Both serotonergic and non-serotonergic neurons located in the medullary nucleus raphe magnus which project to the spinal cord have been implicated in the regulation of pain sensitivity. Activation of these neurons inhibits the transmission of nociceptive information in the dorsal horn of the spinal cord and results in antinociception. Although the ability of raphe magnus neurons to regulate the transmission of nociceptive information at the spinal level is well-documented, little is known about the inputs which regulate the activity of raphe magnus neurons themselves. Previous work is this laboratory has indicated that neurons in the raphe magnus are subject to modulation by both noradrenergic and cholinergic neurons. The proposed studies are designed to characterize the interactions among serotonergic, noradrenergic, and cholinergic neurons in the brainstem and spinal cord and to determine the functions of these neuronal systems in the regulation of nociception. The proposed studies will involve: (1) microinjecting drugs which modify cholinergic and noradrenergic function in the raphe magnus and determining the resulting effects of nociception; (2) determining the effects of iontophoretically-applied cholinergic and noradrenergic drugs on identified neurons in the raphe magnus; (3) determining the capacity of spinally-projecting serotonergic and noradrenergic neurons to produce antinociception by activating them and modifying the resulting antinociception by spinal injections of drugs which alter monoaminergic function; (4) determining whether the antinociception produced by electrical and pharmacological stimulation of brainstem neurons is mediated by the release of endogenous serotonin and norepinephrine in the spinal cord; (5) determining the anatomical connections of cholinergic, noradrenergic, and serotonergic neurons in the brainstem and spinal cord; and (6) determining the location of noradrenergic receptor subtypes involved in modulating nociception in the brainstem and spinal cord. A detailed study of the pharmacology, neurochemistry, anatomy, and electro- physiology of these neuronal systems should provide important information about the mechanisms by which they regulate the transmission of nociceptive information. These pharmacological studies of pain modulatory systems may provide important basic information which could lead to the development of non-opioid analgesic drugs which do not possess the unfortunate side-effects and abuse potential of currently used opioids.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003980-10
Application #
3208888
Study Section
Special Emphasis Panel (SRCD (18))
Project Start
1985-07-01
Project End
1993-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
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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