Ketamine Promoted Breast Cancer Invasion and Metastasis Through Up-regulating Wnt, BMP, and EGFR Signaling.

BACKGROUND/AIM: In this study, we used an orthotropic breast cancer model combined with ketamine addiction and next-generation sequencing (NGS) to comprehensively investigate molecular alterations in ketamine-mediated metastasis. Ketamine is widely used in anesthesia and drug abuse. Our previous study revealed that ketamine promotes the growth of breast cancer cells; however, the detailed molecular mechanism remains unknown. MATERIALS AND METHODS: An orthotropic breast cancer model was established by injecting EO771 breast cancer cells into the mammary fat pad of mice intraperitoneally administered ketamine (30 mg/kg, daily) for 68 days. Tumors collected at day 38 were frozen for future analysis, and their metastasis state was checked at day 68. RESULTS: Tumors were grouped and subjected to NGS analysis, followed by differential gene expression analysis (DEseq) and pathway identification. DEseq analysis showed that ketamine up-regulated metastasis-related signaling, and the key genes were BMP5, FZD6, MMP1B, EGFR, WNT5A, BMP7, and DCN. CONCLUSION: Ketamine addiction up-regulates the expression of genes involved in the Wnt, EGFR, and BMP signaling cascades, which may be associated with breast cancer progression and metastasis.

Massive pulmonary embolism in Klippel-Trenaunay syndrome after leg raising: A case report.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is a rare congenital disorder characterized by a combination of capillary malformations, soft-tissue or bone hypertrophy, and varicose veins or venous malformations. The syndrome predisposes patients to hypercoagulable states, including venous thromboembolism and pulmonary embolism (PE). CASE SUMMARY: A 12-year-old girl with KTS was scheduled excision of verrucous hyperkeratosis in the left foot and posterior aspect of the left leg and left thigh and excision of a cutaneous hemangioma in the right buttock. After induction, the surgeon elevated the patient's leg for sterilization, whereupon she experienced a massive PE and refractory cardiac arrest. Extracorporeal membrane oxygenation (ECMO) was performed after prolonged resuscitation, and she had a return of spontaneous circulation. After this episode, the patient was discharged without any neurologic complications. CONCLUSION: The mechanism of PE, a lethal disease, involves a preexisting deep vein thrombosis that is mechanically dislodged by compression or changing positions and travels to the pulmonary artery. Therefore, patients predisposed to PE should be prescribed prophylactic anticoagulants. If the patient has unstable vital signs, resuscitation should be started immediately, and extracorporeal cardiopulmonary resuscitation should be considered in settings with existing ECMO protocols, expertise, and equipment. Awareness of PE in patients with KTS while leg raising for sterilization is critical.

Combined Programmed Intermittent Bolus and Patient-Controlled Bolus Is a More Favorable Setting for Epidural Pain Relief Than Continuous Infusion.

Epidural analgesia is a suitable and effective treatment for labor pain. However, the preferable modality setting for delivery remains debatable. This study adopted a programmed intermittent epidural bolus (PIEB) setting in conjunction with a patient-controlled epidural analgesia (PCEA) setting to improve the quality of labor analgesia and reduce the number of medical staff. We conducted a prospective observational analysis of primigravida parturients scheduled for spontaneous labor, which required epidural analgesia for painless labor. A total of 483 healthy primigravida parturients with singleton pregnancies were included in this cohort; 135 nulliparous patients were assigned to the continuous infusion setting (CEI) group and 348 to the PIEB + PCEA group. Compared to the CEI setting, the PIEB + PCEA setting significantly reduced the manual rescue by the clinician, extended the time required for the first manual rescue dose, and acclaimed good maternal satisfaction. The use of the CEI mode increased for poor performance requiring more than two rescues with an odds ratio of 2.635 by a binary logistic regression analysis. Using the PIEB + PCEA setting as the maintenance infusion had a longer duration for the first requested manual rescue, fewer manual rescue boluses, excellent satisfaction, and no significant increase in adverse events compared to the CEI setting.

Necroptosis: A Pathogenic Negotiator in Human Diseases.

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Sugammadex for reversing neuromuscular blockages after lung surgery: A systematic review and meta-analysis.

