The long-term goal of this project is to explore the central mechanisms involved in persistent pain. The lack of understanding of central mechanisms has made persistent pain difficult to treat. Peripheral sensitization (increased sensitivity of primary afferent nociceptors) and central sensitization (enhanced nociceptive transmission in the spinal cord) contribute to persistent pain induced by tissue or nerve injury. However, descending influences from supraspinal structures on spinal sensory transmission during persistent pain haven't been investigated. The present proposal tests the hypothesis that descending biphasic (facilitatory and inhibitory) modulation from the rostromedial medulla (RMM) contribute to persistent pain by enhancing spinal sensory transmission. Single neurons in the RMM will be recorded to examine plastic changes of single neurons in the RMM during persistent pain induced by a subcutaneous injection of formalin into the receptive field. Changes in neuron activity in the RMM may effect spinal sensory transmission through descending biphasic modulation. Thus, responses of spinal neurons to noxious stimuli will be recorded to determine the effects of descending biphasic modulation from the RMM on spinal nociceptive transmission during persistent pain. In addition, responses of spinal neurons to non-noxious stimuli will be measured to test the effects of descending biphasic modulation from the RMM on spinal non-nociceptive transmission during persistent pain. Behavioral and pharmacological experiments will be carried out to characterize the effects of descending biphasic modulation on behavioral reflexes and spinal receptor(s) which mediate the effects during persistent pain. Electrophysiological, behavioral and pharmacological approaches will generate converging information about the role of descending influences on spinal plasticity before and during persistent noxious input. It is hypothesized that the RMM plays an important role in the induction and maintenance of spinal changes associated with persistent pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA010833-03
Application #
2837886
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Thomas, David Dale
Project Start
1997-01-10
Project End
2001-11-30
Budget Start
1998-12-15
Budget End
1999-11-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zhuo, Min (2004) Central plasticity in pathological pain. Novartis Found Symp 261:132-45; discussion 145-54
Kerchner, Geoffrey A; Wilding, Timothy J; Huettner, James E et al. (2002) Kainate receptor subunits underlying presynaptic regulation of transmitter release in the dorsal horn. J Neurosci 22:8010-7
Zhuo, Min (2002) Glutamate receptors and persistent pain: targeting forebrain NR2B subunits. Drug Discov Today 7:259-67
Kerchner, Geoffrey A; Zhuo, Min (2002) Presynaptic suppression of dorsal horn inhibitory transmission by mu-opioid receptors. J Neurophysiol 88:520-2
Wang, Guo-Du; Zhuo, Min (2002) Synergistic enhancement of glutamate-mediated responses by serotonin and forskolin in adult mouse spinal dorsal horn neurons. J Neurophysiol 87:732-9
Kim, Susan J; Calejesan, Amelita A; Zhuo, Min (2002) Activation of brainstem metabotropic glutamate receptors inhibits spinal nociception in adult rats. Pharmacol Biochem Behav 73:429-37
Li, P; Zhuo, M (2001) Cholinergic, noradrenergic, and serotonergic inhibition of fast synaptic transmission in spinal lumbar dorsal horn of rat. Brain Res Bull 54:639-47
Li, P; Zhuo, M (2001) Substance P and neurokinin A mediate sensory synaptic transmission in young rat dorsal horn neurons. Brain Res Bull 55:521-31
Wei, F; Zhuo, M (2001) Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J Physiol 532:823-33
Kerchner, G A; Wilding, T J; Li, P et al. (2001) Presynaptic kainate receptors regulate spinal sensory transmission. J Neurosci 21:59-66

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