The Circadian Hormone Melatonin Inhibits Morphine-Induced Tolerance and Inflammation via the Activation of Antioxidative Enzymes.

Opioids are commonly prescribed for clinical pain management; however, dose-escalation, tolerance, dependence, and addiction limit their usability for long-term chronic pain. The associated poor sleep pattern alters the circadian neurobiology, and further compromises the pain management. Here, we aim to determine the correlation between constant light exposure and morphine tolerance and explore the potential of melatonin as an adjuvant of morphine for neuropathic pain treatment. METHODS: Wistar rats were preconditioned under constant light (LL) or a regular light/dark (LD) cycle before neuropathic pain induction by chronic constriction injury. An intrathecal (i.t.) osmotic pump was used for continued drug delivery to induce morphine tolerance. Pain assessments, including the plantar test, static weight-bearing symmetry, and tail-flick latency, were used to determine the impact of the light disruption or exogenous melatonin on the morphine tolerance progression. RESULTS: constant light exposure significantly aggravates morphine tolerance in neuropathic rats. Continued infusion of low-dose melatonin (3 µg/h) attenuated morphine tolerance in both neuropathic and naïve rats. This protective effect was independent of melatonin receptors, as shown by the neutral effect of melatonin receptors inhibitors. The transcriptional profiling demonstrated a significant enhancement of proinflammatory and pain-related receptor genes in morphine-tolerant rats. In contrast, this transcriptional pattern was abolished by melatonin coinfusion along with the upregulation of the Kcnip3 gene. Moreover, melatonin increased the antioxidative enzymes SOD2, HO-1, and GPx1 in the spinal cord of morphine-tolerant rats. CONCLUSION: Dysregulated circadian light exposure significantly compromises the efficacy of morphine's antinociceptive effect, while the cotreatment with melatonin attenuates morphine tolerance/hyperalgesia development. Our results suggest the potential of melatonin as an adjuvant of morphine in clinical pain management, particularly in patients who need long-term opioid treatment.

Oral shea nut oil triterpene concentrate supplement ameliorates pain and histological assessment of articular cartilage deterioration in an ACLT injured rat knee osteoarthritis model.

Osteoarthritis (OA) is a multifactorial joint disease and a common disabling condition in the elderly population. The associated pain and pathohistological changes in cartilage are common features of OA in both humans and animal models. Shea nut oil extract (SheaFlex75) contains a high triterpenoid concentration and has demonstrated anti-inflammatory and antiarthritic effects in both human and animal studies. In this study, we aim to investigate the potential of SheaFlex75 to prevent articular cartilage deterioration in a rat model of chronic OA progression. By employing anterior cruciate ligament transection (ACLT) with medial meniscectomy (MMx)-induced OA, we found attenuation of both early and chronic onset OA pain and cartilage degeneration in ACLT+MMx rats receiving SheaFlex75 dietary supplementation. Under long-term oral administration, the rats with induced OA presented sustained protection of both pain and OA cartilage integrity compared to the OA-control rats. Moreover, rats subjected to long-term SheaFlex75 ingestion showed normal biochemical profiles (AST, BUN and total cholesterol) and presented relatively lower triglycerides (TGs) and body weights than the OA-control rats, which suggested the safety of prolonged use of this oil extract. Based on the present evidence, preventive management is advised to delay/prevent onset and progression in OA patients. Therefore, we suggest that SheaFlex75 may be an effective management strategy for symptom relief and cartilage protection in patients with both acute and chronic OA.

Melatonin and their analogs as a potential use in the management of Neuropathic pain.

Melatonin (N-acetyl-5-methoxytryptamine), secreted by the pineal gland is known to perform multiple functions including, antioxidant, anti-hypertensive, anti-cancerous, immunomodulatory, sedative and tranquilizing functions. Melatonin is also known to be involved in the regulation of body mass index, control the gastrointestinal system and play an important role in cardioprotection, thermoregulation, and reproduction. Recently, several studies have reported the efficacy of Melatonin in treating various pain syndromes. The current paper reviews the studies on Melatonin and its analogs, particularly in Neuropathic pain. Here, we first briefly summarized research in preclinical studies showing the possible mechanisms through which Melatonin and its analogs induce analgesia in Neuropathic pain. Second, we reviewed research indicating the role of Melatonin in attenuating analgesic tolerance. Finally, we discussed the recent studies that reported novel Melatonin agonists, which were proven to be effective in treating Neuropathic pain.

