The proposed experiments will determine the anatomical and functional connections among specific neurons in the brainstem and spinal cord that are involved in the modulation of nociception. The neuronal cell groups to be examined include substance P and met-enkephalin neurons in the ventromedial medulla (VMM) and the periaqueductal gray (PAG), the A7 catecholamine cell group, a group of enkephalin neurons in the dorsolateral pontine tegmentum (DLPT) that innervate the spinal cord dorsal horn, and GABA neurons in the DLPT. Anatomical connections among these identified neurons will be determined using immunocytochemical methods to characterize their neurotransmitters, projections, and the location of synapses formed by these neurons. Functional connections among these immunochemically-identified neurons will be established using pharmacological and electrophysiological approaches. Pharmacological studies will determine changes in nociception induced by electrical or chemical activation of selected, identified neurons and the effect of subsequent microinjection of receptor agonists or antagonists in the regions to which these neurons project. Electrophysiological studies will characterize the response properties of spinally-projecting enkephalin and noradrenergic A7 neurons, and determine the functional connections of substance P and enkephalin neurons in the VMM and the PAG, and GABA neurons in the DLPT, that project to these descending neurons. The importance of the proposed experiments is related to the contributions they will make toward understanding the mechanisms of endogenous pain modulation in the brainstem that also control nociceptive responses in the spinal cord. The ultimate goal of this research is to understand the pain modulatory circuits in sufficient detail to allow the derivation of a computational model of these neuronal circuits that could be used to develop more effective pain control methods. It is hoped that safer and more effective pain controls methods could be developed that do not depend on opioid drugs with their attendant serious side effects and addiction liability.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (03))
Program Officer
Thomas, David D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 39 publications