Tony Yaksh

Affiliation: UCSD SOM

Professor of Anesthesiology and Pharmacology

Biography

Dr. Yaksh obtained his Ph.D. degree from Purdue University (1971) and served in the U.S. Army, working in the Biomedical Laboratory at Edgewood Arsenal, MD (1971-73). He was a research scientist in the School of Pharmacy, University of Wisconsin (1973-76) and an Associate Research Scientist in the Anatomy Department at University College London (1976-77). He was at the Mayo Clinic, Rochester, MN, from 1977 to 1988, reaching the rank of Professor in Pharmacology and Neurosurgery. Dr. Yaksh joined UCSD in 1988 as Professor and Vice Chairman for Research in the Department of Anesthesiology and Professor of Pharmacology. s. He has been funded consistently by the NIH since 1977 and has been a mentor to more than 100 post-graduate Fellow. He has received several awards, including the FWL Kerr award of the American Pain Society, Peter W. Lampert Memorial Lecturer, Academy of Pain Medicine, Award for Outstanding Contributions to Pain Medicine, and the American Society of Anesthesiology (ASA) Annual Award for Excellence in Research.

Research Summary

The goal of my work is to understand the encoding process for nociceptive information to permit development of pharmacological therapies for the management of pain. My current work follows along 3 lines.

Pharmacology of afferent & spinal systems which process nociceptive information

Using well defined behavioral models of nociception, in conjunction with specific techniques to deliver drugs to the spinal cord and perfuse the spinal space, we have focused on several spinal biochemical cascades and their importance to nociceptive processing. Thus, following tissue and nerve injury there is a persistent activation of afferent fibers and a facilitated state of processing (hyperalgesia). We have shown that these facilitated states reflect complex cascades in which substance P (NK1) and glutamate (NMDA) receptors activate a variety of downstream MAPKs which though PLA2 and COX isozymes initiate spinal synthesis and release of a variety of lipidic acid products, including prostanoids. Importantly, these studies have emphasized the significance of non neuronal components (e.g. microglia) in this organization.

Thus, as shown in the figure, there is a low level of activated (phosphorylated) p38 MAPK in rat spinal dorsal horn following lumbar intrathecal injection of physiological saline (A). Intrathecal injection of substance P through a Neurokinin 1 receptor activates p38 MAPK in the spinal dorsal horn (B). The phosphorylated p38 MAPK colocalize with microglia (D) but not with neurons(C). The potent anti-hyperalgesic action of spinal P38 MAPK emphasizes not only the importance of p38 MAPK, but the role of the associated microglia in pain processing. Color key. (A-D) Green: p-P38 MAPK; (C-D) Blue: DAPI-Nuclear; (C) Red: NeurN-neuronal; (D): Red: OX42-microglia. (Svensson, et al 2003)

Mechanisms of cancer pain and the pharmacology of its management

We consider cancer pain to be a major concern. We employ animal models using chronic delivery of anti-metastatic agents and models of osteosarcoma which initiate defined pain states. We have focused our interest on the intervening variables by which cytokines and chemotherapeutic agents induce activation of afferents and alter central processing.

Spinal drug delivery: Kinetics and Safety

Spinal systems are the site of action of much pain pathophysiology. Accordingly, the spinal delivery of analgesics is an appropriate route of drug delivery in certain pain states. To move novel agents for spinal use into humans requires development of appropriate kinetic/ safety data. We have an active preclinical kinetic and toxicology program that permits pivotal GLP-qualified studies for targeted agents in large animals. The preclinical work outlined above has directly led to approval by the US Food and Drug Administration .to deliver a number of agents spinally in humans for pain control, including sufentanil, baclofen, clonidine, neostigmine, adenosine and ziconotide, an N type Calcium channel blocker.

Further discussion of our efforts can be found at our laboratory website: http://yakshlab.ucsd.edu/.

References

References From PubMed (NCBI)