Association of anterior cruciate ligament injury with knee osteoarthritis and total knee replacement: A retrospective cohort study from the Taiwan National Health Insurance Database.

OBJECTIVE: This study aimed to support the potential protective role of anterior cruciate ligament (ACL) reconstruction against the development of osteoarthritis (OA). METHODS: In this retrospective cohort study, the long-term results of ACL reconstruction in Taiwan were evaluated based on data from the National Health Insurance Research Database (NHIRD). In total, 8,769 eligible cases were included from 11,921 ACL-injured patients. The cumulative incidence rates of OA and total knee replacement (TKR) were analyzed using the Kaplan-Meier estimator. Cox proportional hazards models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of OA. RESULTS: There was a lower cumulative incidence of OA among ACL-reconstructed patients (271, 33.1%) than among non-reconstructed patients (1,874, 40.3%; p < 0.001). Patients who underwent ACL reconstruction had a lower cumulative incidence of TKR during the follow-up period (0.6%) than the non-reconstructed patients (4.6%, p < 0.001). After adjusting for covariates, ACL-injured patients who underwent reconstruction within one month after ACL injury showed a significantly lower risk of OA than those who never underwent reconstruction (adjusted HR = 0.83, 95% CI = 0.69-0.99). CONCLUSIONS: These results indicate that ACL reconstruction might not provide complete protection from OA development after traumatic knee injury but does yield a lower cumulative incidence of OA development and TKR. Moreover, based on the present study, ACL-injured patients should undergo reconstruction as early as possible (within one month) to lower the risk of OA.

Shea Nut Oil Triterpene Concentrate Attenuates Knee Osteoarthritis Development in Rats: Evidence from Knee Joint Histology.

BACKGROUND: Shea nut oil triterpene concentrate is considered to have anti-inflammatory and antioxidant properties. Traditionally, it has been used to treat arthritic conditions in humans. This study aimed to investigate the effect of attenuating osteoarthritis (OA)-induced pain and joint destruction in rats by administering shea nut oil triterpene concentrate (SheaFlex75, which is more than 50% triterpenes). METHODS: An anterior cruciate ligament transaction (ACLT) with medial meniscectomy (MMx) was used to induce OA in male Wistar rats. Different doses of SheaFlex75 (111.6 mg/kg, 223.2 mg/kg, and 446.4 mg/kg) were then intragastrically administered daily for 12 weeks after surgery. Body weight and the width of the knee joint were measured weekly. Additionally, incapacitance tests were performed at weeks 2, 4, 6, 8, 10 and 12 to measure the weight bearing of the hind limbs, and the morphology and histopathology of the medial femoral condyles were examined and were evaluated using the Osteoarthritis Research Society International (OARSI) scoring system. RESULTS: This study showed that SheaFlex75 reduced the swelling of the knee joint with OA and rectified its weight bearing after ACLT plus MMx surgery in rats. Treatment with SheaFlex75 also decreased ACLT plus MMx surgery-induced knee joint matrix loss and cartilage degeneration. CONCLUSION: SheaFlex75 relieves the symptoms of OA and protects cartilage from degeneration. SheaFlex75 thus has the potential to be an ideal nutraceutical supplement for joint protection, particularly for injured knee joints.

Melatonin reverses morphine tolerance by inhibiting microglia activation and HSP27 expression.

AIMS: Melatonin has been reported to attenuate opioid tolerance. In this study, we explored the possible mechanism of melatonin in diminishing morphine tolerance. MAIN METHODS: Two intrathecal (i.t.) catheters were implanted in male Wistar rats for drug delivery. One was linked to a mini-osmotic pump for morphine or saline infusion. On the seventh day, 50µg of melatonin or vehicle was injected through the other catheter instantly after discontinuation of morphine or saline infusion; 3h later, 15µg of morphine or saline was injected. The antinociceptive response was then measured using the tail-flick test every 30min for 120min. KEY FINDINGS: The results showed that chronic morphine infusion elicited antinociceptive tolerance and upregulated heat shock protein 27 (HSP27) expression in the dorsal horn of the rat spinal cord. Melatonin pretreatment partially restored morphine's antinociceptive effect in morphine-tolerant rats and reversed morphine-induced HSP27 upregulation. In addition, chronic morphine infusion induced microglial cell activation and was reversed by melatonin treatment. SIGNIFICANCE: The present study provides evidence that melatonin, acting via inhibiting morphine-induced neuroinflammation, can be useful as a therapeutic adjuvant for patients under long-term opioid treatment for pain relief.

