title: Inhibition of Adenylyl Cyclase in the Spinal Cord Alleviates Painful Diabetic Neuropathy in Zucker Diabetic Fatty Rats.
abstract: OBJECTIVE
  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.
authors.affiliation: The Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: The Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Lu
authors.affiliation: The Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Li
authors.affiliation: The Second Hospital of Shandong University, Jinan, Shandong, China. Electronic address: zhonghaoliuu@sina.com.
authors.forename: Zhonghao
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000067956:Adenylyl Cyclase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D007278:Injections, Spinal; D010146:Pain / Q000188:drug therapy*; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D000225:Adenine
keywords: Zucker diabetic fatty rats; adenylyl cyclase; adénylcyclase; diabetic neuropathy; douleur; moelle spinale; neuropathie diabétique; pain; rats Zucker obèses et diabétiques; spinal cord