Hao Feng1, Guodong Lu1, Qingsong Li1, Zhonghao Liu2. 1. The Second Hospital of Shandong University, Jinan, Shandong, China. 2. The Second Hospital of Shandong University, Jinan, Shandong, China. Electronic address: zhonghaoliuu@sina.com.
Abstract
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 Giα, but not Gsα, 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.
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 ZDFrats 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 ZDFrats exhibited attenuated expression of Giα, but not Gsα, in the spinal cord. Furthermore, intrathecal administrations of SQ22536 dose-dependently alleviated mechanical allodynia and thermal hyperalgesia in diabetic ZDFrats 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.
Authors: Ryan B Griggs; Diogo F Santos; Don E Laird; Suzanne Doolen; Renee R Donahue; Caitlin R Wessel; Weisi Fu; Ghanshyam P Sinha; Pingyuan Wang; Jia Zhou; Sebastian Brings; Thomas Fleming; Peter P Nawroth; Keiichiro Susuki; Bradley K Taylor Journal: Neurobiol Dis Date: 2019-02-23 Impact factor: 5.996
Authors: Md Jakir Hossain; Michael D Kendig; Meg E Letton; Margaret J Morris; Ria Arnold Journal: Diabetes Metab J Date: 2022-03-24 Impact factor: 5.893
Authors: Inês Preguiça; André Alves; Sara Nunes; Pedro Gomes; Rosa Fernandes; Sofia D Viana; Flávio Reis Journal: Nutrients Date: 2020-01-18 Impact factor: 5.717