BACKGROUND: This study determined whether sugammadex was associated with a lower risk of postoperative pulmonary complications and improved outcomes in lung surgeries. METHODS: A systematic literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Library from January 2000 to March 2022. The characteristics of lung surgeries using sugammadex treatment compared with control drugs and postoperative outcomes were retrieved. The primary outcome was estimated through a pooled odds ratio (OR) and its 95% confidence interval (CI) was identified using a random-effects model. RESULTS: From 465 citations, 7 studies with 453 patients receiving sugammadex and 452 patients receiving a control were included. The risk of postoperative pulmonary complication (PPCs) was lower in the sugammadex group than in the control group. Also, it showed that the effect of sugammadex on PPCs in the subgroup analysis was significantly assessed on the basis of atelectasis or non-atelectasis. Furthermore, subgroup analysis based on the relationship between high body mass index (BMI) and PPCs also showed that sugammadex had less occurrence in both the high BMI (defined as BMI ≥ 25) and low BMI groups. No difference in length of hospital stay (LOS) between the two groups was observed. CONCLUSION: This study observed that although reversing neuromuscular blockages with sugammadex in patients undergoing thoracic surgery recorded fewer PPCs and shorter extubation periods than conventional reversal agents, no difference in LOS, postanaesthesia care unit (PACU) stay length and chest tube insertion duration in both groups was observed.

Ketamine promotes breast tumor growth in a mouse breast tumor model involving with high expression of miR-27b-3p and EGFR.

Non-medical use of ketamine as an adulterant to ecstasy is more prevalent than amphetamine in Taiwan. Ketamine's effect on immunosuppression might play some functional role in tumor growth, while it is still controversial whether ketamine abuse could increase tumor growth or not. This study aimed to investigate the influence of ketamine addiction in breast tumors and related gene expressions. The effect of ketamine treatment on proliferation, colony formation, migration, and invasion of triple-negative breast cancer cell line EO771 was examined. In addition, a ketamine addiction mice model was established by intraperitoneal injection (IP) of ketamine in mice and used to investigate the effects of ketamine addiction on tumor growth and the possible mechanisms. In the in vitro studies, ketamine treatment at different concentrations did not affect EO771 cell proliferation and colony formation. But ketamine did enhance migration and invasion of EO771 cells. The in vivo experiments showed significantly increased breast tumor volume and weight in ketamine-addicted mice than in normal saline groups. miR-27b-3p level, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor (EGFR) significantly increased in tumors of ketamine addiction mice compared to control mice. In vivo evidence showed that Ketamine might increase tumor growth on the tumor microenvironment, and miR-27b-3p, HER2, and EGFR might play a role in the process.

Does surgical plethysmographic index-guided analgesia affect opioid requirement and extubation time? A systematic review and meta-analysis.

PURPOSE: This meta-analysis of all relevant clinical trials investigated surgical plethysmographic index (SPI)-guided analgesia's efficacy under general anesthesia for perioperative opioid requirement and emergence time after anesthesia. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched up to January 2022 to identify clinical trials comparing SPI-guided and conventional clinical practice for patients who underwent general anesthesia. With the random-effects model, we compared intraoperative opioid consumption, emergence time, postoperative pain, analgesia requirement, and incidence of postoperative nausea and vomiting (PONV). RESULTS: Thirteen randomized controlled trials (RCTs) (n = 1314) met our selection criteria. The overall pooled effect sizes of all RCTs indicated that SPI-guided analgesia could not significantly reduce opioid consumption during general anesthesia. SPI-guided analgesia accompanied with hypnosis monitoring could decrease intraoperative opioid consumption (standardized mean difference [SMD] - 0.31, 95% confidence interval [CI] - 0.63 to 0.00) more effectively than SPI without hypnosis monitoring (SMD 1.03, 95% CI 0.53-1.53), showing a significant difference (p < 0.001). SPI-guided analgesia could significantly shorten the emergence time, whether assessed by extubation time (SMD - 0.36, 95% CI - 0.70 to - 0.03, p < 0.05, I2 = 67%) or eye-opening time (SMD - 0.40, 95% CI - 0.63 to - 0.18, p < 0.001, I2 = 54%). SPI-guided analgesia did not affect the incidence of PONV, postoperative pain, and analgesia management. CONCLUSION: SPI-guided analgesia under general anesthesia could enhance recovery after surgery without increasing the postoperative complication risk. However, it did not affect intraoperative opioid requirement. Notably, SPI-guided analgesia with hypnosis monitoring could effectively reduce intraoperative opioid requirement.

