ObjectivePain is the most common symptom of osteoarthritis (OA), yet where it originates in the joint and how it is driven are unknown. The aim of this study was to identify pain‐sensitizing molecules that are regulated in the joint when mice subjected to surgical joint destabilization develop OA‐related pain behavior, the tissues in which these molecules are being regulated, and the factors that control their regulation.MethodsTen‐week‐old mice underwent sham surgery, partial meniscectomy, or surgical destabilization of the medial meniscus (DMM). Pain‐related behavior as determined by a variety of methods (testing of responses to von Frey filaments, cold plate testing for cold sensitivity, analgesiometry, incapacitance testing, and forced flexion testing) was assessed weekly. Once pain‐related behavior was established, RNA was extracted from either whole joints or microdissected tissue samples (articular cartilage, meniscus, and bone). Reverse transcription–polymerase chain reaction analysis was performed to analyze the expression of 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature hips from wild‐type or genetically modified mice or by explanting articular cartilage from porcine joints preinjected with pharmacologic inhibitors. Levels of nerve growth factor (NGF) protein were measured by enzyme‐linked immunosorbent assay.ResultsMice developed pain‐related behavior 8 weeks after undergoing partial meniscectomy or 12 weeks after undergoing DMM. NGF, bradykinin receptors B1 and B2, tachykinin, and tachykinin receptor 1 were significantly regulated in the joints of mice displaying pain‐related behavior. Little regulation of inflammatory cytokines, leukocyte activation markers, or chemokines was observed. When tissue samples from articular cartilage, meniscus, and bone were analyzed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage, although there were some differences between the 2 models. NGF and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a transforming growth factor β–activated kinase 1–, fibroblast growth factor 2–, and Src kinase–dependent manner.ConclusionDamaged joint tissues produce proalgesic molecules, including NGF, in murine OA.

Murine models of osteoarthritis (OA) provide a potentially powerful tool to elucidate mechanisms responsible for OA pain. However, few studies have examined pain behaviours in relevant OA models in mice. We have therefore characterized the time course and pharmacological sensitivities of pain-related behaviours in a model of OA in C57Bl/6 mice induced by partial medial meniscectomy. Progressive degenerative joint damage developed in a time-dependent manner and was first detected 4 weeks after surgery. Pain was assessed by monitoring weight bearing, mechanical hyperalgesia, cold allodynia, mechanical allodynia and vocalisation in response to knee compression for 12 weeks postsurgery. No significant weight-bearing deficits were observed during the course of the study. Significant mechanical allodynia was present in the ipsilateral hind limb from 9 weeks after surgery. Hind limb mechanical hyperalgesia and cold allodynia, and increased vocalisation in response to knee compression developed in the ipsilateral limb in 2 phases. An early phase of hypersensitivities lasted for up to 3 weeks and was reversed by treatment with a nonsteroidal anti-inflammatory drug (NSAID), diclofenac. Pain then resolved for several weeks, followed by a second phase of NSAID-insensitive pain after 7 weeks postsurgery. During this phase, all pain behaviours could be reversed by morphine. In contrast, other analgesic drugs (paracetamol, gabapentin, and tramadol) had selective effects on only 1 or 2 modalities. Pain levels fluctuated during the second phase, with transient periods of reduced pain. At these times, underlying hypersensitivities could be unmasked by administration of naloxone, indicating that reduced pain was due to endogenous opioids.

A questionnaire was sent to 2951 mixed and small animal veterinary practices to examine the use of perioperative antimicrobials in cats and dogs in the UK. The percentage of respondents who always used antimicrobials in two surgical procedures classified according to NRC criteria as 'clean' was 25.3 per cent for removal of a 1 cm cutaneous mass and 32.1 per cent for routine prescrotal castration. Factors considered important in decision-making about when to use antimicrobial agents included immunosuppression, presence of a drain, degree of wound contamination, potential for spillage of visceral contents and implantation of prosthesis. The most common antimicrobial agents mentioned were potentiated amoxicillin (98.0 per cent), amoxicillin (60.5 per cent), clindamycin (21.8 per cent), enrofloxacin (21.7 per cent), cephalexin (18.6 per cent) and metronidazole (12.7 per cent). Forty-three per cent of all responding veterinarians listed a long-acting preparation for perioperative use. The routes used were subcutaneous (76.1 per cent), intravenous (25.8 per cent), intramuscular (19.8 per cent), oral (13.5 per cent) and topical (7.7 per cent). Antimicrobials were given before surgery (66.6 per cent), during surgery (30.2 per cent), immediately after surgery (12.0 per cent) and after surgery (6.3 per cent). This survey has identified the suboptimal use of perioperative antimicrobials in small animal surgery with improvements needed with respect to timing, duration, choice of antimicrobial and a more prudent selection of surgical cases requiring prophylaxis.

ObjectiveOsteoarthritis (OA) is a common chronic disease for which disease-modifying therapies are not currently available. Studies to seek new targets for slowing the progress of OA rely on mouse models, but these do not allow for longitudinal monitoring of disease development. This study was undertaken to determine whether gait can be used to measure disease severity in the STR/Ort mouse model of spontaneous OA and whether gait changes are related to OA joint pain.MethodsGait was monitored using a treadmill-based video system. Correlations between OA severity and gait at 3 treadmill speeds were assessed in STR/Ort mice. Gait and pain behaviors of STR/Ort mice and control CBA mice were analyzed longitudinally, with monthly assessments.ResultsThe best speed to identify paw area changes associated with OA severity in STR/Ort mice was found to be 17 cm · seconds−1. Paw area was modified with age in CBA and STR/Ort mice, but this began earlier in STR/Ort mice and correlated with the onset of OA at 20 weeks of age. In addition, task noncompliance appeared at 20 weeks. Surprisingly, STR/Ort mice did not show any signs of pain with OA development, even when treated with the opioid antagonist naloxone, but did exhibit normal pain behaviors in response to complete Freund's adjuvant–induced arthritis.ConclusionThe present results identify an animal model in which OA severity and OA pain can be studied in isolation from one another. The findings suggest that paw area and treadmill noncompliance may be useful tools to longitudinally monitor nonpainful OA development in STR/Ort mice. This will help in providing a noninvasive means of assessing new therapies to slow the progression of OA.