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
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