Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain is the predominant clinical feature, yet therapy is ineffective for many patients. While there are considerable insights into the mechanisms underlying tissue remodelling, there is poor understanding of the link between disease pathology and pain. This is in part owing to the lack of animal models that combine both osteoarthritic tissue remodelling and pain. Here, we provide an analysis of pain related behaviours in two models of OA in the rat: partial medial meniscectomy and iodoacetate injection. Histological studies demonstrated that in both models, progressive osteoarthritic joint pathology developed over the course of the next 28 days. In the ipsilateral hind limb in both models, changes in the percentage bodyweight borne were small, whereas marked mechanical hyperalgesia and tactile allodynia were seen. The responses in the iodoacetate treated animals were generally more robust, and these animals were tested for pharmacological reversal of pain related behaviour. Morphine was able to attenuate hyperalgesia 3, 14 and 28 days after OA induction, and reversed allodynia at days 14 and 28, providing evidence that this behaviour was pain related. Diclofenac and paracetamol were effective 3 days after arthritic induction only, coinciding with a measurable swelling of the knee. Gabapentin varied in its ability to reverse both hyperalgesia and allodynia. The iodoacetate model provides a basis for studies on the mechanisms of pain in OA, and for development of novel therapeutic analgesics.

Objective. The modest association between radiographic joint damage and pain in osteoarthritis (OA) has led to the suggestion of facilitated central pain processing. This study evaluated the importance of ongoing tissue pathology in the maintenance of enhanced central pain processing.Methods. Pain assessment was performed on 48 patients with symptomatic knee OA and 21 sex-and age-matched pain-free healthy control subjects. Twenty of the OA patients subsequently underwent total knee replacement surgery and were reassessed. Pressurepain thresholds (PPTs) were recorded using a pressure algometer (both over and distant from the knee) and a double-chamber inflatable cuff mounted around the calf. Spatial summation was assessed by relating PPTs using the dual-and single-chamber cuff. Conditioned pain modulation (CPM) was assessed by recording the increase in PPT in response to experimental arm pain.Results. PPTs at the knee and at sites away from the knee were reduced in OA patients as compared with healthy pain-free control subjects (P < 0.0001). Cuff PPTs were decreased in OA patients as compared with the healthy controls (P < 0.05), who also exhibited a greater degree of spatial summation (P < 0.05). Whereas an elevation of PPTs was noted in the healthy controls in response to experimental arm pain (P < 0.0001), no such CPM was observed in the OA patients. Following joint replacement in the OA patients, there was a reduction in the widespread mechanical hyperesthesia, along with normalization of spatial summation ratios and restoration of CPM.Conclusion. The widespread hyperesthesia and enhanced spatial summation observed in OA patients imply sensitized central pain mechanisms together with the loss of CPM. Normalization of the results following joint replacement implies that these central pain processes are maintained by peripheral input.

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This study describes the first known model of bone cancer pain in the rat. Sprague-Dawley rats receiving intra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells developed behavioural signs indicative of pain, including: mechanical allodynia, difference of weight bearing between hind paws and mechanical hyperalgesia. The development of the bone tumour and structural damage to the bone was monitored by radiological analysis, quantitative measurement of mineral content and histology. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) syngeneic MRMT-1 cells produced a rapidly expanding tumour within the boundaries of the tibia, causing severe remodelling of the bone. Radiographs showed extensive damage to the cortical bone and the trabeculae by day 10-14 after inoculation of 3 x 10(3) MRMT-1 cells, and by day 20, the damage was threatening the integrity of the tibial bone. While both mineral content and mineral density decreased significantly in the cancerous bone, osteoclast numbers in the peritumoural compact bone remained unchanged. However, tartarate-resistant acid phosphatase staining revealed a large number of polykariotic cells, resembling those of osteoclasts within the tumour. No tumour growth was observed after the injection of heat-killed MRMT-1 cells. Intra-tibial injections of 3 x 10(3) or 3 x 10(4) MRMT-1 cells, heat-killed cells or vehicle did not show changes in body weight and core temperature over 19-20 days. The general activity of animals after injection with live or heat-killed MRMT-1 cells was higher than that of the control group, however, the activity of the MRMT-1 treated group declined during the progress of the disease. Rats receiving intra-tibial injections of MRMT-1 cells displayed the gradual development of mechanical allodynia and mechanical hyperalgesia/reduced weight bearing on the affected limb, beginning on day 12-14 or 10-12 following injection of 3 x 10(3) or 3 x 10(4) cells, respectively. These symptoms were not observed in rats receiving heat-killed cells or vehicle. Behavioural data suggest a reasonable time window for evaluation of anti-nociceptive agents between day 14 and 20 after cancer cell inoculation in this model. Acute treatment with morphine (1-3mg/kg, subcutanously (s.c.)) produced a dose-dependent reduction in the response frequency of hind paw withdrawal to von Frey filament stimulation 17 or 19 days following intra-tibial injections of 3 x 10(3) MRMT-1 cells. A significant reduction in the difference in hind limb weight bearing was also observed. Acute treatment with celebrex (10-30 mg/kg, s.c.) did not affect mechanical allodynia or difference in weight bearing in rats 20 days following treatment with 3 x 10(3) MRMT-1 cells. Although the pathophysiology of cancer pain is largely unknown, significant enhancement of glial fibrillary acidic protein (GFAP) staining in the corresponding segments of the ipsilateral spinal cord highlights the possible involvement of astrocytes. In summary, the induction of bone cancer in the rat by the syngeneic MRM...