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Pain is the primary clinical indication of osteoarthritis (OA), and behavioral assessments in rodent pain models are widely used to understand pain patterns. These preclinical pain assessments can also help us to understand the effectiveness of emerging therapeutics for prolonged OA pain management. Along with evoked methods like mechanical allodynia and thermal hyperalgesia, non-evoked methods such as dynamic weight bearing (DWB) analysis are valuable tools for behavioral assessments of pain. Both these methods were utilized to study pain-induced behavioral changes in a monoiodoacetate (MIA)-induced osteoarthritic pain model, which is a well-established preclinical OA pain model. However, the utility of DWB analysis as an indicator of long-term pain sensitivity (more than 4 weeks) remains largely unexplored. Understanding the long-term sensitivity of DWB is valuable to study the effectiveness of novel prolonged pain-relieving therapeutics. Here, we studied the dynamic behavioral changes in MIA-induced OA rats over a period of 16 weeks using DWB measurements. Female Sprague Dawley rats were injected in the right knee joint with MIA (3 mg) using X-ray guidance. Multiple dynamic postural evaluations such as ipsilateral weight percentage, paw area, contralateral/ipsilateral weight ratio and area ratio were assessed to understand the behavioral changes. The data showed that the ipsilateral weight bearing percentage alone is not sufficient to assess pain-related behavior beyond 6 weeks. This study shows the advantages and limitations of dynamic weight bearing as an assessment tool for the long-term progression of pain behavior in MIA-induced OA rats. [ABSTRACT FROM AUTHOR]

Naoki Aoyama, Masashi Izumi, Toru Morimoto, Hiroyuki Wada, Junpei Dan, Yusuke Kasai, Yoshinori Satake, Koji Aso, Masahiko Ikeuchi Department of Orthopedic Surgery, Kochi Medical School, Kochi University, Nankoku, JapanCorrespondence: Masashi Izumi, Department of Orthopedic Surgery, Kochi Medical School, Kochi University, 185-1 Oko-cho Kohasu, Nankoku, 783-8505, Japan, Tel +81-88-880-2386, Fax +81-88-880-2388, Email izumim@kochi-u.ac.jpPurpose: The mechanisms underlying chronic postsurgical pain after joint replacement (JR) are complex, and it has been suggested that chronic postsurgical pain can develop as a result of inadequate acute pain management. Few studies have addressed acute pain after JR using specific animal models. This study aimed to develop a novel JR model focused on postsurgical pain assessment and the time course of pain recovery.Materials and Methods: Rats were allocated to the following three groups: sham (joint exposure), joint destruction (JD; resection of the femoral head), and JR (femoral head replacement using an originally developed implant). The time course of postsurgical pain behavior was measured using a dynamic weight-bearing apparatus, along with radiological assessments. The expression of calcitonin gene-related peptide-immunoreactive (CGRP-IR) neurons in the dorsal root ganglion (DRG) was evaluated by immunohistochemistry on days 28 and 42.Results: The ratio of weight-bearing distribution in the JR group gradually recovered from day 14 and reached the same level as that in the sham group on day 42, which was significantly greater than that in the JD group after day 7 (p< 0.05). Radiologically, no significant issues were found, except for transient central migration of the implant in the JR group. The percentage of CGRP-IR DRG neurons in the JR group was significantly lower than that in the JD group on day 28 (mean, 37.4 vs 58.1%, p< 0.05) and day 42 (mean, 32.3 vs 50.0%, p< 0.05).Conclusion: Our novel JR model presented acute postsurgical pain behavior that was successfully recovered to the baseline level at day 42 after surgery. Difference of the pain manifestation between the JR and JD groups could be supported by the expression of CGRP-IR in DRG neurons. This model is the first step toward understanding detailed mechanisms of post-JR pain.Keywords: joint replacement, postsurgical pain, dynamic weight bearing, CGRP

