The objectives of this proposal center around an improved understanding of the spinal nicotinic acetylcholine receptors in the spinal cord of normal and nerve-injured rats. A further understanding of spinal nicotinic systems will result in novel, specific pharmacological targets for the treatment of neuropathic pain. The spinal nicotinic system has been largely ignored because the intrathecal administration of nicotinic agonists generally produces more pronociception than antinociception. Recently, data from our laboratory and others, has shown that the pharmacology of nicotinic agonists in the presence of chronic, neuropathic pain is altered. In nerve-injured mice and rats, intrathecal nicotinic agonists produce only antinociception. Data from our laboratory has shown that several nicotinic acetylcholine receptor subunits are upregulated following spinal nerve ligation. Spinal interneurons upregulate their expression of the alpha3 and the alpha7 subunits while primary afferents increase their expression of the alpha5 subunit. Previously, we have also found that the alpha5 subunit contributes to mechanical allodynia in neuropathic rats. However, the contributions of the alpha3 and alpha7 subunits are still unknown. This proposal outlines both anatomical and functional experiments to determine the contribution of these upregulated subunits to the maintenance of mechanical allodynia following nerve injury. We will use immunocytochemistry to identify the spinal structures that upregulate these two nicotinic subunits. We will use the anatomical data obtained from these studies to further investigate the function of these upregulated subunits in the spinal cord of neuropathic rats. The functionality of these subunits will be investigated using in vitro release experiments. Selective nicotinic agonists and antagonists will be used to elicit the release of GABA in the isolated spinal cord slice and in synaptosomes. Finally, the behavioral implications of nicotinic subunit upregulation will be determined with the intrathecal administration of selective nicotinic agonists and antagonists in normal and spinal nerve-ligated rats. The results of these studies will further define spinal nicotinic anatomy and functioning in the nerve-injured animal thereby, providing unique potential targets for the pharmacological treatment of neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048158-04
Application #
7435309
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2005-06-15
Project End
2009-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$157,325
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Suzuki, Hiromichi; Aoyama, Youhei; Senzaki, Kouji et al. (2010) Characterization of sensory neurons in the dorsal root ganglia of Bax-deficient mice. Brain Res 1362:23-31
McIntosh, J Michael; Absalom, Nathan; Chebib, Mary et al. (2009) Alpha9 nicotinic acetylcholine receptors and the treatment of pain. Biochem Pharmacol 78:693-702
Gurun, Mine Sibel; Parker, Renee; Eisenach, James C et al. (2009) The effect of peripherally administered CDP-choline in an acute inflammatory pain model: the role of alpha7 nicotinic acetylcholine receptor. Anesth Analg 108:1680-7
Young, Tracey; Wittenauer, Shannon; McIntosh, J Michael et al. (2008) Spinal alpha3beta2* nicotinic acetylcholine receptors tonically inhibit the transmission of nociceptive mechanical stimuli. Brain Res 1229:118-24
Young, Tracey; Wittenauer, Shannon; Parker, Renee et al. (2008) Peripheral nerve injury alters spinal nicotinic acetylcholine receptor pharmacology. Eur J Pharmacol 590:163-9
Brett, Kyle; Parker, Renee; Wittenauer, Shannon et al. (2007) Impact of chronic nicotine on sciatic nerve injury in the rat. J Neuroimmunol 186:37-44
Vincler, Michelle; McIntosh, J Michael (2007) Targeting the alpha9alpha10 nicotinic acetylcholine receptor to treat severe pain. Expert Opin Ther Targets 11:891-7
Lough, Chris; Young, Tracey; Parker, Renee et al. (2007) Increased spinal dynorphin contributes to chronic nicotine-induced mechanical hypersensitivity in the rat. Neurosci Lett 422:54-8
Vincler, Michelle; Wittenauer, Shannon; Parker, Renee et al. (2006) Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors. Proc Natl Acad Sci U S A 103:17880-4