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Neuroscience Graduate Program at UCSF
The Neurobiological Basis of Pain and its Control
Although there is considerable information about the mechanisms through which injury produces acute pain, much less is known about the long-term consequences of persistent injury. Pain is exacerbated, in part, because of a reorganization of spinal cord circuitry in the setting of persistent injury. Our laboratory uses neuroanatomical (light and electron microscopic immunocytochemistry), molecular and neuropharmacological/ behavioral approaches to study the mechanisms through which these long-term changes are produced. One focus is the contribution of the primary afferent neurotransmitters, glutamate and substance P to these changes. Using immunocytochemistry, we can monitor internalization of neurotransmitter receptors as markers of activity of populations of "pain" responsive neurons. Using this approach we have determined the types of inputs that evoke the release of substance P and activate dorsal horn "pain" transmission neurons. A major goal is to determine the extent to which these changes occur when the injury persists, as it does in clinical pain conditions. Most recently we found that the magnitude and distribution of neurons that respond to substanceP (as indicated by receptor internalization) increase significantly in the setting of persistent inflammation.
We have also introduced molecular approaches to study the contribution of substance P to pain transmission. To this end, we have generated and are studying mice with a deletion of the gene that encodes substance P. Because the induction of long-term changes in pain processing involves activation of a variety of second messenger systems in dorsal horn neurons, we are also studying the consequences of their deletion. For example, we demonstrated that mice with a deletion of the gamma isoform of protein kinase C have a very discrete loss of peripheral nerve injury-induced persistent pain (so-called neuropathic pain). By contrast, acute pain responsiveness is intact in these mice, indicating that the processing of acute and persistent pain messages can be differentially regulated. In related studies in collaboration with the laboratory of David Julius we have studied mice with a deletion of the gene that encodes the vanniloid receptor (VR1), which is targeted by capsaicin, the active ingredient in hot peppers. Our results not only established that VR1 contributes to the heat pain sensitivity, but that injury-induced exacerbation of heat sensitivity is lost in the mutant mice.
To address the regulation of pain, we also study the mechanisms through which pain-relieving drugs, notably opioids, exert their effect. The latter studies continue our long-standing interest in the organization of pain control networks in the brainstem and spinal cord. In one series of studies we monitor expression of the Fos protein to follow the activity of neurons that are driven by noxious stimuli; the patterns of inhibition of Fos expression by opioids that act at different receptor subtypes can then be determined. We are also interested in the changes that occur in the CNS when tolerance to opioids develops. Evidence is accumulating that tolerance develops because of compensatory responses in CNS circuits and we have identified the spinal cord as a locus for these responses. Interestingly, features of the compensatory response are remarkably similar to the long-term changes that are produced by persistent injury. For example, antagonists of the NMDA receptor not only counteract exacerbated pain conditions, but also the development of tolerance and dependence. This observation is critical to developing approaches to overcome what appear to be largely deleterious consequences of persistent injury, so that better control of clinical pain conditions can be obtained. That is the long-term goal of the research in our laboratory.
We have recently identified a structurally related, vanilloid receptor-like channel (VRL-1) that does not respond to capsaicin, acid, or moderate noxious heat. Instead, VRL-1 is activated by relatively high temperatures, with a threshold of ~ 52¡C. Indeed, pain-producing heat is detected by several classes of nociceptive sensory neurons that differ in their thermal response thresholds. Within sensory ganglia we find that VR1 is expressed by a subset of small- to medium-diameter neurons, whereas VRL-1 is most prominently expressed by medium- to large-diameter neurons. Thus VR1 and VRL-1 are candidate receptors for transducing moderate and high-threshold noxious heat responses in these classes of nociceptors, respectively. Responses to noxious heat may therefore involve related, but distinct ion channel subtypes that together detect a range of stimulus intensities. We are testing this hypothesis and examining roles for VR1 and VRL-1 in vivo using genetic approaches.
My group also has a long-standing interest in the structure, function, and expression of mammalian serotonin and purinergic receptors. We are continuing to investigate ligand-receptor interactions and physiological roles for 5-HT and ATP receptors using biochemical and genetic methods.
Andrew Ahn
Postdoctoral Fellow
M.D., Ph.D. Harvard Medical School
Identification of migrane-relevant genes
Joao Braz
Postdoctoral Fellow
Ph.D., University of Paris
Tracing of "pain" pathways in the CNS using virus
Javier Mazario
Postdoctoral Fellow
Ph.D. University de Alcala, Spain
Mechanisms of injury-induced persistent pain
Simona Neumann
Postdoctoral Fellow
Ph.D., University College London
Recovery of function after spinal cord injury
Kate Skinner
Assistant Research Anatomist
Ph.D. UC Davis
M.D. Medical College of Pennsylvania
Dorsal horn synaptic circuitry
Robin LeWinter
Graduate student
Mechanisms of tolerance development of opiods
Shannon Shields
Graduate student
Identification of novel genes involved in primary afferent pain processing
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.
Trafton, J.A, Abbadie, C., Marchand, S., Mantyh, P.W. and Basbaum, A.I. 1999 Spinal opioid analgesia: how critical is the regulation of substance P signaling? J. Neurosci. 19: 9642-9653.
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.
Mogil J.S., Yu L., Basbaum A.I. 2000 Pain Genes?: natural variation and transgenic mutants. Annu. Rev. Neuroscience 23:777-811.
Julius, D. and Basbaum, A.I. 2001 Molecular mechanisms of nociception. Nature (Lond.) 413: 203-210.
Zeitz, K.P., Guy, N., Malmberg, A.B., Dirailal, S., Martin, W.J., Sun, L., Bonhaus, D.W., Stucky, C.L., Julius, D. and Basbaum, A.I. 2002 The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J. Neurosci. 22: 1010-1019.
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.
Mitrovic, I., Margeta-Mitrovic, M., Bader, S., Stoffel, M., Jan, L.Y. and Basbaum, A.I. 2003 Contribution of GIRK2-mediated postsynaptic signaling to opiate and {alpha}2-adrenergic analgesia and analgesic sex differences. Proc. Natl. Acad. Sci. (USA) 100: 271-276.
Allan Basbaum, Ph.D.
415-476-5270
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Mission Bay
Rock Hall
RH348E
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UCSF
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