ObjectiveThe aim of this study was to determine the ability of undenatured native chicken type II collagen (UC-II) to prevent excessive articular cartilage deterioration in a rat model of osteoarthritis (OA).MethodsTwenty male rats were subjected to partial medial meniscectomy tear (PMMT) surgery to induce OA. Immediately after the surgery 10 rats received vehicle and another 10 rats oral daily dose of UC-II at 0.66 mg/kg for a period of 8 weeks. In addition 10 naïve rats were used as an intact control and another 10 rats received sham surgery. Study endpoints included a weight-bearing capacity of front and hind legs, serum biomarkers of bone and cartilage metabolism, analyses of subchondral and cancellous bone at the tibial epiphysis and metaphysis, and cartilage pathology at the medial tibial plateau using histological methods.ResultsPMMT surgery produced moderate OA at the medial tibial plateau. Specifically, the deterioration of articular cartilage negatively impacted the weight bearing capacity of the operated limb. Immediate treatment with the UC-II preserved the weight-bearing capacity of the injured leg, preserved integrity of the cancellous bone at tibial metaphysis and limited the excessive osteophyte formation and deterioration of articular cartilage.ConclusionStudy results demonstrate that a clinically relevant daily dose of UC-II when applied immediately after injury can improve the mechanical function of the injured knee and prevent excessive deterioration of articular cartilage.

Assessing the efficacy of botulinum neurotoxin (BoNT) in vivo is essential given the growing number of BoNT products used in the clinic. Here, we evaluated the dynamic weight bearing (DWB) test for sensitivity to paralytic effects of BoNT-A following intramuscular administration. The toxin was administered into the gastrocnemius lateralis as a single bolus or into the gastrocnemius lateralis and medialis as two boluses. The effects of BoNT-A in DWB were compared to those in the compound muscle action potential (CMAP) and the Digit Abduction Score (DAS) tests. Female Sprague-Dawley rats received an acute, intramuscular (i.m.) injection of BoNT-A1 (0.1, 1, 10 pg/rat) into the right gastrocnemius muscle, while the left received vehicle. The DWB and CMAP tests were performed one-two days after the injection in order to detect the onset of sub-maximal BoNT-A activity. Both tests were preceded by the DAS test. BoNT-A produced dose-related reductions in both the weight-bearing and surface-bearing outcomes of up to 60% while showing moderate activity in the DAS. BoNT-A effects in the DWB test were well-aligned with those in the CMAP test, which showed dose-dependent reductions in CMAP amplitude and the area under the curve (AUC; up to 100%) as well as increases in latency (up to 130%). The efficacy of BoNT-A in DWB and CMAP was more pronounced with two boluses. Thus, the DWB test can be used to assess the properties of BoNTs following i.m. administration. It can be used to assess the candidate therapies and is more ethical than the mouse lethality assay.

Objective: We aimed to investigate mechano-sensitivity at the afferent nerve fibers projecting to degenerated intervertebral disc (IVD) and nociceptive behaviour in a rat model of low back pain (LBP).Design: Animal model with LBP was established by lumbar 4/5 IVD puncture and nucleus pulposus aspiration. In vivo single nerve recordings (n = 121) were introduced to measure discharge frequency at the afferent nerve fiber innervating the IVD during mechanical stimulations (von Frey filament or intradiscal pressure). Nerve growth factor (NGF) expression levels in the IVD (n = 20) were assessed by Western blot. LBP-related behaviour (n = 22) was assessed by measuring changes in rearing, mechanical paw-withdrawal threshold, and dynamic weight bearing in a freely walking rat. Inhibitory effect of morphine on the neuronal excitability (n = 19) and painful behaviour (n = 28) was also assessed.Results: Compared to those with sham or naïve IVD, animal group with degenerated IVD displayed the sensitized neuronal responses and painful behaviour, with hyperexcitability of the afferent nerve fibers in any range of mechanical stimulations (von Frey filament stimulation; 1, 2, and 26 g; intradiscal pressure, 1,500-3,000 mm Hg), strong upregulation of NGF (200-250 % increase), and LBP-like behaviour such as failure of rearing, front limbs-dependent walking pattern, and hypersensitivity in hind-paws. However, the neuronal hyperexcitability and pain behaviour were attenuated after local (30 μM) or systemic (3 mg kg-1) morphine administration.Conclusions: Our study suggests that enhanced mechano-sensitivity at the afferent nerve fiber innervating degenerated IVD is deeply correlated with LBP development, which supports the hypothesis that hyperexcited responses at the nerve fibers represent a decisive source of LBP. [ABSTRACT FROM AUTHOR]

