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 with myelinated axons that transmit injury-associated mechanical, rather than thermal (heat) pain sensitivity.
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. 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.
Most recently, we have turned out attention to the possibility of overcoming the neurological consequences of peripheral nerve damage, by transplanting embryonic cortical GABAergic precursor cells into the spinal cord, a procedure that we find can ameliorate the persistent pain associated with nerve damage. Taken together, these studies are revealing an entirely new perspective on the circuits that process the injury messages that generate acute and persistent pain and on novel approaches to therapy.
Joao Braz, Postdoctoral Fellow
Ferda Cevikbas, Postdoctoral Fellow
Todd Dembo, Graduate Student
Alex Etlin, Postdoctoral Fellow
Noemie Frezel, Intern
Zhonghui Guan, Postdoctral Fellow
Dina Juarez-Salinas, Graduate Student
Julia Kuhn, Postdoctoral Fellow
Karuna Meda, Graduate Student
Carlos Solorzano, Postdoctoral Fellow
May Tran, Graduate Student
Smitha Vaman, Research Technician
David Villafuerte, Research Technician
Xidao Wang, Postdoctoral Fellow
Xiaobing Yu, Postdoctoral Fellow
Basbaum, A.I., Clanton, C. and Fields, H.L. 1976 Opiate and stimulus-produced analgesia: Functional anatomy of a medullo-spinal pathway. Proc. Natl. Acad. Sci. (USA) 73:465-468.1.
Glazer, E.J. and Basbaum, A.I. 1980 Leucine-enkephalin: Localization in and axoplasmic transport by sacral parasympathetic preganglionic neurons. Science, 208: 1479-1481.1.
Levine, J.D., Clark, R.E., Helms, C., Moskowitz, M.A. and Basbaum, A.I. 1984 Intraneuronal substance P contributes to the severity of experimental arthritis. Science 226: 547-549.
Malmberg, A.B., Chen, C., Tonegawa, S. and Basbaum, A.I. 1997 Preserved acute pain and reduced neuropathic pain in mice lacking PKCg. Science 278: 279-283.
Liu, H., Mantyh, P.W. and Basbaum, A.I. 1997 NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature (Lond.) 386:721-724.
Cao, Y.Q., Mantyh, P.W., Carlson, E.J., Gillespie, A.-M., Epstein, C.J. and Basbaum, A.I. 1998 Primary afferent tachykinins are required to experience moderate to intense pain. Nature (Lond.), 392: 390-394
Caterina, M.J., Leffler, A., Malmberg, A.B., Martin, W.F., Trafton, J.A., Petersen-Zeitz, K,R., Koltzenburg, M., Basbaum, A.I. and Julius, D. 2000 Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288: 306-313.
Chen, Z.-F., Rebelo, S., White, F., Malmberg, A.B., Baba, H., Lima, D., Woolf, C.F., Basbaum, A.I. and Anderson, D.J. 2001 The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord. Neuron 31: 59-73.
Neumann S., Bradke F., Tessier-Lavigne M. and Basbaum, A.I. 2002 Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34: 885-893.
Braz, J.M., Rico, B. and Basbaum, A.I. 2002 Transneuronal tracing of diverse CNS circuits by Cre-mediated induction of wheat germ agglutinin in transgenic mice. Proc. Natl. Acad. (USA), 99 15148-15153.
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.
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.
Neumann S, Braz JM, Skinner K, Llewellyn-Smith IJ, Basbaum AI. 2008 Innocuous, not noxious, input activates PKCg interneurons of the spinal dorsal horn via myelinated afferent fibers. J Neurosci. 28:7936-7944.
Seal, RP, Wang, X, Guan, Y, Raja, SN, Woodbury, CJ, Basbaum, AI, Edwards, RH. 2009 Low threshold C-mechanoreceptors are required for injury-induced mechanical hypersensitivity. Nature 462: 651-655.
Cavanaugh, DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ. 2009 Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci (USA) 106: 9075-9080.
Scherrer G, Imamachi N, Cao Y-Q, Contet C, Mennicken F, O’Donnell D, Kieffer BL, Basbaum AI. 2009 Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell, 137: 1148-1169.
Scherrer G, Low SA, Wang X, Zhang J, Yamanaka H, Urban R, Solorzano C, Harper B, Hnasko TS, Edwards RH, Basbaum AI. 2010 VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity. Proc Natl Acad Sci (USA) 2010 107:22296-301
Cavanaugh DJ, Chesler AT, Jackson AC, Sigal YM, Yamanaka H, Grant R, O'Donnell D, Nicoll RA, Shah NM, Julius D, Basbaum AI. 2011 Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells. J Neurosci. 31:5067-5077.
Bráz JM, Sharif-Naeini R, Vogt D, Kriegstein A, Alvarez-Buylla A, Rubenstein JL, Basbaum AI. 2012 Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron 74: 663-675.
Wang X, Zhang J, Eberhart D, Urban R, Meda K, Solorzano C, Yamanaka H, Rice D, Basbaum AI. 2013 Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch. Neuron, 78: 312-324.
Allan Basbaum, Ph.D. FRS
UCSF Box 2722
Department of Anatomy
1550 4th Street, RH-348E
San Francisco, CA 94158