A breakdown in the regulation of the vascular system within the nervous system is strongly associated with the onset of many neurological disease states, including diabetes. One of the most common diabetic complications is neuropathic pain, with complaints including heightened pain sensitivity and ongoing pain. However, very few patients gain relief through current pain treatments/regimes. Few studies have investigated the role of the blood neural barrier within the central nervous system in terms of neuropathic pain. Here we hypothesised that changes in the spinal cord vasculature contribute to the lack of analgesic action in diabetic neuropathy. Streptozotocin (STZ) -induced diabetes (50mg/kg STZ i.p.) in insulin-supplemented Sprague Dawley female rats 230-250g) was used as a model of Type I diabetes. Diabetic rats (n=9) developed hyperalgesia; exaggerated response to the application of formalin (total time of nociceptive response to formalin 107.6±19.6s week 2) compared with naïve age matched controls (n=6, 48.8±7.5s; **p<0.01 One way ANOVA, post-hoc Bonferroni test, all values mean+SEM). Rats were terminally anaesthetized (i.p. pentobarbital 60mg/kg) prior to evans blue administration (i.v. 45mg/kg). Extravasation of Evan’s blue into the spinal cord was reduced in diabetic rodents after 1 week (0.0025+0.00044 EB ul/g/hr n=12) when compared to naïve controls (0.016+0.0060, **p<0.01 Kruskal Wallis test, n=10). At week 7, experiments were terminated (i.p. 60mg/kg pentobarbital) the lumbar spinal cords were removed, fixed and stained for isolectin B4. Staining demonstrated a high degree of disorganization of the vascular network as well as a reduction in vessel number within the lumbar region of the spinal cord of diabetic animals compared to naïve controls. Cultured endothelial cells (human umbilical vein endothelial cells) treated with high (30mM) glucose for 24hrs had higher levels of the apoptotic marker cleaved caspase III (CCIII) vs those in low glucose (5mM), indicating endothelial damage in hyperglycaemia (30mM glu: proportion of CCIII cells 47+2%; 5mM glu: 8+2%;n=4/group, ***p<0.001 One way ANOVA with post-hoc Bonferroni). Administration of the neural and endothelial protective and analgesic agent, vascular endothelial growth factor-A165b (20ng/g twice weekly), resulted in attenuation of hyperalgesia to a chemical irritant at week 2 but not week 7, compared to untreated diabetic animals (Wk 2: diabetic+VEGF-A165b = 65.8±15.3s, diabetic 107.6±19.6s *p<0.05 One way ANOVA with post-hoc Bonferroni test; Wk 7: diabetic = 80.7±4.7s; diabetic+VEGF-A165b = 69±8s). Here we propose that a vascular rarefaction occurs within the spinal cord associated with the onset of diabetic neuropathy. Altered spinal cord vascular morphology or function may result in reduced analgesic penetration in diabetic neuropathy.