Viable Allogeneic Mitochondria Transplantation Improves Gas Exchange and Alveolar-Capillary Permeability in Rats with Endotoxin-Induced Acute Lung Injuries.

Background: Acute lung injuries (ALI) cause disruption of the alveolar-capillary barrier and is the leading cause of death in critically ill patients. This study tested the hypothesis that the administration of freshly isolated viable allogeneic mitochondria can prevent alveolar-capillary barrier injuries at the endothelial level, as mitochondrial dysfunction of the pulmonary endothelium is a critical aspect of ALI progression. Methods: ALI was induced by intratracheal lipopolysaccharide instillation (LPS, 1mg/kg) in anesthetized rats. Mitochondria (100 µg) were isolated from the freshly harvested soleus muscles of naïve rats and stained with a green fluorescence MitoTracker™ dyne. A mitochondria or placebo solution was randomly administered into the jugular veins of the rats at 2 h and 4 h after ALI induction. An arterial blood gas analysis was done 20 h later. The animals were then sacrificed and lung tissues were harvested for analysis. Results: An IVIS Spectrum imaging system was used to obtain ex vivo heart-lung block images and track the enhancement of MitoTracker™ fluorescence in the lungs. Mitochondria transplantation significantly improved arterial oxygen contents (PaO2 and SaO2) and reduced CO2 tension in rats with ALI. Animals with mitochondrial transplants had significantly higher ATP concentrations in their lung tissues. Allogeneic mitochondria transplantation preserved alveolar-capillary barrier function, as shown by a reduction in protein levels in the bronchoalveolar lavage fluid and decreased extravasated Evans blue dyne and hemoglobin content in lung tissues. In addition, relaxation responses to acetylcholine and eNOS expression were potentiated in injured pulmonary arteries and inflammatory cells infiltration into lung tissue was reduced following mitochondrial transplantation. Conclusions: Transplantation of viable mitochondria protects the integrity of endothelial lining of the alveolar-capillary barrier, thereby improving gas exchange during the acute stages of endotoxin-induced ALI. However, the long-term effects of mitochondrial transplantation on pulmonary function recovery after ALI requires further investigation.

Calycosin Alleviates Paraquat-Induced Neurodegeneration by Improving Mitochondrial Functions and Regulating Autophagy in a Drosophila Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder with limited clinical treatments. The occurrence of PD includes both genetic and environmental toxins, such as the pesticides paraquat (PQ), as major contributors to PD pathology in both invertebrate and mammalian models. Calycosin, an isoflavone phytoestrogen, has multiple pharmacological properties, including neuroprotective activity. However, the paucity of information regarding the neuroprotective potential of calycosin on PQ-induced neurodegeneration led us to explore whether calycosin can mitigate PD-like phenotypes and the underlying molecular mechanisms. We used a PQ-induced PD model in Drosophila as a cost-effective in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. We reported that calycosin shows a protective role in preventing dopaminergic (DA) neuronal cell death in PQ-exposed Canton S flies. Calycosin-fed PQ-exposed flies exhibit significant resistance against PQ-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, the depletion of dopamine content, and phosphorylated JNK-caspase-3 levels. Additionally, mechanistic studies show that calycosin administration improves PQ-induced mitochondrial dysfunction and stimulates mitophagy and general autophagy with reduced pS6K and p4EBP1 levels, suggestive of a maintained energy balance between anabolic and catabolic processes, resulting in the inhibition of neuronal cell death. Collectively, this study substantiates the protective effect of calycosin against PQ-induced neurodegeneration by improving DA neurons' survival and reducing apoptosis, likely via autophagy induction, and it is implicated as a novel therapeutic application against toxin-induced PD pathogenesis.

Colorectal Cancer Risk in Patients with Hemorrhoids: A 10-Year Population-Based Retrospective Cohort Study.

