• Ashley J Wiese, Michael Rathbun, Mark T Butt, Shelle A Malkmus, Philip J Richter, Kent G Osborn, Qinghao Xu, Samantha L Veesart, Joanne J Steinauer, Denise Higgins, Douglas A Lappi, Brian Russell, and Tony L Yaksh.
• * Research Fellow, † Staff Research Associate, # Postdoctoral Fellow, §§ Professor of Anesthesiology and Pharmacology, Department of Anesthesiology, University of California, San Diego, California. ‡ President, Tox Path Specialists, LLC, Frederick, Maryland. § Director, Campus Veterinary Medicine, ‖ Associate Director, Diagnostic Laboratory, Office of Animal Research, University of California. ** Vice President, †† President/CSO, ‡‡ Research Scientist, Advanced Targeting Systems, San Diego, California.
• Anesthesiology. 2013 Nov 1; 119 (5): 1163-77.

BackgroundNeurokinin-1 receptors (NK1-rs) located on superficial dorsal horn neurons are essential for integration of nociceptive input. Intrathecal injection of substance P-saporin (SP-SAP) leads to local loss of spinal NK1-r (+) neurons suggesting its potential as a therapeutic agent for chronic pain. The authors determined, in a canine model, effects of lumbar intrathecal SP-SAP.MethodsDistribution of SP-SAP and Saporin was determined in plasma, lumbar cerebrospinal fluid, and tissue. Safety of intrathecal SP-SAP was determined in four groups (six dogs each) administered 0 (0.9% saline), 1.5, 15, or 150 µg SP-SAP through lumbar intrathecal catheters. Behavioral, physiologic, and biochemical variables were assessed. Spinal tissues were collected at 7 and approximately 90 days, or earlier if significant morbidity developed, and analyzed for NK1-r (+) neuron loss and histopathology.ResultsSP-SAP and Saporin were detectable in lumbar cerebrospinal fluid for up to 4 and 24 h, respectively. Animals receiving intrathecal saline, 1.5, or 15 µg of SP-SAP showed no persistent neurologic deficits. Three animals receiving 150 µg of SP-SAP developed pelvic limb paraparesis and were euthanized prematurely. Immunohistochemistry and in situ hybridization cell counts confirmed a significant reduction in NK1-r (+) in superficial dorsal horn neurons from lumbar spinal cord after intrathecal administration of 15 and 150 µg of SP-SAP. A significant loss of NK1-r neurons in the lumbar ventral horn occurred only with 150-µg SP-SAP.ConclusionIntrathecal 15-µg SP-SAP reduced dorsal, but not ventral, NK1-r (+) neurons at the spinal level of delivery with minimal side effects, whereas 150-µg SP-SAP resulted in motor neuron toxicity.

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