRPA1 in muscle pain and mechanical hypersensitivity under inflammatory conditions in rats

Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is expressed in muscle afferents and direct activation of these receptors induces acute mechanical hypersensitivity. However, the functional role of TRPA1 under pathological muscle pain conditions and mechanisms by which TRPA1 mediate muscle pain and hyperalgesia are not clearly understood. Two rodent behavioral models validated to assess craniofacial muscle pain conditions were used to study ATP- and N-Methyl-d-aspartate (NMDA)-induced acute mechanical hypersensitivity and complete Freund’s adjuvant (CFA)-induced persistent mechanical hypersensitivity. The rat grimace scale (RGS) was utilized to assess inflammation-induced spontaneous muscle pain. Behavioral pharmacology experiments were performed to assess the effects of AP18, a selective TRPA1 antagonist under these conditions. TRPA1 expression levels in trigeminal ganglia (TG) were examined before and after CFA treatment in the rat masseter muscle. Pre-treatment of the muscle with AP18 dose-dependently blocked the development of acute mechanical hypersensitivity induced by NMDA and α,β-methylene adenosine triphosphate (αβmeATP), a specific agonist for NMDA and P2X3 receptor, respectively. CFA-induced mechanical hypersensitivity and spontaneous muscle pain responses were significantly reversed by post-treatment of the muscle with AP18 when CFA effects were most prominent. CFA-induced myositis was accompanied by significant up-regulation of TRPA1 expression in TG. Our findings showed that TRPA1 in muscle afferents plays an important role in the development of acute mechanical hypersensitivity and in the maintenance of persistent muscle pain and hypersensitivity. Our data suggested that TRPA1 may serve as a downstream target of pro-nociceptive ion channels, such as P2X3 and NMDA receptors in masseter afferents, and that increased TRPA1 expression under inflammatory conditions may contribute to the maintenance of persistent muscle pain and mechanical hyperalgesia. Mechanistic studies elucidating transcriptional or post-translational regulation of TRPA1 expression under pathological pain conditions should provide important basic information to further advance the treatment of craniofacial muscle pain conditions.

Intramuscular pH modulates glutamate-evoked masseter muscle pain magnitude in humans.

This study was conducted to determine whether glutamate-evoked jaw muscle pain is modulated by the acidity and temperature of the solution injected. Thirty two participants participated and received injections of high-temperature acidic (HT-A) glutamate (pH 4.8, 48 °C), high-temperature neutral (HT-N) glutamate (pH 7.0, 48 °C) and neutral temperature neutral (NT-N) glutamate (pH 7.0, 38 °C) solutions (0.5 mL) into the masseter muscle. Pain intensity was assessed with an electronic visual analogue scale (eVAS). Numerical rating scale (NRS) scores of unpleasantness and temperature perception, pain-drawing areas, mechanical sensitivity and pressure pain thresholds (PPT) were also measured. Participants filled out the McGill Pain Questionnaire (MPQ). One or two way ANOVAs were used for data analyses. Injection of HT-A glutamate solutions significantly increased the area under the VAS-time curve compared with injection of HT-N glutamate and NT-N glutamate solution (p < 0.040). The duration of glutamate-evoked pain was significantly longer when HT-A glutamate was injected than when NT-N glutamate was injected (p < 0.017). No significant effects of acidity were detected on pain drawings, NRS unpleasantness and heat perception, but there was a significant effect of acidity on MPQ scores and mechanical sensitivity. Acidity and temperature modulate glutamate-evoked jaw muscle pain suggesting an interaction between acid sensing and glutamate receptors which could be of importance for understanding clinical muscle pain conditions.