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Abstract

Grant Number:	5R01NS029797-12
Project Title:	Synaptic regulation of dorsal horn projection neurons

PI Information:	Name	Email	Title
	MACDERMOTT, AMY B.	abm1@columbia.edu	ASSOCIATE PROFESSOR

Abstract: DESCRIPTION (provided by applicant): In the spinal cord dorsal horn, lamina I and II are the primary sites of synaptic innervation by high threshold pain and temperature sensory afferent fibers whereas low threshold (touch) afferent fibers generally terminate in deeper lamina. The rostrally rising projection neurons that carry pain and temperature signals to higher brain centers arise primarily in lamina I, III and V. Because more than 80% of the lamina I and III projection neurons express receptor for substance P, called the NK1 receptor (NK1R), it has been possible to selectively ablate them and thus demonstrate their key role in expression of hyperalgesia and allodynia (Mantyh et al, 1997; Nichols et al, 1999; Mantyh and Hunt, 2004). In this grant, we propose to investigate 3 aspects of regulation of synaptic transmission onto these critical lamina I neurons expressing the NK1R. To do this, we take advantage of our ability to label NK1R expressing (NK1R+) neurons in live rat spinal cord slices using fluorescently labeled substance P. Because acute intrathecal administration of strychnine and bicuculline produces tactile allodynia (Yaksh, 1989), we hypothesize that in the absence of local inhibition, low threshold input will become prominent while high threshold input onto NK1R+ neurons will be enhanced. To test this hypothesis, we will characterize which primary afferent fibers, defined by threshold and conduction velocity, synapse onto the NK1R+ neurons in lamina I. Then we will assess alterations in afferent input to NK1R+ neurons in the absence of inhibition. If this disinhibition reveals enhanced excitatory drive onto NK1R+ lamina I neurons, we will determine whether the NMDA receptors play a critical role in mediating this activity. To investigate the synaptic basis for such control, we will estimate the power with which NMDA receptors control excitatory synaptic activity onto lamina I NK1R+ neurons. Taking advantage of a transgenic mouse with EGFP expressing GABAergic neurons, we will identify the inhibitory neurons that directly regulate synaptic excitation of NK1R+ neurons in lamina I. Furthermore, we will test the hypotheses that fast synaptic inhibition of NK1R+ neurons is predominantly glycinergic and that inhibitory transmitter release onto NK1R+ neurons is regulated through ionotropic glutamate receptor activation. Identifying and characterizing the excitatory and inhibitory synapses impinging on the NK1R+ lamina I neurons is an undertaking that goes to the heart of understanding the synaptic drive contributing to allodynia and hyperalgesia and therefore is key to development of targeted drugs for chronic pain.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
calcium channel, dorsal horn, glutamate receptor, nociceptor
AMPA receptor, NMDA receptor, action potential, calcium flux, central neural pathway /tract, neural transmission, pain, receptor expression, spinal cord, synapse
fluorescent dye /probe, immunocytochemistry, laboratory rat, mixed tissue /cell culture, voltage /patch clamp

Institution:	COLUMBIA UNIVERSITY HEALTH SCIENCES
	Columbia University Medical Center
	NEW YORK, NY 100323702
Fiscal Year:	2006
Department:	PHYSIOLOGY AND CELLULAR BIOPHYSICS
Project Start:	01-APR-1992
Project End:	30-JUN-2009
ICD:	NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:	NTRC

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