Journal
CANADIAN JOURNAL OF DIABETES
Volume 41, Issue 2, Pages 177-183Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jcjd.2016.09.006
Keywords
adenylyl cyclase; diabetic neuropathy; pain; spinal cord; Zucker diabetic fatty rats
Categories
Funding
- Science and Technology Development Project of Shandong Province [2014Gsf118160]
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Objectives: Diabetic neuropathy is the most common complication of both type 1 and type 2 diabetes. In this study, we tested the hypotheses that impaired Gi protein expression/function in the spinal cord is associated with the development of painful neuropathy in people with type 2 diabetes and that reduction of cyclic adenosine monophosphate (cAMP) production by inhibiting adenylyl cyclase in the spinal cord can alleviate diabetic neuropathy. Methods: To this end, we examined the levels of cAMP, cAMP-dependent protein kinase (PKA) and cAMP response element-binding protein (CREB) in the spinal cord after the development of neuropathic pain in Zucker diabetic fatty (ZDF) rats with type 2 diabetes. We evaluated the effects of intrathecal injections of SQ22536, an adenylyl cyclase inhibitor, on mechanical allodynia and thermal hyperalgesia in rats with painful diabetic neuropathy. Results: We found that diabetic ZDF rats exhibited mechanical allodynia and thermal hyperalgesia, which are associated with enhanced cAMP production, increased PKA activation and elevated CREB phosphorylation in the spinal cord. Additionally, diabetic ZDF rats exhibited attenuated expression of Gi alpha, but not Gs alpha, in the spinal cord. Furthermore, intrathecal administrations of SQ22536 dose-dependently alleviated mechanical allodynia and thermal hyperalgesia in diabetic ZDF rats and reduced cAMP production, PKA activation and p-CREB expression in the spinal cord. Conclusions: Taken together, our study suggested that cAMP-mediated signalling in the spinal cord is likely critical for the development of painful neuropathy in people with type 2 diabetes. (C) 2016 Canadian Diabetes Association.
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