Diabetic neuropathy is one of the most important complications afflicting diabetic patients. Since chronic pain caused by diabetic neuropathy often is not adequately relieved by traditional analgesics, it represents an important unmet clinical need. The major objectives of this proposal are to study changes in spinal muscarinic receptors and mechanisms of muscarinic analgesia in diabetic neuropathic pain. Preliminary evidence is presented that muscarinic receptors in the spinal cord are up-regulated in diabetes, which may account for the enhanced muscarinic analgesia in diabetic neuropathic pain. Furthermore, the preliminary study suggests that inhibition of the glutamatergic synaptic input to dorsal horn neurons is an important analgesic mechanism of spinally administered cholinergic agents in diabetic neuropathic pain. The following hypotheses will be tested using animal models of diabetes: 1) Muscarinic receptors in the spinal cord dorsal horn are up-regulated in diabetes; Increased spinal muscarinic M2/M4 receptors play a major role in the enhanced analgesic action of spinally administered cholinergic agents in diabetes; 2) Activation of muscarinic receptors causes a more significant reduction in spinal glutamate release from primary afferent terminals in diabetes; Muscarinic receptor agonists elicit GABA release, which activates presynaptic GABAB receptors to inhibit glutamate release onto spinal lamina II neurons in diabetes; and 3) The inhibitory effects of spinally administered cholinergic agents on spinothalamic tract neurons and nociception are mediated, to a greater extent, by spinal GABAB receptors in diabetes. Quantitative measurements of G protein-coupled receptors, single-unit recordings of spinal dorsal horn neurons, whole-cell voltage-clamp recordings of glutamate- and GABA-mediated postsynaptic currents in spinal cord slices, and behavioral assessment of nociception will be used. These integrated studies are important for our understanding of the mechanisms of altered spinal cord pharmacology in diabetic neuropathic pain. This new information also will provide a rationale for development of improved therapies for patients with diabetic neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS045602-01A1
Application #
6730446
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Mitler, Merrill
Project Start
2003-09-30
Project End
2007-06-30
Budget Start
2003-09-30
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$298,231
Indirect Cost
Name
Pennsylvania State University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu et al. (2014) Differential regulation of primary afferent input to spinal cord by muscarinic receptor subtypes delineated using knockout mice. J Biol Chem 289:14321-30
Xiong, Wei; Chen, Shao-Rui; He, Liming et al. (2014) Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease. Nat Neurosci 17:232-9
Guo, Yue-Xian; Li, De-Pei; Chen, Shao-Rui et al. (2013) Distinct intrinsic and synaptic properties of pre-sympathetic and pre-parasympathetic output neurons in Barrington's nucleus. J Neurochem 126:338-48
Li, Li; Cao, Xue-Hong; Chen, Shao-Rui et al. (2012) Up-regulation of Cav?3 subunit in primary sensory neurons increases voltage-activated Ca2+ channel activity and nociceptive input in neuropathic pain. J Biol Chem 287:6002-13
Zhou, Hong-Yi; Chen, Shao-Rui; Byun, Hee-Sun et al. (2012) N-methyl-D-aspartate receptor- and calpain-mediated proteolytic cleavage of K+-Cl- cotransporter-2 impairs spinal chloride homeostasis in neuropathic pain. J Biol Chem 287:33853-64
Cao, Xue-Hong; Chen, Shao-Rui; Li, Li et al. (2012) Nerve injury increases brain-derived neurotrophic factor levels to suppress BK channel activity in primary sensory neurons. J Neurochem 121:944-53
Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu et al. (2011) Increased presynaptic and postsynaptic ?2-adrenoceptor activity in the spinal dorsal horn in painful diabetic neuropathy. J Pharmacol Exp Ther 337:285-92
Cao, Xue-Hong; Byun, Hee Sun; Chen, Shao-Rui et al. (2011) Diabetic neuropathy enhances voltage-activated Ca2+ channel activity and its control by M4 muscarinic receptors in primary sensory neurons. J Neurochem 119:594-603
Zhou, Hong-Yi; Chen, Shao-Rui; Chen, Hong et al. (2011) Functional plasticity of group II metabotropic glutamate receptors in regulating spinal excitatory and inhibitory synaptic input in neuropathic pain. J Pharmacol Exp Ther 336:254-64
Zhou, Hong-Yi; Chen, Shao-Rui; Pan, Hui-Lin (2011) Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain. Expert Rev Clin Pharmacol 4:379-88

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