Colorectal cancer (CRC) is a common disease and one of the leading causes of cancer deaths worldwide. This retrospective cohort study evaluated the risk of developing CRC in people with hemorrhoids. Using Taiwan's National Health Insurance Research Database, we established three sets of retrospective study cohorts with and without hemorrhoids. The first set of cohorts were matched by sex and age, the second set of cohorts were matched by propensity score without including colonoscopies, and the third set of cohorts were matched by propensity score with colonoscopies, colorectal adenomas, and appendectomies included. In the second set of cohorts, 36,864 persons with hemorrhoids that were diagnosed from 2000 to 2010 and a comparison cohort, with the same size and matched by propensity score, were established and followed up to the end of 2011 to assess the incidence and Cox proportional regression-measured hazard ratio (HR) of CRC. The overall incidence rate of CRC was 2.39 times greater in the hemorrhoid cohort than it was in the comparison cohort (1.29 vs. 0.54 per 1000 person-years), with a multivariable model measured adjusted HR of 2.18 (95% CI = 1.78-2.67) after controlling for sex, age, and comorbidity. Further analysis on the CRC incidence rates among colorectal sites revealed higher incidence rates at the rectum and sigmoid than at other sites, with adjusted HRs 2.20 (95% CI = 1.48-3.28) and 1.79 (95% CI = 1.06-3.02), respectively. The overall incidence rates of both cohorts were similar in the first and second sets of cohorts, whereas the rate was lower in the third set of hemorrhoid cohorts than in the respective comparison cohorts, probably because of overmatching. Our findings suggest that patients with hemorrhoids were at an elevated risk of developing CRC. Colonoscopy may be strongly suggested for identifying CRC among those with hemorrhoids, especially if they have received a positive fecal occult blood test result.

Perioperative hemodynamic optimization in laparoscopic sleeve gastrectomy using stroke volume variation to reduce postoperative nausea and vomiting.

BACKGROUND: Risk of postoperative nausea and vomiting (PONV) is usually high among patients undergoing laparoscopic sleeve gastrectomy (LSG). Perioperative hemodynamic optimization using goal-directed fluid therapy (GDFT) based on stroke volume variation (SVV) has been suggested to reduce PONV. OBJECTIVES: This study aimed to investigate the effectiveness of GDFT on reducing PONV. SETTING: The operating rooms in China Medical University Hospital. METHODS: This prospective cohort study included 75 patients undergoing LSG. Patients were randomized into 3 groups: controls (conventional fluid therapy), GDFT-hydroxyethyl starch (GH), and GDFT-lactated Ringer's (GL) groups. In both GDFT groups, optimization of fluid administration was achieved by continuous monitoring and adjusting of SVV. Severity of PONV was evaluated using a standardized questionnaire. Other clinically relevant events, including in-hospital surgical site infections and length of hospital stay were also investigated. RESULTS: In the GH group, the total volume of fluid administered intraoperatively was significantly lower than that in the GL and control groups (P < .001). Assessment of PONV severity showed a significantly higher score at postoperative 24 hours in the GH group (P < .05), while no significant differences were found between the 3 groups at postoperative 48 hours. No significant differences were observed between the 3 groups in surgical site infections and length of hospital stay. CONCLUSION: No significant benefit is found in reducing PONV by using GDFT in patients undergoing LSG, although GDFT effectively avoids excessive volume of fluid administration. PONV incidence appears to be higher with intraoperative colloid infusion for GDFT during LSG. Further investigation is warranted to elucidate the mechanism underlying PONV in postoperative LSG.

Aptamer-guided targeting of the intracellular long-noncoding RNA HOTAIR.

