Diabetic neuropathy is one of the most important complications that afflict people with diabetes. Because chronic pain caused by diabetic neuropathy is not adequately relieved by existing analgesics, it represents an important unmet clinical need. The cholinergic system in the spinal cord is critically involved in the control of pain transmission. Although distinct M"""""""" M3 , and M. subtypes are involved in the regulation of excitatory and inhibitory neurotransmitter release to spinal dorsal horn neurons, little is known about how the function of these mAChR subtypes is altered in diabetic neuropathic pain. The major objectives of this proposal are to study the functional plasticity of spinal muscarinic acetylcholine receptor (mAChR) subtypes in the regulation of nociceptive transmission in painful neuropathy associated with type 1 diabetes. Our preliminary findings suggest that diabetic neuropathy affects primarily the M, and M. mAChR subtypes in the dorsal root ganglion and spinal cord.
The specific aims of this project are to determine (1) the functional changes in mAChR subtypes in the spinal dorsal horn and dorsal root ganglion after induction of painful neuropathy in type 1 diabetes and (2) the roles of individual mAChR subtypes in the spinal cord in the control of nociception in diabetic neuropathic pain. Our central hypothesis is that diabetic neuropathy primarily upregulates M, and M. mAChRs on the primary sensory neurons and spinal dorsal horn neurons to inhibit nociceptive transmission. We will use a combination of multidisciplinary approaches including whole-cell patch-clamp recordings of postsynaptic currents in perfused spinal cord slices, real-time RT-PCR, and knockdown of spinal mAChR subtypes with small interfering RNA. These studies will provide substantial novel information about the mechanisms of plasticity in the spinal cholinergic system and mAChR subtypes in diabetic neuropathy. Findings from this project will provide a rationale for the development of new therapies for patients with intractable diabetic neuropathic pain.

Public Health Relevance

This proposal will study the mechanisms of changes in the transmission of sensory information in the spinal cord in the nerve damage caused by diabetes. We will also determine the specific acetylcholine receptors that are most important for the regulation of the pain transmission in diabetes. This information will be important for the development of more effective treatments for intractable pain in diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045602-07
Application #
7895931
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Porter, Linda L
Project Start
2003-04-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$401,858
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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
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
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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