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Background: Previous work from our group showed that tissue ischemia activates a nociceptive reflex that through the local release of the neuropeptide Substance P (SP) leads to attraction of proangiogenic cells from the bone marrow to the ischemic site thereby supporting revascularization and tissue healing. Objective: To investigate if diabetes mellitus, a known cardiovascular risk factor, inhibits nociceptive signalling following induction of unilateral limb ischemia. Methods and Results: CD1 mice were induced diabetes by streptozotocin and studied 17 weeks after first confirmation of overt glycosuria. Age-matched non diabetic mice served as controls. Mice were anesthetized with 2,2,2 tribromo ethanol (0.3gm/kg, i.p.) and Limb ischemia was produced by ligature of the left femoral artery. We found that diabetes reduces the density of SP-positive sensory nerve fibers in bone marrow (H:368±4.5mm vs T1D: 169±2.5mm in per 20x magnification section, p<0.05. n=5). But the expression of the SP receptor NK1 was not significant modified by diabetes. The responsiveness of total and lineage negative bone marrow cells to SP-induced migration in a Boyden chamber assay was significantly reduced by diabetes (Total BM cells migration, H: 6.51 ±0.2% vs T1D: 5.11 ±0.2%, p<0.05. n=5. lineage negative bone marrow cells migration, H: 9.18±0.3% vs T1D: 7.66±0.2%, p<0.05. n=5)). Likewise lineage negative cKit+Sca+ cells expressing NK1R from bone marrow of diabetic mice were depleted in the migrated fraction by 61% percent (p<0.05. n=5). Furthermore, limb ischemia increases the levels of SP in adductor muscles of nondiabetic mice (SP positive staining: 1939329.4±42 pixel) with this effect being reduced in diabetic mice (SP positive staining: 324262.3±21 pixel. p<0.05. n=4). Ischemia increased the peripheral blood levels of NK1R positive progenitor cells in nondiabetic mice with concomitant reduction in bone marrow thus indicating cell mobilization. The NK1R positive progenitor cell mobilization was reduced by 67% and 32% in diabetic mice at 3 and 7 days post-ischemia, respectively. (p<0.05. n=4). Conclusions: We show for the first time the altered sensory innervation of bone marrow in a murine diabetic model. Furthermore, diabetes inhibits the in vitro and in vivo attractive action of nociceptive mediator SP on proangiogenic bone marrow cells. Depression of pain-induced stem cell mobilization following ischemia might contribute to failed reparative response in patients with diabetes. [ABSTRACT FROM AUTHOR]