title: Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy.
abstract: Diabetic peripheral neuropathy is a common complication of diabetes mellitus, and a significant proportion of individuals suffer debilitating pain that significantly affects their quality of life. Unfortunately, symptomatic treatment options have limited efficacy, and often carry significant risk of systemic adverse effects. Activation of the adenosine A1 receptor (A1R) by the analgesic small molecule adenosine has been shown to have antinociceptive benefits in models of inflammatory and neuropathic pain. The current study used a mouse model of painful diabetic neuropathy to determine the effect of diabetes on endogenous adenosine production, and if central or peripheral delivery of adenosine receptor agonists could alleviate signs of mechanical allodynia in diabetic mice. Diabetes was induced using streptozocin in male A/J mice. Mechanical withdrawal thresholds were measured weekly to characterize neuropathy phenotype. Hydrolysis of AMP into adenosine by ectonucleotidases was determined in the dorsal root ganglia (DRG) and spinal cord at 8 weeks post-induction of diabetes. AMP, adenosine and the specific A1R agonist, N(6)-cyclopentyladenosine (CPA), were administered both centrally (intrathecal) and peripherally (intraplantar) to determine the effect of activation of adenosine receptors on mechanical allodynia in diabetic mice. Eight weeks post-induction, diabetic mice displayed significantly decreased hydrolysis of extracellular AMP in the DRG; at this same time, diabetic mice displayed significantly decreased mechanical withdrawal thresholds compared to nondiabetic controls. Central delivery AMP, adenosine and CPA significantly improved mechanical withdrawal thresholds in diabetic mice. Surprisingly, peripheral delivery of CPA also improved mechanical allodynia in diabetic mice. This study provides new evidence that diabetes significantly affects endogenous AMP hydrolysis, suggesting that altered adenosine production could contribute to the development of painful diabetic neuropathy. Moreover, central and peripheral activation of A1R significantly improved mechanical sensitivity, warranting further investigation into this important antinociceptive pathway as a novel therapeutic option for the treatment of painful diabetic neuropathy.
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
authors.forename: N K
authors.initials: NK
authors.lastname: Katz
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
authors.forename: J M
authors.initials: JM
authors.lastname: Ryals
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160, United States. Electronic address: dwright@kumc.edu.
authors.forename: D E
authors.initials: DE
authors.lastname: Wright
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D058907:Adenosine A1 Receptor Agonists / Q000008:administration & dosage*; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005528:Foot; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006614:Hindlimb; D006868:Hydrolysis / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D014110:Touch
chemical_list: D058907:Adenosine A1 Receptor Agonists; D018712:Analgesics, Non-Narcotic; D043682:Receptor, Adenosine A1; C048599:N(6)-cyclopentyladenosine; D000249:Adenosine Monophosphate; D000241:Adenosine
keywords: adenosine A(1) receptor; diabetes; mechanical allodynia; neuropathy; pain