Cutaneous nociceptive signaling is carried into the CNS by high threshold primary afferent fibers, or nociceptors, that form glutamatergic/peptidergic synapses with neurons in the superficial dorsal horn. Glutamate released from these terminals acts on multiple receptor types including the ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors. The two main types of Ca2+ permeable glutamate receptors expressed by dorsal horn neurons, the NMDA and Ca2+ permeable AMPA receptors, have different voltage dependent properties making Ca2+ entry through these receptors have different activity dependence. Both of these receptors have been implicated in forms of central sensitization association with hyperalgesia and allodynia. In addition to glutamatergic synaptic transmission, GABA and glycine are also importantly involved in regulating nociception (Willis and Coggeshall, 1991; Dickenson et al, 1997). It is not known whether the critical importance of non-NMDA receptors in the regulation of nociception is due to their action to enhance inhibition by mediating excitation of GABA/glycinergic neurons at postsynaptic sites or even at the nerve terminals of these inhibitory neurons. Understanding the role of Ca2+ permeable glutamate receptors in activation of projection neurons and modulating excitation of inhibitory neurons is key to understanding regulation of information flow through the superficial dorsal horn. We plan to use postnatal rat spinal cord slices to study the role of pre and postsynaptic AMPA receptors in regulating synaptic transmission in the spinal cord dorsal horn. Using electrophysiology, Ca2+ and general fluorescent imaging, and immunocytochemistry, we will clarify the location and function of the Ca2+ permeable non-NMDA receptors in the dorsal horn. We will use co-cultures of nociceptors and dorsal horn neurons grown on microislands to determine the rules for sorting of Ca2+ permeable AMPA receptors and NMDA receptors at individual synaptic sites and how that impacts on the activity dependence of each synapse studied. In addition to developing our understanding of regulation of nociceptive information transmission in the dorsal horn, these studies may also contribute to the development of new drugs for alleviating pain that are targeted to the unexplored cell specific AMPA receptors we propose to study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029797-08
Application #
6393485
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Kitt, Cheryl A
Project Start
1992-04-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
8
Fiscal Year
2001
Total Cost
$295,908
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Takazawa, Tomonori; Choudhury, Papiya; Tong, Chi-Kun et al. (2017) Inhibition Mediated by Glycinergic and GABAergic Receptors on Excitatory Neurons in Mouse Superficial Dorsal Horn Is Location-Specific but Modified by Inflammation. J Neurosci 37:2336-2348
Betelli, Chiara; MacDermott, Amy B; Bardoni, Rita (2015) Transient, activity dependent inhibition of transmitter release from low threshold afferents mediated by GABAA receptors in spinal cord lamina III/IV. Mol Pain 11:64
Tong, Chi-Kun; MacDermott, Amy B (2014) Synaptic GluN2A and GluN2B containing NMDA receptors within the superficial dorsal horn activated following primary afferent stimulation. J Neurosci 34:10808-20
Bardoni, Rita; Tawfik, Vivianne L; Wang, Dong et al. (2014) Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn. Neuron 81:1312-1327
Joseph, Donald J; Williams, Damian J; MacDermott, Amy B (2011) Modulation of neurite outgrowth by activation of calcium-permeable kainate receptors expressed by rat nociceptive-like dorsal root ganglion neurons. Dev Neurobiol 71:818-35
Gangadharan, Vijayan; Wang, Rui; Ulzhöfer, Bettina et al. (2011) Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice. J Clin Invest 121:1608-23
Takazawa, Tomonori; MacDermott, Amy B (2010) Synaptic pathways and inhibitory gates in the spinal cord dorsal horn. Ann N Y Acad Sci 1198:153-8
Takazawa, Tomonori; MacDermott, Amy B (2010) Glycinergic and GABAergic tonic inhibition fine tune inhibitory control in regionally distinct subpopulations of dorsal horn neurons. J Physiol 588:2571-87
Shiokawa, Hiroaki; Kaftan, Edward J; MacDermott, Amy B et al. (2010) NR2 subunits and NMDA receptors on lamina II inhibitory and excitatory interneurons of the mouse dorsal horn. Mol Pain 6:26
Daniele, Claire A; MacDermott, Amy B (2009) Low-threshold primary afferent drive onto GABAergic interneurons in the superficial dorsal horn of the mouse. J Neurosci 29:686-95

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