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ALPHA2-ADRENERGIC ANALGESIA

Award Number: R01GM035523
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: HEALTH SERVICES
PERIOD OF PERFORMANCE START DATE: 09/01/1985
PERIOD OF PERFORMANCE END DATE: 03/31/2007

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ALPHA2-ADRENERGIC ANALGESIA - DESCRIPTION (provided by applicant): We have, in the past 15 years, examined the mechanisms of alpha2-adrenoceptor mediated analgesia in the spinal cord and their plasticity following nerve injury. We shift our focus in this application to alpha2- adrenoceptors on peripheral afferents, due to two clinical observations. First, injection of clonidine at the site of nerve injury causes a delayed onset, long-lasting analgesia in patients and in animals. Preliminary data show this is an effect on alpha2-adrenoceptors, likely on macrophages, and results in altered phenotype of injured afferents. We will investigate the mechanisms of action of alpha2-adrenoceptors at the site of nerve injury, specifically: 1. Determine by what mechanisms alpha2-AR stimulation at the site of nerve injury affects the balance between macrophages with a pro-inflammatory phenotype, which release factors, which drive neuronal hypersensitivity (TNFalpha, IL-1beta, and NGF), and those with an anti-inflammatory phenotype. 2. Determine the consequences of alpha2-AR stimulation at the site of nerve injury on the phenotype of injured afferents, focusing on functional Na+ channels in the cell body and peripheral nerve. The second clinical observation is that epidural injection of clonidine does not cause pain in patients with peripheral nerve injury, and often causes analgesia. Yet, studies in animals convincingly demonstrate novel expression of excitatory alpha2-adrenoceptors on injured afferents and nociceptors. Preliminary studies show that nerve injury leads to increased alpha2-adrenoceptor expression, and alpha2-adrenoceptor mediated inhibition of electrically stimulated cell bodies, and increased clonidine-induced release by afferents of the inhibitory neurotransmitter, somatostatin. To further investigate mechanisms of these effects, we will: 3. Determine the role of alpha-AR types and subtypes underlying reduced response to stimulation in injured DRG cell bodies, the classes of cells affected, and the indirect role of SST in this inhibition.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2006 ( Subtotal = $353,649 )
2006	2006	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	20	3/31/2006	NON-COMPETING CONTINUATION	$353,649
														Subtotal = $353,649

Issue Date FY: 2005 ( Subtotal = $351,694 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	19	3/28/2005	NON-COMPETING CONTINUATION	$351,694
														Subtotal = $351,694

Issue Date FY: 2004 ( Subtotal = $341,830 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	18	3/18/2004	NON-COMPETING CONTINUATION	$341,830
														Subtotal = $341,830

Issue Date FY: 2003 ( Subtotal = $362,824 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	17		COMPETING CONTINUATION	$362,824
														Subtotal = $362,824

Issue Date FY: 2002 ( Subtotal = $346,093 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	16	3/28/2002	NON-COMPETING CONTINUATION	$346,093
														Subtotal = $346,093

Issue Date FY: 2001 ( Subtotal = $337,916 )
2001	2001	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	15	3/14/2001	NON-COMPETING CONTINUATION	$337,916
														Subtotal = $337,916

Issue Date FY: 2000 ( Subtotal = $329,978 )
2000	2000	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	14	3/13/2000	NON-COMPETING CONTINUATION	$329,978
														Subtotal = $329,978

Issue Date FY: 1999 ( Subtotal = $331,803 )
1999	1999	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	13	3/11/1999	COMPETING CONTINUATION	$331,803
														Subtotal = $331,803

Grand Total All Awards = $2,755,787

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ALPHA2-ADRENERGIC ANALGESIA

Award Number: R01GM035523

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: HEALTH SERVICES

PERIOD OF PERFORMANCE START DATE: 09/01/1985

PERIOD OF PERFORMANCE END DATE: 03/31/2007

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