Rachel Tobias Young Investigator Award for 2006-2007

The first Young Investigator Award has been given to Drs. Lee and Oaklander at Harvard University. They will study contralesional mirror-pain and nerve damage and the investigation of mechanisms in the distal nerve injury (DNI) rat model of CRPS.

Abstract

One of the major unexplained features of CRPS is the spread of pain and other symptoms to the opposite uninjured limb (the contralesional limb) at the location that mirrors the pain in the injured limb (the ipsilesional limb). There are no known nerve-cell connections or mechanisms that explain how an injury to one's left ankle could cause right as well as left foot pain. Explaining this would improve care for patients with mirror symptoms, lessen general suspicion about CRPS, and advance understanding of how the nervous system works. Oaklander and Lee's group has been interested in mirror-pain and nerve damage since it discovered contralesional nerve damage in patients who developed postherpetic neuralgia after shingles. Because this might have been caused by direct spread of the shingles virus, they turned instead to CRPS patients and animals with one-leg nerve injuries to study this further.

The proposed experiments use the DNI rat model of CRPS. Distal nerve injuries model CRPS by causing abnormal hindpaw pain-behavior, posture, autonomic function, and bone loss in some rats. Under anesthesia, rats have their lift tibial nerve partially or totally cut, and the effects on sensory, motor, and autonomic function in both hindpaws are carefully measured. Some rats appear unaffected, just the way that not all humans develop CRPS after injuries, but many rats develop pain behavior (such as exaggerated hindpaw withdrawal from touch, pin, or cold) in their left hindpaw, inside and outside the area innervated by the damaged tibial nerve. In some DNI rats, the right hindpaw also develops pain behaviors, and all DNI rats appear to lose some of the PGP-labeled nerve endings it heir right hindpaw skin. DNI does not interfere with weight gain, walking, exploration, and feeding behaviors, so these effects do not seem to be caused by altered use patterns. Our objective is to find out the real reason that signals can spread from an injured CRPS limb to the opposite uninjured limb.

To do so, they will first measure pain behavior and numbers of nerve cells in the uninjured leg contralesional to tibial nerve DNI. They will study the nerve endings in the skin, the nerves within the leg, and nerve cell bodies in the dorsal root ganglia (DRG). Myelinated fibers in the nerve and DRG neural cells will be quantitated by light microscopy, and pain-sensitive unmyelinated fibers by electron microscopy (EM). Our preliminary data suggest that there may be decreased numbers of unmyelinated axons in contralesional nerves from DNI rats that develop mirror pain. They will immunohistochemically label various spinal-cord cells (incoming axons, inhibitory interneurons, astrocytes) to measure if there are changes in cells numbers in the contralesional spinal cord dorsal horn. StereoInvestigator software will be used for cellular quantification.

Then they will investigate which spinal cord pathways are involved in cross over of these injury signals by cutting specific spinal cord pathways (hemisection, thoracic myelotomy, quadrantectomy) and determining if this blocks signal cross-over from the injured to the uninjured side.

Animal models of CRPS demonstrate the legitimacy of this syndrome, and using them to unravel the mysteries of mirror-pain and nerve damage in CRPS may help us learn how to stop pain from spreading after focal injuries.

April 23, 2007