Alma Rosales-Hernandez

The pathophysiology of diabetic peripheral neuropathy (DPN) is complex and uncertain. A potential comorbidity in diabetes mellitus (DM) that may contribute to greater severity of DPN is a lipid disorder, such as with elevated cholesterol, low density lipoproteins or triglycerides. Oxidized low density lipoprotein (oxLDL) is a form of cholesterol that exerts direct toxic effects and contributes to pathogenicity through ligating a receptor called lectin-like receptor (LOX-1). We examined plasma oxLDL levels in cohorts of patients with DPN with neuropathic pain (NeP), DPN patients without NeP, DM patients without DPN, patients with idiopathic peripheral neuropathy, and control subjects without DM or neuropathy. Our outcome measure was extent of oxLDL elevation, measured as fasting with Enzyme-Linked ImmunoSorbant Assay (ELISA) studies. Severity of diabetes was assessed using hemoglobin A1C measurements. Neuropathic severity was measured with the Utah Early Neuropathy Score (UENS). We hypothesized that DPN presence would be associated with oxLDL elevations. A total of 115 subjects (47 with DPN and NeP, 23 with DPN without NeP, 12 with diabetes only, 13 with idiopathic peripheral neuropathy, and 20 control subjects without diabetes or neuropathy) were studied. Duration of diabetes and diabetic glycemic measures were similar between populations with DM. Severity of DPN was similar between cohorts with DPN and NeP and DPN without NeP. Plasma oxLDL levels were similar between all cohorts, without any elevation in the presence of DM noted in any cohort with DM. oxLDL levels are not different in patients with DPN, and their lack of greater presence suggests that any pathogenic role in human DPN is likely limited.

Background: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα₂δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects. Results: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα₂δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα₂δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα₂δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα₂δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation. Conclusions: Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα₂δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.