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Genetic and Synaptic Studies of Sensory-related Central Sensitization

Natcher Conference Center
National Institutes of Health
June 9–10, 2005

Min Zhuo, Ph.D., Department of Physiology, Faculty of Medicine, University of Toronto Centre for the Study of Pain, University of Toronto, Toronto, Ontario, Canada

Neuronal synapses in the central nervous systems are plastic, and can undergo long-term changes throughout life. Studies of molecular and cellular mechanisms of such changes not only provide important insight into how we learn and store new knowledge in our brains, but also reveal the mechanisms of pathological changes occurring following a noxious stimulus. Using integrative approaches including genetic, pharmacological, electrophysiological and behavioral studies, we demonstrated that neuronal mechanisms underlying physiological functions such as learning and memory may share some common signaling molecules with abnormal or injury-related changes in the brain. In the first sensory synapses of spinal cord dorsal horn, serotonin (5-HT), a key neuromodulatory transmitter, recruited silent glutamatergic synapses through the AMPA receptor-PDZ protein interaction. The recruitment of silent synapses provides a potential mechanism for long-term facilitation of sensory transmission in case of neuropathic pain. Activity-dependent potentiation also takes place in the higher brain structures that are critical for pain perception and pain-related unpleasantness. In the anterior cingulate cortex (ACC), N-methyl-D-aspartate (NMDA) receptor-dependent, calcium-calmodulin activated adenylyl cyclases (AC1 and AC8) are important for the induction of long-term potentiation, a potential cellular model for the expression of persistent inflammatory and neuropathic pain. Long-term plastic changes in glutamate receptors, including the upregulation NMDA NR2B receptors in the ACC, may contribute to behavioral allodynia. Finally, neuronal activity in the ACC can also influence nociceptive transmission in the spinal cord dorsal horn through activation of endogenous descending facilitatory system. Our results provide important synaptic and molecular insights into physiological responses to the injury, including behavioral, emotional and memory.

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