This application by a new investigator addresses the molecular consequences of chronic pain and how pain-induced neuronal plasticity alters sensory processing. Neurokinin-1 receptors (NK-1 receptor) and substance P (SP) are as mediators of nociceptive (pain- related) information. Nociception increase NK-1 receptor gene expression in sensory systems. We hypothesize that continued transmission of nociceptive information by substance-P containing neurons produces molecular events that increase gene expression of the NK-1 receptor, increase the sensitivity of NK-1 receptor-expressing neurons in sensory systems, and ultimately enhance the sensitivity of the intact animal to subsequent stimuli.
Specific aims are to: 1) Determine where and when NK-1 receptor gene expression is altered by painful stimuli. NK-1 receptor mRNA levels will be measured in the rat using solution hybridization-nuclease protection assays and in situ hybridization following chemogenic inflammation. Formalin and Freund's complete adjuvant will be used as inflammatory nociceptive stimuli and compared to non-noxious thermal and mechanical stimuli. The sensitivity of evoked NK-1 receptor gene expression to graded doses of NK-1 receptor antagonist drugs will also be assessed. 2) Determine whether painful stimuli increase the functional sensitivity of NK-1 receptor expressing cells. NK- 1 receptor agonist-stimulated [35S]GTPgammaS binding will be used to assess the functional coupling of NK-1 receptor as the initial step in signal transduction following G-protein activation assessed in rats undergoing the inflammatory treatments described above. 3) determine the mechanistic contribution of altered NK-1 receptor gene expression to the behavioral sensitization that develops following persistent pain. The production of a sensitized (hyperalgesic or allodynic) state will be assessed by measuring withdrawal thresholds to mechanical or thermal stimulation of the hindpaws. The sensitivity of inflammation-evoked hyperalgesia or allodynia to graded doses of selective non-peptide NK-1 receptor antagonist drugs will be assessed. Detailed correlative analyses of the effects of NK-1 receptor antagonist drugs on the molecular, cellular and behavioral end points measured will characterize the relationship between molecular and behavioral events regulating NK-1 receptor function. By testing the hypothesis at the level of the gene, the cell, and the intact behaving animal, these experiments will have important consequences on our understanding of the involvement of NK-1 receptor function in the sensitization of the central nervous system by long-term pain, and may identify novel targets or therapies for the control of the pain-enhancing effects of nociception resulting from increased NK-1 receptor gene expression in the spinal cord.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA012505-01A1
Application #
6127456
Study Section
Special Emphasis Panel (ZRG1-IFCN-4 (01))
Program Officer
Thomas, David D
Project Start
2000-09-30
Project End
2005-03-31
Budget Start
2000-09-30
Budget End
2001-03-31
Support Year
1
Fiscal Year
2000
Total Cost
$250,000
Indirect Cost
Name
University of Kansas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Ralya, Andrew; McCarson, Kenneth E (2014) Acute estrogen surge enhances inflammatory nociception without altering spinal Fos expression. Neurosci Lett 575:91-5
Enna, S J; McCarson, Kenneth E (2013) Characterization of GABA receptors. Curr Protoc Pharmacol 63:Unit 1.7.
Rook, Jerri M; Hasan, Wohaib; McCarson, Kenneth E (2009) Morphine-induced early delays in wound closure: involvement of sensory neuropeptides and modification of neurokinin receptor expression. Biochem Pharmacol 77:1747-55
Rook, Jerri M; Hasan, Wohaib; McCarson, Kenneth E (2008) Temporal effects of topical morphine application on cutaneous wound healing. Anesthesiology 109:130-6
Rook, Jerri M; McCarson, Kenneth E (2007) Delay of cutaneous wound closure by morphine via local blockade of peripheral tachykinin release. Biochem Pharmacol 74:752-7
Duric, Vanja; McCarson, Kenneth E (2007) Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain. Mol Pain 3:32
Duric, Vanja; McCarson, Kenneth E (2006) Effects of analgesic or antidepressant drugs on pain- or stress-evoked hippocampal and spinal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression in the rat. J Pharmacol Exp Ther 319:1235-43
Duric, Vanja; McCarson, Kenneth E (2006) Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. J Pain 7:544-55
Duric, V; McCarson, K E (2005) Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience 133:999-1006
Allen, Amy L; McCarson, Kenneth E (2005) Estrogen increases nociception-evoked brain-derived neurotrophic factor gene expression in the female rat. Neuroendocrinology 81:193-9

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