The Second Hospital of Shandong University, Jinan, Shandong, China.
The Second Hospital of Shandong University, Jinan, Shandong, China.
Can J Diabetes. 2017 Apr;41(2):177-183. doi: 10.1016/j.jcjd.2016.09.006. Epub 2016 Nov 23.
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.
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.
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.
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.
糖尿病性神经病是 1 型和 2 型糖尿病最常见的并发症。在这项研究中，我们检验了以下假设：脊髓中 Gi 蛋白表达/功能受损与 2 型糖尿病患者疼痛性神经病的发生有关，以及通过抑制脊髓中的腺苷酸环化酶来减少环磷酸腺苷 (cAMP) 的产生可以缓解糖尿病性神经病。
为此，我们检查了 2 型糖尿病 Zucker 糖尿病肥胖 (ZDF) 大鼠发生神经性疼痛后脊髓中 cAMP、cAMP 依赖性蛋白激酶 (PKA) 和 cAMP 反应元件结合蛋白 (CREB) 的水平。我们评估了鞘内注射腺苷酸环化酶抑制剂 SQ22536 对痛性糖尿病性神经病大鼠机械性痛觉过敏和热痛觉过敏的影响。
我们发现，糖尿病 ZDF 大鼠表现出机械性痛觉过敏和热痛觉过敏，这与脊髓中 cAMP 产生增加、PKA 激活增加和 CREB 磷酸化升高有关。此外，糖尿病 ZDF 大鼠脊髓中 Giα表达减弱，但 Gsα表达无变化。此外，鞘内给予 SQ22536 可剂量依赖性地缓解糖尿病 ZDF 大鼠的机械性痛觉过敏和热痛觉过敏，并降低脊髓中 cAMP 的产生、PKA 的激活和 p-CREB 的表达。
综上所述，我们的研究表明，脊髓中的 cAMP 介导的信号转导可能对 2 型糖尿病患者疼痛性神经病的发生至关重要。
