The proposed experiments have been designed to determine the anatomical and functional connections among specific neurons in the brainstem and spinal cord that are involved in modulating nociception. The neuronal cell groups to be examined include the nucleus raphe magnus, nucleus reticularis gigantocellularis pars a, periaqueductal gray, pedunculopontine tegmental nucleus, A5 and A7 catecholamine cell groups, and an enkephalin cell group in the dorsolateral pontine tegmentum that innervates the spinal cord dorsal horn. Neurons in these cell groups are neurochemically diverse and contain neurotransmitters such as serotonin, norepinephrine, acetylcholine, enkephalins, neurotensin, substance P, excitatory amino acids, and probably many other unidentified peptides and amino acids. These experiments will determine the neurotransmitters contained in these neurons, the anatomical connections among these immunochemically-identified neurons, including the axonal trajectories, and the location of synaptic contacts made by these neurons. Functional neuronal connections will be determined by activating selected neurons using electrical or chemical stimulation and determining the resulting effects on nociception and electrophysiological recordings of postsynaptic neurons. Pharmacological analysis using selective neurotransmitter agonists and antagonists will be used to provide evidence for the function of specific neurons in nociceptive modulation. These anatomical, electrophysiological, and pharmacological experiments are designed to provide converging evidence that will be used to identify and define specific neuronal circuits in the brainstem and spinal cord that modulate nociception. Understanding the neural circuits that regulate nociception could lead to new and effective treatments for the numerous pain states that are refractory to current therapeutic methods. In addition, understanding the pharmacology of pain modulatory circuits may provide insights into new drug treatments for pain states that are currently treated with opioid drugs. Thus, non-opioid drugs may be developed that lack the unfortunate and dangerous side effects of the opioid analgesic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003980-14
Application #
2116900
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Program Officer
Thomas, David D
Project Start
1985-07-01
Project End
1998-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
14
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Bajic, Dusica; Proudfit, Herbert K (2013) Projections from the rat cuneiform nucleus to the A7, A6 (locus coeruleus), and A5 pontine noradrenergic cell groups. J Chem Neuroanat 50-51:11-20
Buhler, A V; Proudfit, H K; Gebhart, G F (2008) Neurotensin-produced antinociception in the rostral ventromedial medulla is partially mediated by spinal cord norepinephrine. Pain 135:280-90
Buhler, A V; Choi, J; Proudfit, H K et al. (2005) Neurotensin activation of the NTR1 on spinally-projecting serotonergic neurons in the rostral ventromedial medulla is antinociceptive. Pain 114:285-94
Buhler, A V; Proudfit, H K; Gebhart, G F (2004) Separate populations of neurons in the rostral ventromedial medulla project to the spinal cord and to the dorsolateral pons in the rat. Brain Res 1016:12-9
Bajic, D; Van Bockstaele, E J; Proudfit, H K (2001) Ultrastructural analysis of ventrolateral periaqueductal gray projections to the A7 catecholamine cell group. Neuroscience 104:181-97
Van Bockstaele, E J; Bajic, D; Proudfit, H et al. (2001) Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus. Physiol Behav 73:273-83
Nuseir, K; Proudfit, H K (2000) Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic A7 neurons. Neuroscience 96:773-83
Graham, B A; Hammond, D L; Proudfit, H K (2000) Synergistic interactions between two alpha(2)-adrenoceptor agonists, dexmedetomidine and ST-91, in two substrains of Sprague-Dawley rats. Pain 85:135-43
Nuseir, K; Heidenreich, B A; Proudfit, H K (1999) The antinociception produced by microinjection of a cholinergic agonist in the ventromedial medulla is mediated by noradrenergic neurons in the A7 catecholamine cell group. Brain Res 822:1-7
Holden, J E; Schwartz, E J; Proudfit, H K (1999) Microinjection of morphine in the A7 catecholamine cell group produces opposing effects on nociception that are mediated by alpha1- and alpha2-adrenoceptors. Neuroscience 91:979-90

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