Long non-coding RNAs (lncRNAs) are increasingly recognized as promising targets in cancer treatment. However, compared to targeting the ordinary protein-coding genes, suppressing non-coding RNAs expressed in cancer cells has been a more challenging task. The major hurdles lay on the requirement of a tumor-specific delivery system for the designated inhibitor to suppress the target transcripts within the cellular compartment. EGFR is a cancer driver gene which is frequently associated with the triple-negative phenotype of breast cancer. Prior studies have shown that expression of the tumor-promoting lncRNA HOTAIR (HOX antisense intergenic RNA) is positively regulated by the epithelial growth factor receptor (EGFR) in triple-negative breast cancer (TNBC), and consistently the expression of both genes is closely correlated in breast cancer. Here we show that a chimeric aptamer recognizing the epithelial growth factor receptor (EGFR) coupled with a siRNA against HOTAIR (EGFR aptamer-coupled siHOTAIR) preferentially and effectively down-regulated HOTAIR in EGFR-expressing cancer cells. Functionally, the EGFR aptamer-coupled siHOTAIR more potently inhibited the growth, migration, and invasion of EGFR-expressing TNBC cells as well as cells with reconstituted EGFR compared to cancer cells with low EGFR expression. Our results demonstrate a novel strategy of targeting cancer progression by aptamer-directed delivery of anti-lncRNA RNA interference that can be applicable to other cellular contexts and cancer types.

Human antigen R regulates hypoxia-induced mitophagy in renal tubular cells through PARKIN/BNIP3L expressions.

Mitochondrial dysfunction contributes to the pathophysiology of acute kidney injury (AKI). Mitophagy selectively degrades damaged mitochondria and thereby regulates cellular homeostasis. RNA-binding proteins (RBPs) regulate RNA processing at multiple levels and thereby control cellular function. In this study, we aimed to understand the role of human antigen R (HuR) in hypoxia-induced mitophagy process in the renal tubular cells. Mitophagy marker expressions (PARKIN, p-PARKIN, PINK1, BNIP3L, BNIP3, LC3) were determined by western blot analysis. Immunofluorescence studies were performed to analyze mitophagosome, mitolysosome, co-localization of p-PARKIN/TOMM20 and BNIP3L/TOMM20. HuR-mediated regulation of PARKIN/BNIP3L expressions was determined by RNA-immunoprecipitation analysis and RNA stability experiments. Hypoxia induced mitochondrial dysfunction by increased ROS, decline in membrane potential and activated mitophagy through up-regulated PARKIN, PINK1, BNIP3 and BNIP3L expressions. HuR knockdown studies revealed that HuR regulates hypoxia-induced mitophagosome and mitolysosome formation. HuR was significantly bound to PARKIN and BNIP3L mRNA under hypoxia and thereby up-regulated their expressions through mRNA stability. Altogether, our data highlight the importance of HuR in mitophagy regulation through up-regulating PARKIN/BNIP3L expressions in renal tubular cells.

The functional interplay of lncRNA EGOT and HuR regulates hypoxia-induced autophagy in renal tubular cells.

Autophagy, an important cellular homeostatic mechanism regulates cell survival under stress and protects against acute kidney injury. However, the role of long noncoding RNA (lncRNA) in autophagy regulation in renal tubular cells (HK-2) is unclear. The study was aimed to understand the importance of lncRNA in hypoxia-induced autophagy in HK-2 cells. LncRNA eosinophil granule ontogeny transcript (EGOT) was identified as autophagy-associated lncRNA under hypoxia. The lncRNA EGOT expression was significantly downregulated in renal tubular cells during hypoxia-induced autophagy. Gain- and loss-of-EGOT functional studies revealed that EGOT overexpression reduced autophagy by downregulation of ATG7, ATG16L1, LC3II expressions and LC 3 puncta while EGOT knockdown reversed the suppression of autophagy. Importantly, RNA-binding protein, (ELAVL1)/Hu antigen R (HuR) binds and stabilizes the EGOT expression under normoxia and ATG7/16L1 expressions under hypoxia. Furthermore, HuR mediated stabilization of ATG7/16L1 expressions under hypoxia causes a decline in EGOT levels and thereby promotes autophagy. Altogether, the study first reveals the functional interplay of lncRNA EGOT and HuR on the posttranscriptional regulation of the ATG7/16L1 expressions. Thus, the HuR/EGOT/ATG7/16L1 axis is crucial for hypoxia-induced autophagy in renal tubular cells.

Isoflurane attenuates carbogen-induced blood-brain barrier disruption independent of body temperature in mice and rats.

