Substantia gelatinosa (SG) neurons in the spinal cord are the principal site of termination of primary afferents, many of which innervate nociceptors. Endogenous opiates or synthetic compounds are thought to produce their anti-nociceptors. Endogenous opiates or synthetic compounds are thought to produce their anti-nociception by interacting with subtypes of opiate receptors on SG neurons. Two recently isolated tetrapeptides endomorphin (Endo) 1 and 2 are believed to be the endogenous ligand for the mu-subtype of opioid receptors. Preliminary results showed endomorphin-like immunoreactivity (Endo-LI) subtype of opioid receptors. Preliminary results showed that endomorphin-like immunoreactivity (Endo-LI) is localized to dense networks of nerve fibers in the superficial layers of the rat dorsal horn. Thus, the rat dorsal horn offers a unique opportunity to test the hypothesis that Endo-1/Endo-2 is released endogenously and that it may modulate the activity of SG neurons. Two major issues will be addressed. First, release of endogenous of endogenous endomorphins will be evaluated in anesthetized rats in vivo or isolated rat spinal cords in vitro by the radioactive microprobe techniques. Electrical stimulation of afferent fibers of painful stimulus to the hindpaw will be employed to evaluate whether or not endomorphin release is altered under these conditions. Second, whole-cell patch recording techniques will be used to study the cellular action and the signal transduction mechanism underlying the action of Endo on single SG neurons in rat transverse spinal cord slices. Our preliminary results show that Endo inhibits the activity of SG neurons by hyperpolarizing the membrane and/or attenuating synaptic transmission. In this proposal, the pre- and post-synaptic actions of Endo will be evaluated electrophysiologically and pharmacologically. The subtype(s) of K+ channels that may underlie the hyperpolarizing action of Endo will be examined. Similarly, the subtype(s) of Ca2+ and/or K+ channels coupled to the presynaptic opiate receptor that may mediate the synaptic depressant action of Endo will be evaluated. The long term goal of this project is to improve our current understanding of the site and mechanism of action of this new class of opioid peptides on dorsal horn neurons, with the aim toward developing a novel class of opiate compounds with therapeutic potentials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS039646-01
Application #
6052393
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Kitt, Cheryl A
Project Start
1999-12-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
1
Fiscal Year
2000
Total Cost
$221,419
Indirect Cost
Name
East Tennessee State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
051125037
City
Johnson City
State
TN
Country
United States
Zip Code
37614
Ng, Y K; Brailoiu, G C; Dun, S L et al. (2006) Beacon immunoreactivity in the rat hypothalamus. J Neurosci Res 83:1106-17
Hua, Fang; Harrison, Theresa; Qin, Chao et al. (2004) c-Fos expression in rat brain stem and spinal cord in response to activation of cardiac ischemia-sensitive afferent neurons and electrostimulatory modulation. Am J Physiol Heart Circ Physiol 287:H2728-38
Brailoiu, Eugen; Hoard, Jennifer; Brailoiu, G Cristina et al. (2004) Ultra low concentrations of morphine increase neurite outgrowth in cultured rat spinal cord and cerebral cortical neurons. Neurosci Lett 365:10-3
Dun, Siok L; Brailoiu, G Cristina; Parsons, Amy et al. (2003) Metastin-like immunoreactivity in the rat medulla oblongata and spinal cord. Neurosci Lett 335:197-201
Brailoiu, E; Brailoiu, G C; Miyamoto, M D et al. (2003) The vasoactive peptide urotensin II stimulates spontaneous release from frog motor nerve terminals. Br J Pharmacol 138:1580-8
Brailoiu, G Cristina; Dun, Siok L; Chi, Michelle et al. (2003) Beacon/ubiquitin-like 5-immunoreactivity in the hypothalamus and pituitary of the mouse. Brain Res 984:215-23
Brailoiu, Eugen; Miyamoto, Michael D; Dun, Nae J (2003) Inositol derivatives modulate spontaneous transmitter release at the frog neuromuscular junction. Neuropharmacology 45:691-701
Wu, Su-Ying; Ohtubo, Yoshitaka; Brailoiu, G Cristina et al. (2003) Effects of endomorphin on substantia gelatinosa neurons in rat spinal cord slices. Br J Pharmacol 140:1088-96
Brailoiu, Eugen; Patel, Sandip; Dun, Nae J (2003) Modulation of spontaneous transmitter release from the frog neuromuscular junction by interacting intracellular Ca(2+) stores: critical role for nicotinic acid-adenine dinucleotide phosphate (NAADP). Biochem J 373:313-8
Brailoiu, Eugen; Dun, Nae J (2003) Extra- and intracellular sphingosylphosphorylcholine promote spontaneous transmitter release from frog motor nerve endings. Mol Pharmacol 63:1430-6

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