Peripheral neuropathy is a major clinical problem that afflicts about 20 million persons in the U.S. alone. Pain is a prominent feature and it is generally stubbornly resistant to treatment. Our preliminary data have shown that transection of the 5th lumbar ventral root (L5 Ventral Rhizotomy) in rat results in pain behavior, altered C-fiber electrophysiology, and changes in C-fiber cell biology. In the L5 Ventral Rhizotomy model of neuropathic pain, C-fiber sensory axons are not directly injured but respond briskly to degeneration of nearby motor axons. The degenerating and uninjured axons co-mingle in peripheral nerve but do not interact directly in the spinal cord, sensory ganglion or skin. Our central hypothesis is: Degenerating axons in the peripheral nerve signal uninjured C-fibers via diffusible factors and that this leads to neuropathic pain.
SPECIFIC AIM 1 is to determine the role of peripheral nerve interactions between uninjured and degenerating axons in neuropathic pain behavior. This will be studied using a newly developed model of neuropathic pain that implants a degenerating nerve segment from an inbred donor over a fenestration in the sciatic nerve of a recipient animal. A complementary approach will be taken by minimizing peripheral nerve interactions using L3 ventral rhizotomy;in general, L3 axons do not enter the sciatic nerve.
SPECIFIC AIM 2 is to examine the response of uninjured C-fibers to degenerating axons in peripheral nerve using these same models. The responses of uninjured C-fibers will be measured as changes in C-fiber conduction velocity properties and increased mitosis of nonmyelinating Schwann cells.
SPECIFIC AIM 3 will assess the role of NGF, as a potential diffusible factor released after nerve injury that is responsible for pain behavior and neuropathic C-fiber change. This will be studied by translating the above methods into mouse species and studying the responses to these same models in a strain of mice that has inducible inhibition of signaling through the TrkA, high-affinity NGF receptor. The long term objectives of this research are to identify therapeutic targets for the treatment of neuropathic pain. This research will be conducted during a period of mentored career development emphasizing advanced skills in pain research and the responsible conduct of science.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS048146-05
Application #
7809509
Study Section
NST-2 Subcommittee (NST)
Program Officer
Porter, Linda L
Project Start
2006-05-16
Project End
2010-10-16
Budget Start
2010-05-01
Budget End
2010-10-16
Support Year
5
Fiscal Year
2010
Total Cost
$88,047
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Murinson, Beth B; Gordin, Vitaly; Flynn, Susie et al. (2013) Recommendations for a new curriculum in pain medicine for medical students: toward a career distinguished by competence and compassion. Pain Med 14:345-50
Murinson, Beth B; Haughey, Norman J; Maragakis, Nicholas J (2012) Selected statins produce rapid spinal motor neuron loss in vitro. BMC Musculoskelet Disord 13:100
Mezei, Lina; Murinson, Beth B; Johns Hopkins Pain Curriculum Development Team (2011) Pain education in North American medical schools. J Pain 12:1199-208
Murinson, Beth B; Nenortas, Elizabeth; Mayer, Roberts Sam et al. (2011) A new program in pain medicine for medical students: integrating core curriculum knowledge with emotional and reflective development. Pain Med 12:186-95
Murinson, Beth B; Klick, Brendan; Haythornthwaite, Jennifer A et al. (2010) Formative experiences of emerging physicians: gauging the impact of events that occur during medical school. Acad Med 85:1331-7
Murinson, Beth B; Yarnitsky, David (2009) Psychophysical studies of imagined stimuli: Testing the limits of self-knowledge. Pain 146:13-4
Williams, Brian A; Murinson, Beth B; Grable, Benjamin R et al. (2009) Future considerations for pharmacologic adjuvants in single-injection peripheral nerve blocks for patients with diabetes mellitus. Reg Anesth Pain Med 34:445-57
Murinson, Beth B; Guarnaccia, Joseph B (2008) Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 71:1955-8
Murinson, Beth B; Maragakis, Nicolas J; Jacobson, Terry A (2008) Fluvastatin, rhabdomyolysis, and myotoxicity. Mayo Clin Proc 83:1296;author reply 1297
Murinson, Beth B; Agarwal, Aakash K; Haythornthwaite, Jennifer A (2008) Cognitive expertise, emotional development, and reflective capacity: clinical skills for improved pain care. J Pain 9:975-83