Highlights • Peripheral group III mGluRs recover pain-like behaviors in the CFA-inflamed rats. • Peripheral group III mGluRs alleviate neuronal firing rates at the CFA-inflamed knee joint. • Inhibitory pain modulation mediated by peripheral group III mGluRs is observed only in inflammation. Abstract Peripheral group III metabotropic glutamate receptors (mGluRs) function to modulate pain signaling in inflammatory states. Here, we established in vivo experimental settings, including dynamic weight bearing test and in vivo single nerve recording, to elucidate how the group III mGluRs contribute to inhibiting pain transmission at the peripheral sensory nerve terminal in inflammatory states (1 and 3 days) elicited by Complete Freund's Adjuvant (CFA). As a result, CFA-induced nociceptive behaviors were significantly alleviated after administration of 100 and 200 μM L-AP4 (l-2-amino-4-phosphonobutylate; group III mGluR agonist). In addition, neuronal discharges evoked by 6- and 26-g von Frey filaments at the nerve significantly decreased after administration of 200 μM L-AP4. However, this event was not observed in non-inflammatory state. These results suggest that the group III mGluRs negatively regulate nociceptive behavior and pain transmission by lessening neuronal firing rates at the peripheral nerve in inflammation. [ABSTRACT FROM AUTHOR]

Objective: to investigate the changes associated with age in gait characteristics and dynamic weight bearing pattern of sound and prosthetic limb of persons with unilateral amputation. Participant: two groups of seven young (24±3.8 years) and seven elderly unilateral amputee (71±6 years) were selected for this study. Setting: both groups walked at their self selected speed over a 20 second duration plane surface walk way in trans-tibial prosthesis with PTB socket and SACH foot. The raw data of force and EMG sensors of gait analyzer were filtered, processed and analyzed with help of ‘matlab 7.0. A blue tooth enabled heart rate telemetry system was used for calculating gait efficiency in terms of physiological cost index (PCI). Results: significant differences were found in stride duration, (p=0.003), step duration sound limb (p

Background: To acquire the most meaningful understanding of human arthritis, it is essential to select the disease model and methodology translatable to human conditions. The primary objective of this study was to evaluate a number of analytic techniques and biomarkers for their ability to accurately gauge bone and cartilage morphology and metabolism in the medial meniscal tear (MMT) model of osteoarthritis (OA). Methods: MMT surgery was performed in rats to induce OA. A dynamic weight bearing system (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs in rats. At the end of a 10-week study cartilage pathology was evaluated by micro computed tomography (μCT), contrast enhanced μCT (EPIC μCT) imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization. Results: The study results showed a negative impact of MMT surgery on the weight-bearing capacity of the operated limb. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by elevated CTX-II in serum, EPIC μCT and histology. Bone analysis by μCT showed thickening of the subchondral bone beneath the damaged cartilage, loss of cancellous bone at the metaphysis and active osteophyte formation. Conclusions: The study emphasizes the need for using various methodologies that complement each other to provide a comprehensive understanding of the pathophysiology of OA at the organ, tissue and cellular levels. Results from this study suggest that use of histology, μCT and EPIC μCT, and functional DWB tests provide powerful combination to fully assess the key aspects of OA and enhance data interpretation. [ABSTRACT FROM AUTHOR]

Bone metastases represent a frequent complication of advanced breast cancer. As tumor growth-induced bone remodeling progresses, episodes of severe pain and fractures of weight-bearing limbs increase. All of these skeletal-related events influence the patient's quality of life and survival. In the present study, we sought to determine whether some of these pain-related behaviors could be directly correlated to tumor progression and bone remodeling. For this purpose, we used a rat model of bone cancer pain based on the implantation of mammary carcinoma cells in the medullary cavity of the femur. The bone content and tumor growth were monitored over time by magnetic resonance imaging (MRI) and micro X-ray computed tomography (μCT). The same animals were evaluated for changes in their reflexive withdrawal responses to mechanical stimuli (allodynia) and weight-bearing deficits. As assessed by MRI, we found a negative correlation between tumor volume and allodynia or postural deficits throughout the experiment. Using μCT, we found that the bone volume/total volume (BV/TV) ratios for trabecular and cortical bone correlated with both mechanical hypersensitivity and weight-bearing impairment. However, whereas trabecular BV/TV stabilized between days 7 and 10 post-tumor detection, the cortical bone loss reached its maximum at that time. Our imaging approach also allowed us to consistently detect the tumor before the onset of pain, paving the way for the preemptive identification of at-risk patients. Altogether, these results improve our understanding of the events leading to tumor-induced bone pain and could eventually help in the design of novel strategies for the management of bone diseases. [ABSTRACT FROM AUTHOR]

Assessment of pain in animal models of osteoarthritis is integral to interpretation of a model's utility in representing the clinical condition, and enabling accurate translational medicine. Here we describe behavioral pain assessments available for small and large experimental osteoarthritic pain animal models., (Copyright © 2013 Elsevier B.V. All rights reserved.)