The pathogenesis of inflammatory muscle pain

ABSTRACT The aim of my thesis is to further investigate the mechanisms underlying inflammatory muscle pain. Despite numerous studies investigating the mechanisms of inflammatory hyperalgesia, little is known of the mechanisms underlying inflammatory muscle hyperalgesia. Using rats as experimental animals, I investigated inflammatory hyperalgesia in muscle and compared it to that of inflamed cutaneous tissue. I injected carrageenan, a plant-origin polysaccharide, into leg muscle and into the hind paw of rats, and measured the behavioural response, as well as cytokine changes, in both plasma and inflamed tissue. Carrageenan induced inflammatory hyperalgesia but the cytokine cascade was not the same in muscle and cutaneous tissue. At no time following carrageenan injection was muscle tumour necrosis factor alpha (TNF-&) concentration elevated above that of muscle injected with saline. TNF-& is a key inflammatory mediator in cutaneous tissue, but apparently not in muscle. Interleukin-1) (IL-1)) and interleukin-6 concentrations also were different during muscle inflammation compared to those of cutaneous inflammation. IL-1) and IL- 6 concentrations, following carrageenan injection, were elevated later in muscle compared to in cutaneous tissue. IL-1) is a potent sensitizer of nociceptors in cutaneous tissue, and also may play an important role in sustaining muscle pain, but it is unlikely to be an initiator of the inflammatory muscle hyperalgesia. In the course of comparing muscle hyperalgesia and cutaneous hyperalgesia, I aimed to identify whether these differences in cytokine concentrations were unique to muscle tissue or if similar differences in cytokine concentrations existed between the hind paw and other cutaneous sites. To explore an alternative cutaneous tissue site, I injected carrageenan into the rat tail and measured the behavioural response, changes in cytokine concentrations and histological changes. Elevations of pro-inflammatory cytokines occurred concurrently with the infiltration of leukocytes into the inflamed tail tissue with the thermal and mechanical hyperalgesia similar to that found in the hind paw. Different mechanisms therefore appear to underlie muscle and cutaneous inflammatory hyperalgesia, regardless of the site used to investigate cutaneous inflammation. One of the consequences of the poor understanding of muscle pain is the lack of a reliable regimen for treating human muscle pain, including delayedonset muscle soreness (DOMS). DOMS, which has a partial inflammatory pathogenesis, is not relieved by non-selective cyclo-oxygenase inhibitors. This phenomenon may be that prostaglandins are not produced peripherally or centrally, when muscle tissue is damaged. I investigated the effect of inhibiting cyclo-oxygenase-2, the isoform released during inflammation, on DOMS in human volunteers. I found that rofecoxib, a cyclo-oxygenase-2 inhibitor, did not attenuate DOMS and nor did tramadol, a central-acting analgesic. The neurochemical pathway underlying DOMS therefore appears to be distinct from the pathways which underlie pain and hyperalgesia in other syndromes. Future research should include investigations into the central mechanisms of muscle pain and blocking the action of IL-1) and CINC-1 both peripherally and centrally may prove a beneficial target for the treatment of clinical muscle pain

SWIMMING ENHANCES BONE MASS ACQUISITION IN GROWING FEMALE RATS

Growing bones are most responsive to mechanical loading. We investigated bone mass acquisition patterns following a swimming or running exercise intervention of equal duration, in growing rats. We compared changes in bone mineral properties in female Sprague Dawley rats that were divided into three groups: sedentary controls (n = 10), runners (n = 8) and swimmers (n = 11). Runners and swimmers underwent a six week intervention, exercising five days per week, 30min per day. Running rats ran on an inclined treadmill at 0.33 m.s-1, while swimming rats swam in 25oC water. Dual energy X-ray absorptiometry scans measuring bone mineral content (BMC), bone mineral density (BMD) and bone area at the femur, lumbar spine and whole body were recorded for all rats before and after the six week intervention. Bone and serum calcium and plasma parathyroid hormone (PTH) concentrations were measured at the end of the 6 weeks. Swimming rats had greater BMC and bone area changes at the femur and lumbar spine (p < 0.05) than the running rats and a greater whole body BMC and bone area to that of control rats (p < 0.05). There were no differences in bone gain between running and sedentary control rats. There was no significant difference in serum or bone calcium or PTH concentrations between the groups of rats. A swimming intervention is able to produce greater beneficial effects on the rat skeleton than no exercise at all, suggesting that the strains associated with swimming may engender a unique mechanical load on the bon