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Research

Current and Recent Clinical Studies

Vanilloid Receptor 1 (VR1)-Positive Neurons Mediate Neuropathic Pain

Principal Investigators: Gabriel Tender GC, MD and J.G. Cui MD, PhD

New treatment approaches directed at mechanisms of neuropathic pain have led to the description of the vanilloid receptor 1 (VR1), a molecular integrator for pain. Nociceptive (type 2 A-delta-fiber and C-fiber) neurons expressing this receptor mediate hyperalgesia, neurogenic inflammation, and neuropathic pain. Resiniferatoxin (RTX) is a VR1-agonist that induces calcium-mediated cell death within minutes of binding to VR1-expressing neurons. Because VR1 is expressed only by this subset of nociceptive neurons, targeting and RTX-induced ablation of these cells may permit selective elimination of pathologic pain, while preserving tactile sensation (A-beta and type 1 A-delta-fiber neurons) and motor neurons.

Preliminary data of our current research project regarding pain treatment with Resiniferatoxin have shown that VR1-positive neurons are the initiating factor for neuropathic pain, since ablation of these neurons with RTX before the nerve injury does not lead to allodynia nor to hyperalgesia. Moreover, in neuropathic rats, the VR1-positive neurons mediate the most sensitive part of allodynia, as demonstrated by our testing results when RTX was injected after the nerve injury. This research program is sponsored by the 2005 North American Spine Society Annual Grant Award.

The Role of VR1-positive Dorsal Horn Neurons in Central Sensitization: Neuropathic Pain Management

Principal Investigators: Gabriel Tender GC, MD and J.G. Cui MD, PhD

Central sensitization involves enhancement of nociceptive and innocuous transmission and the disruption of the dynamic and delicate balance between excitatory and inhibitory mechanisms in CNS. After nerve injury, glutamate release (the main excitatory neurotransmitter in the dorsal horn), together with bradikinin, substance P and CGRP, is increased in the dorsal horn, while inhibitory neurotransmitters (GABA, adenosine) are decreased . Growth factors and neurotrophins also have important functions in mediating inflammation as well as neuropathic pain. BDNF release from nociceptors enhances NMDA-induced depolarization, while NT3 binds to all the trk receptors (although preferentially to trkC) as well as the p75 receptor, and may have an inhibitory role in central sensitization. The variety of mediators, neurotransmitters, and enzymes involved in neuropathic pain in general, and central sensitization in particular, suggests that blocking only one element may not lead to effective analgesia. In contrast, RTX injection in the sensory ganglia selectively removes a class of neurons involved in nociception and may globally inhibit central sensitization and neuropathic pain, without affecting normal sensory and motor function.

The specific aims of this project are to define the role of VR1-positive neurons, i.e. type 2 A-delta-fiber and C-fiber neurons, in the development of central sensitization following peripheral nerve injury. We expect that selective ablation of VR1-positive neurons by Resiniferatoxin (RTX) in the DRG of neuropathic rats will partially inhibit central sensitization by decreasing the release or expression of excitatory mediators in the dorsal horn (such as glutamate and CGRP), while potentiating the action of protective modulators (NT3, trk, p75). We also expect that selective ablation of VR1-positive neurons in the DRG before nerve injury will prevent the development of central sensitization via up-regulation of NT3, trk and p75. RTX may be used on patients with neuropathic pain if the deeper mechanisms of action for RTX are explored.

Posterior Lumbar Interbody Fusion in Long Segment Pedicle Screw Fixation. A Biomechanical Study

Principal Investigators: Gabriel Tender MD and Rand Voorhies MD

Long segment lumbar fusions (more than three levels) usually include the sacrum, since “floating” fusions have a high incidence of lumbosacral failure. Pedicle screw and rod fixation supplementing posterolateral fusion in these long constructs involves only the posterior column (in the three column model of Dennis) and may provide insufficient immobilization, thus leading to a lack of fusion. The addition of interbody fusion includes the anterior and middle columns and enhances the biomechanical stability of these constructs, but adds to the complexity of the case and encumbers additional surgical risks. The need for additional anterior support appears to be the greatest at the lower levels, which act as a fulcrum between a long rigid construct above and the sacrum below. The risk of additional levels of interbody fusion has to be outweighed by the advantage of biomechanical stability. Therefore, the addition of interbody fusion at L5-S1, L4-L5, and/or L3-L4 may be justified in patients requiring long segment lumbosacral fixation.

Our current research project investigates spine mobility in long segment (T11-S1) pedicle screw fixation alone compared to pedicle screw fixation supplemented by interbody fusion at L5-S1, L4-L5, and/or L3-L4.

Genetic Regulatory Mechanisms in Growth and Invasiveness of Glioblastoma Multiforme (GBM)

Principal investigators: Walter J. Lukiw, MS, PhD and Frank Culicchia, MD

This study examines basic gene expression and regulatory mechanisms in glioblastoma multiforme (GBM), samples of which will be obtained from approximately 25 surgical specimens. Global gene expression profiles employing DNA arrays will be obtained that quantify the expression level for every single human gene (N=33,000) using HG-U133 plus 2.0 GeneChips and the Affymetrix analytical system. Altered gene expression levels will be independently verified using Northern blot analysis, RT-PCR analysis and/or Western immunoassay, and GBM morphometry will be analyzed using phase contrast microscopy and neuronal/glial specific staining. The promoters of up regulated genes will be further analyzed for transcription-factor DNA binding sites and promoter maps for mis-regulated gene families will be created. This integrated genomic-proteomic-morphometric approach will further understanding of the basic molecular mechanisms involved in GBM, and will lead to the discovery of novel therapeutic strategies and targets in the clinical treatment of GBM.

Study of Bioactive Endovascular Coils in an Animal Model

Principal Investigator: Robert Dawson MD

Aneurysm coils coated with two formulations of a non-collagen polymer have been implanted in an animal model against standard aneurysm coils with the same animal controls. Survival harvests were obtained at intervals to six months. Histopathology has been obtained and angiographic studies were done prior to sacrifice. Data are being evaluated by independent observers.

The Use of H-Reflexes to Monitor Spinal Cord Function During Surgery

Principal Investigator: Dr. Happel

Monitoring Recurrent Laryngeal Nerve Function During Surgery

Principal Investigator: Dr. Happel