Instantaneous Respiratory Estimation from Thoracic Impedance by Empirical Mode Decomposition.

Impedance plethysmography provides a way to measure respiratory activity by sensing the change of thoracic impedance caused by inspiration and expiration. This measurement imposes little pressure on the body and uses the human body as the sensor, thereby reducing the need for adjustments as body position changes and making it suitable for long-term or ambulatory monitoring. The empirical mode decomposition (EMD) can decompose a signal into several intrinsic mode functions (IMFs) that disclose nonstationary components as well as stationary components and, similarly, capture respiratory episodes from thoracic impedance. However, upper-body movements usually produce motion artifacts that are not easily removed by digital filtering. Moreover, large motion artifacts disable the EMD to decompose respiratory components. In this paper, motion artifacts are detected and replaced by the data mirrored from the prior and the posterior before EMD processing. A novel intrinsic respiratory reconstruction index that considers both global and local properties of IMFs is proposed to define respiration-related IMFs for respiration reconstruction and instantaneous respiratory estimation. Based on the experiments performing a series of static and dynamic physical activates, our results showed the proposed method had higher cross correlations between respiratory frequencies estimated from thoracic impedance and those from oronasal airflow based on small window size compared to the Fourier transform-based method.

Computer-aided diagnosis with textural features for breast lesions in sonograms.

RATIONALE AND OBJECTIVES: Computer-aided diagnosis (CAD) systems provided second beneficial support reference and enhance the diagnostic accuracy. This paper was aimed to develop and evaluate a CAD with texture analysis in the classification of breast tumors for ultrasound images. MATERIALS AND METHODS: The ultrasound (US) dataset evaluated in this study composed of 1020 sonograms of region of interest (ROI) subimages from 255 patients. Two-view sonogram (longitudinal and transverse views) and four different rectangular regions were utilized to analyze each tumor. Six practical textural features from the US images were performed to classify breast tumors as benign or malignant. However, the textural features always perform as a high dimensional vector; high dimensional vector is unfavorable to differentiate breast tumors in practice. The principal component analysis (PCA) was used to reduce the dimension of textural feature vector and then the image retrieval technique was performed to differentiate between benign and malignant tumors. In the experiments, all the cases were sampled with k-fold cross-validation (k=10) to evaluate the performance with receiver operating characteristic (ROC) curve. RESULTS: The area (A(Z)) under the ROC curve for the proposed CAD system with the specific textural features was 0.925±0.019. The classification ability for breast tumor with textural information is satisfactory. CONCLUSIONS: This system differentiates benign from malignant breast tumors with a good result and is therefore clinically useful to provide a second opinion.

Computer-Aided Diagnosis Applied to 3-D US of Solid Breast Nodules by Using Principal Component Analysis and Image Retrieval.

Textural features have been shown to be valuable in tumor diagnosis. This study combines three practical textural features in ultrasound (US) images, i.e. spatial gray-level dependence matrices (SGLDMs), gray-level difference matrix (GLDM) and auto-covariance matrix, to identify breast tumor as benign or malignant. The textural features were extracted from 147 3-D ultrasound cases and each case composes a volume of interest (VOI). Usually, the larger region of interest (ROI) sub-image contains considerable textural information. Thus the feature vector extraction utilizes only the adjacent frames with the largest ROI sub-image. The textural features always perform as a high dimensional vector that is unfavorable to differentiate breast tumors in practice. The principal component analysis (PCA) is used to reduce the dimension of textural feature vector and then the image retrieval technique was utilized to differentiate between benign and malignant tumors. The proposed computer-aided diagnosis (CAD) system differentiates solid breast nodules with a relatively high accuracy in the US imaging and helps inexperienced operators avoid misdiagnosis.