Diabetic neuropathy and exercise: Experiemental investigation of effects of irisin on diabetic neuropathic pain

Peripheral neuropathy is a neurodegenerative condition characterised by damage to the peripheral nervous system. Diabetes mellitus is among to the most common cause of this condition which often associates with neuropathic pain. Because of the lacking of ideally effective therapy and prominent side effects of drugs used for the treatment of neuropathic pain, evaluation and utilization of endogenous mechanisms controlling pain has become an optimistic idea and promising target for this purpose. Exercise has been suggested to be an effective treatment modality for neurodegenerative diseases but the mechanism is not clear yet. Irisin, released in response to exercise and referred as exercise hormone, has been proposed to mediate the beneficial effects of exercise on neurodegenerative diseases but information on its effect on neuropathic pain is lacking. In this thesis study, possible effects of irisin on neuropathic pain is examined. For this purpose, in addition to the triggering endogenous irisin release by exercise, irisin was exogenously administered and effects of irisin on neuropathic pain was investigated by use of behavioral pain model. Additionally, effects of exercise/irisin on "painful signalling" in sensory neurones by capsaicin, the ingredient of chili peppers, stimulation. A total of 60 male Sprague Dawley rats were used. Animals were divided into groups consistent of control, diabetes, exercise + low-intensity, exercise + high-intensity exercise groups. Following diabetes induction by streptozotocin, animals in exercise groups performed low intensity (0.5 km/h 30 min) and high intensity (1 km/h 60 min) exercise, for 8 weeks. Thermal and mechanical pain thresholds were measured in all groups at 0th 4th, 6th and 8th week. Serum irisin levels were measured at the 4th and 8th weeks for the exercise groups and at the 8th week for the control and diabetes groups. In exercise group, thermal pain thresholds returned to normal compared to diabetic group at the end of 8th week (p<0.05). Mechanical pain latencies tented to return basal levels from 6th week of exercise. Impact of exercise intensity did not differ significantly for both mechanical and thermal pain latencies in any time period. Irisin levels of the diabetic group were lower in diabetic group which were restored in the exercise groups. The levels of irisin was significantly different between the high and low-intensity exercise groups for only 4th week. In additional group, irisin was administered to diabetic groups (1, 10 and 20 μg/kg) and the control group (10 μg /kg). Thermal pain thresholds were measured at 0th, 15th, 30th, 60th and 90th minute time points. While the pain latencies were unchanged in the control group, for all doses, the pain latencies decreased at 60th minutes compared to the diabetic group. In conclusion, exercise mediated endogenous irisin release did not prevent the development of painful neuropathy in the current model but, as the exercise continued the pain latencies returned toward the baseline values. The calcium signalling data from peripheral sensory neurons indicates that endogenous irisin does not affect peripheral pain sensitivity. Key Words: Calcium, Diabetes, Exercise, Irisin, Neurodegeneration, Neuropathic Pain