AMPA receptors mediate pain transmission and have been implicated as critical components in initiating some forms of central hyperalgesia and allodynia. Ca2+ is a second messenger often involved in plasticity at central synapses and some of the AMPA receptors are directly permeable to Ca2+. However the role of these Ca2+ permeable receptors in synaptic plasticity, even their role in synaptic transmission in the spinal cord (but see Preliminary studies), is unknown. If Ca2+ entry through synaptic AMPA receptors is responsible for regulating synaptic strength in the dorsal horn pain pathway, then pharmacological intervention with those receptors would provide an entirely new way to control conditions leading to pathological pain states. Joro spider toxin (JSTX), a polyamine purified from the spider Nephila clavata, selectively blocks Ca2+ permeable AMPA receptors without blocking Ca2+ impermeable AMPA receptors, providing a good example of such selective drug action. Furthermore, due to the unique properties of the Ca2+ -permeable AMPA receptors compared to NMDA receptors, synaptically evoked Ca2+ entry through the AMPA receptors should be enhanced by co-incident inhibitory synaptic activation (rather than inhibited as is the case for the NMDA receptors) making the Ca2+- permeable AMPA receptors a novel type of co-incidence detector. Using synthetic JSTX-3, we have evidence establishing that the Ca2+- permeable AMPA receptors are expressed postsynaptically on dorsal horn neurons. We now intend to clarify the role of Ca2+-permeable AMPA receptors in the central transmission and modulation of pain information. We plan to determine the role of Ca2+-permeable AMPA receptors in the modification of neighboring synaptic receptors in a manner dependent on Ca2+ entry through the AMPA channels themselves. We have already demonstrated that Ca2+ entry through the Ca2+-permeable AMPA receptors causes desensitization of the NMDA receptors (Kyrozis et al, 1995) and now we will determine if this happens during synaptic transmission. We will measure the Ca2+ accumulation following entry through Ca2+-permeable AMPA receptors and determine its dependence on membrane potential. We will contrast these observations with those made on synaptically gated Ca2+ accumulation through the NMDA receptors in the presence of Mg2+ as a way of determining if Ca2+-permeable AMPA receptors could function as co- incidence detectors for inhibitory input. Finally, we will identify which subpopulation of neurons in laminae I and II of the dorsal horn pain pathway most prominently express Ca2+-permeable AMPA receptors at synaptic sites which will give us insight into the major role these receptors play in pain transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029797-05
Application #
2393111
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Baughman, Robert W
Project Start
1992-04-01
Project End
1999-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
5
Fiscal Year
1997
Total Cost
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
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
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
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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