Neurovations
Tony_Yaksh

Tony L. Yaksh PhD

Professor, Anesthesiology and Pharmacology, University of California, San Diego

Tony L. Yaksh, PhD's laboratory at Mayo Clinic (1976 to 1988) and at the University of California San Diego (1989-present) has been continuously involved in NIH-supported research on the mechanisms of pain and analgesia. Their work provided the first description of the specific analgesic actions of spinally-delivered drugs such as opiates and alpha 2 agonists and the complexity of spinal agents in specifically altering pain processing (>150 papers). His group has been very active with >850 papers, >46,000 citation in >20,000 papers.

Several specific areas of their current research are noted:

Role of immune signaling. We have an ongoing interest in the role played by inflammatory mediators and innate and adaptive immunity in pain processing. Our group demonstrated that KO of TLR4 signaling and spinal TLR4 blockers prevented the transition from an acute inflammation to a chronic neuropathic-like pain state and the differential role of sex in this cascade. In the course of these ongoing studies, we developed a very strong collaborative interaction with UCSD professor Dr. Yury Mlller. Our collaboration revealed the important modulatory role played by A1 binding protein in regulating TLR4 function and pain processing.

Role of spinal toxins. In our early work, we showed that intrathecal trypV1 agonists resulted in a KO of spinal substance afferents, and this resulted in a persistent analgesia. Some 25 years later, others at NIH fostered the development of intrathecal resniferotoxin for persistent pain management. In subsequent work, we demonstrated in the large animal model, the selective targeting of substance P saporin to the neurokinin 1 receptor and its safety, enabling clinical studies. Recently our work has focused on the peripheral and intrathecal delivery of botulinum toxins. In this work, we showed that botulinum toxin was taken up and transported to the central terminals to block transmitter release and potentially have a postsynaptic action-altering pain behavior in mono- and polyneuropathies and in persistent inflammation.

Pathology of intrathecally delivered drugs. The widespread adoption of the intrathecal route of drug delivery in humans for acute delivery and chronic infusion was largely accomplished in the absence of any systematic assessment of safety. In the early 1990's, the peculiar pathology known as the intrathecal opiate granuloma was noted, and our preclinical work led to the appreciation that this collection of inflammatory cells rose from meninges and resulted from high concentrations of morphine (and other opioids). Our work characterized this effect as being independent of the opiate receptor and potentially mediated through degranulation of meningeal mast cells and activation of fibroblasts. Aside from opiates, our group has been responsible for the development of safety data for the intrathecal delivery of a variety of drugs in adult and neonatal models.
I have a long history of mentoring: over 150 students, doctoral and postdoctoral colleagues have trained in my labs, many of whom have been successful in their subsequent research and clinical careers.


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