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Neuroscience Graduate Program at UCSF
The Neurobiological Basis of Pain and its Control
The development of persistent pain following tissue or nerve injury results to a great extent from profound reorganization of CNS circuits. These changes contribute to a central sensitization/hyperexcitability state that underlies allodynia and hyperalgesia, the hallmarks of persistent pain. Many studies have focused on the injury-induced sprouting of primary afferents and on the physiological properties of altered “pain” transmission neurons in the spinal cord dorsal horn, but there is little information about the tissue and nerve-injury-induced local and long distant circuit changes that occur, in the spinal cord and at more rostral sites. Our laboratory takes a multidisciplinary approach to the problem, using molecular, pharmacological and behavioral analyses. Recently, we developed a transgenic mouse in which wheat germ agglutinin transneuronal labeling of complex circuits can be triggered from neurons in any region of the brain or spinal cord, during development or in the adult. We are using these mice to study the development and adult organization of CNS circuits engaged by small diameter primary afferent nociceptors (“pain fibers”) and to study their modifications after tissue or nerve injury. Through a highly novel modification of this transneuronal tracing method, in which the tracer is induced in primary afferent neurons only if their peripheral axon has been transected, we are now also able to study nerve injury-induced reorganization of CNS circuits. Paralleling these studies, we have generated a variety of reporter mice to localize the channels, receptors and transducers through which painful stimuli activate and modulate the nociceptors. Of particular interest are our recent studies demonstrating that the delta opioid receptor is largely associated with sensory neurons that generate mechanical, rather than thermal (heat) pain sensitivity.
Finally, as our objective is to understand the functional significance of the neurochemically distinct nociceptors, our behavioral studies address the consequence of deleting single genes that are enriched in the primary afferent nociceptor, or of deleting populations of nociceptors. Many of these studies are performed in collaboration with other faculty at UCSF, notably David Julius and Robert Edwards. Among the genes that we have studied are the V1, A1 and M8 members of the TRP channel family as well as different glutamate transporters. Taken together, these studies are revealing an entirely new perspective on the circuits that process the injury messages that generate acute and persistent pain.
Larry Ackerman
Andrew Ahn
Joao Braz
Dan Cavanaugh
Jennifer Gibbs
Simona Neumann
Gregory Scherrer
Rochelle Urban
Xidao Wang
Braz, J.M., Nassar, M.A., Wood, J.N. and Basbaum, A.I. 2005 Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor. Neuron 47: 797-93.
Neumann S., Skinner K., Basbaum A.I. 2005 Sustaining intrinsic growth capacity of adult neurons promotes spinal cord regeneration. Proc. Natl. Acad. Sci. (USA) 102:16848-16852.
Ahn, A.H. and Basbaum, A.I. 2006 Tissue injury regulates serotonin 1D receptor expression: implications for the control of migraine and inflammatory pain. J Neurosci. 226: 8332-8338.
Bautista, D.M., Jordt, S.E., Nikai, T., Tsuruda, P.R., Read, A.J., Poblete, J., Yamoah, E.H., Basbaum, A.I. and Julius, D. 2006 TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124: 1269-1282.
Mazario, J. and Basbaum, A.I. 2007 Contribution of substance P and neurokinin A to the differential injury-induced thermal and mechanical responsiveness of laminae I and V neurons. J Neurosci. 27: 762-770.
Basbaum, A.I. and Julius, D. 2006 Toward better pain control. Scientific Amer., 294: 60-67.
Bushnell, M.C. and Basbaum, A.I. 2008 (Eds.) The Senses: A Comprehensive Reference: Pain (Vol. 5), Elsevier, Amsterdam, pp 1024.
Allan Basbaum, Ph.D. FRS
415-476-5270
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