Modulation of Nociception in Painful Diabetic Neuropathy

Abstract

Diabetes mellitus has become a global pandemic, with almost 350 million individuals world-wide affected by the disease. There are two common forms, characterized by either a lack of insulin production or peripheral insulin resistance. Diabetic peripheral neuropathy is the most common and debilitating complication in both forms, and approximately 30% of individuals with diabetic neuropathy will experience pain that significantly impacts their quality of life. Unfortunately, symptomatic treatment modalities are often ineffective and carry significant risk of systemic adverse effects. The work contained herein used a rodent model of painful diabetic neuropathy following induction of diabetes with the pancreatic beta cell toxin, streptozocin (STZ). Results show that diabetes reduces the ability of specialized enzymes, termed ectonucleotidases, to hydrolyze extracellular AMP into the analgesic small molecule adenosine. At this same time, diabetic mice displayed significant mechanical allodynia, suggesting that altered adenosine production and decreased activation of the antinociceptive A1 adenosine receptor (A1R) may contribute to the development of painful diabetic neuropathy. In the dorsal horn of the spinal cord, A1R is highly expressed where peripheral pain sensing neurons terminate, placing it in prime location to modulate nociceptive signaling. Central delivery of A1R agonists, such as AMP, adenosine and the specific A1R agonist, N6-cyclopentyladenosine (CPA), significantly improved mechanical withdrawal thresholds in diabetic mice to levels that were not significantly different from nondiabetic mice. A1R is a G-protein coupled receptor whose activation results in initiation of downstream second messenger systems. Inhibition of cAMP production and robust activation of Akt were observed following central delivery of adenosine and CPA, suggesting these pathways contribute to the antiallodynic effects of activation of A1R. Central delivery of A1R agonists is not ideal for translation to the human population. Accordingly, peripheral delivery methods were evaluated to determine the efficacy of this therapeutic intervention in painful diabetic neuropathy. Surprisingly, peripheral delivery of CPA resulted in significant improvement in mechanical allodynia in diabetic mice, confirming that the A1R-mediated antinociceptive pathway is accessible from the periphery. These observations warrant further investigation into this endogenous antinociceptive pathway for the development of novel therapeutic treatment options for individuals suffering from painful diabetic neuropathy.