Isoflurane protects the blood-brain barrier (BBB) against cerebral extravasation of Evans blue dye (EBD), a commonly used serum protein tracer, in animals subjected to BBB disruption. As such, it has been implicated as a therapeutic agent that can prevent brain edema and damage caused by a number of brain insults, including focal ischemia and subarachnoid hemorrhage. Recently, it has been shown that isoflurane inhibits the cerebral extravasation of EBD following ischemic stroke chiefly by inducing hypothermia, raising the intriguing possibility that isoflurane protected against other causes of BBB disruption also through hypothermia. To test this hypothesis, we subjected mice and rats to inhalation of 20-30% carbogen, an inducer of BBB disruption, in the presence or absence of isoflurane while measuring their rectal temperature. In mice, carbogen inhalation on its own decreased rectal temperature from 36.4 ± 0.4 to 26.2 ± 0.6°C over a period of 60 minutes, and under this condition, isoflurane had no additional effect on body temperature. Nevertheless, isoflurane protected against carbogen-induced cerebral extravasation of EBD. In addition, when the body temperature was maintained in the normothermic range using an automated heating pad, isoflurane remained protective against cerebral extravasation of EBD. In rats, isoflurane also protected against cerebral extravasation of EBD, while having no effect on plasma pH, electrolyte concentrations, or osmolarity. In conclusion, isoflurane protected against BBB disruption caused by carbogen inhalation in mice and rats, but unlike isoflurane-mediated protection against ischemic BBB disruption, the effect could not be explained by anesthesia-induced hypothermia.

Casticin inhibits human prostate cancer DU 145 cell migration and invasion via Ras/Akt/NF-κB signaling pathways.

Casticin, a polymethoxyflavone derived from natural plants, has biological activities including induction of cell apoptosis. In this study, we showed the beneficial effects of casticin on the inhibition of prostate cancer cell metastasis. Casticin reduced total viable cell number, thus, we selected low doses of casticin for following experiments. Casticin decreased cell mobility, suppressed cell migration and invasion, and reduced cell gelatinolytic activities of MMP-2/-9. Furthermore, casticin inhibited the protein levels of AKT, GSK3 αß, Snail, and MMPs (MMP-2, -9, -13, and -7) at 24 and 48 hr treatment. Casticin diminished the expressions of NF-κB p65, GRB2, SOS-1, MEK, p-ERK1/2, and p-JNK1/2 at 48 hr treatment only. However, casticin reduced the level of E-cadherin at 24 hr treatment but elevated at 48 hr. The novel findings suggest that casticin may represent a new and promising therapeutic agent for the metastatic prostate cancer. PRACTICAL APPLICATIONS: Casticin derived from natural plants had been used for Chinese medicine in Chinese population for thousands of years. In the present study, casticin attenuated metastatic effects, including decreasing viable cell number, inhibiting the migration, invasion, and adhesion, and reducing matrix metalloproteinases activity on human prostate DU 145 cancer cells. In addition, the results also provided possible pathways involved in casticin anti-metastasis mechanism. We conclude that casticin may be an aptitude anticancer agent or adjuvant for the metastatic prostate cancer in the future.

Ovarian Hormone-dependent and Spinal ERK Activation-regulated Nociceptive Hypersensitivity in Female Rats with Acid Injection-induced Chronic Widespread Muscle Pain.

Symptoms of chronic widespread muscle pain (CWP) meet most of the diagnostic criteria for fibromyalgia syndrome, which is prevalent in females. We used an acid injection-induced muscle pain (AIMP) model to mimic CWP. After female rats received an ovariectomy (OVX), acid saline solution was injected into the left gastrocnemius muscle. Time courses of changes in pain behaviours and p-ERK in the spinal cord were compared between groups. Intrathecal injections of oestradiol (E2) to the OVX group before two acid injections and E2 or progesterone (P4) injections in male rats were compared to evaluate hormone effects. We found that repeated acid injections produced mechanical hypersensitivity and enhanced p-ERK expression in the spinal dorsal horn. OVX rats exhibited significantly less tactile allodynia than did the rats in the other groups. The ERK inhibitor U0126 alleviated mechanical allodynia with lower p-ERK expression in the sham females but did not affect the OVX rats. Intrathecal E2 reversed the attenuated mechanical hypersensitivity in the OVX group, and E2 or P4 induced transient hyperalgesia in male rats. Accordingly, our results suggested that ovarian hormones contribute to AIMP through a spinal p-ERK-mediated pathway. These findings may partially explain the higher prevalence of fibromyalgia in females than males.