NNS 2015 Abstract Book

pathogenesis of bTBI has not been explored. We have reported earlier

that blast exposure causes significant decrease in the levels of the

neurotransmitter and tryptophan metabolite serotonin, which has been

implicated in affective disorders such as depression and anxiety. Our

preliminary studies using rat and mouse models of single and repeated

bTBI utilizing a compressed air-driven shock tube revealed up-regu-

lation of indoleamine 2,3-dioxygenase (IDO1), in different regions of

the brain which increased with repeated blast exposures. This up-

regulation of IDO1 after blast exposure, which may be an endogenous

immunosuppressive protective mechanism mediated through the ky-

nurenine pathway, could account for decreased levels of serotonin.

Blast exposure also acutely increased expression of IDO1 in the

spleen and the expression was further elevated with repeated blast

exposures, which by depleting circulating tryptophan can decrease

synthesis of serotonin. These results reveal that systemic and central

tryptophan metabolism are disrupted following blast exposure which

might play a significant role in the pathogenesis of neurobehavioral

deficits associated with bTBI.

Keywords: Traumatic brain injury, Blast exposure, Tryptophan,

Serotonin, Indoleamine 2,3-dioxygenase

C5 Poster Session V - Group C: Pain

C5-01

MORPHINE TREATMENT AFTER TBI EXACERBATES

COGNITIVE IMPAIRMENTS AND REDUCES NEURONAL

SURVIVAL IN A RAT MODEL

Jennifer Jernberg

1,3,4

, James Zadina

1–3

Tulane University, Neuroscience, New Orleans, USA

Tulane University School of Medicine, Medicine and Pharmacology,

New Orleans, USA

SE LA Veterans Healthcare System, Research Service, New Orleans,

USA

Johns Hopkins School of Medicine, Anesthesiology and Critical Care

Medicine, Baltimore, USA

The most commonly used treatment for pain after Traumatic Brain

injury (TBI) is morphine (Bratton el al., J. Neurotrauma 24:S1 pS71,

2007). This treatment meets a critical need for alleviating the severe

pain typically accompanying TBI. However, morphine has several

well-known adverse effects including some particularly relevant to

TBI. In the short-term, respiratory depression can cause increased

and intracranial pressure. In the long term, a lesser known side

effect, a proinflammatory response (Hutchinson et al., Pharmacol Rev

63:772, 2011) could exacerbate long-term secondary neuropatholog-

ical sequelae of TBI (Bachstetter et al., J Neurosci

: 6143, 2013).

Here we tested the effects of 3-day infusion of morphine beginning

24 hr

after

fluid percussion TBI on subsequent cognitive and neuronal

changes. The post-TBI treatment paradigm was chosen over typical

pre- or concurrent treatment paradigms for clinical relevance. Mor-

phine exacerbated TBI-induced impairment of spatial memory ac-

quisition during a standard 5-day Morris Water Maze (MWM)

training test. In 1-day and multiday reversal tests, TBI

morphine

impaired learning of a new position of the escape platform. Following

the behavioral tests, immunohistochemical analyses were conducted

and showed that TBI

morphine decreased NeuN-labeled neurons in

the molecular layer of the dentate gyrus of the hippocampus and in the

reticular nucleus of thalamus. Changes in both of these areas are

considered major contributors to the pathophysiological effects of

TBI. The results indicate an unmet need for novel treatments for TBI

pain with the effectiveness of morphine but without the associated

respiratory and pro-inflammatory effects that can exacerbate subse-

quent cognitive and neuronal pathologies.

Supported by the VA and DOD

Keywords: Spatial Memory, Morphine

C5-02

TRAUMATIC BRAIN INJURY IN MICE INDUCES CHRONIC

HYPERESTHESIA

Junfang Wu

, Zaorui Zhao, Xiya Zhu, Nicole Ward, Shuxin Zhao,

Alan Faden

University of Maryland, School of Medicine, Anesthesiology, Balti-

more, USA

Clinical studies indicate that traumatic brain injury (TBI) patients fre-

quently experience chronic post-traumatic pain, particularly vascular-

type headache. Although headache descriptions predominate, patients

may also experience allodynia, hyperesthesia, or spontaneous pain.

Periorbital and extra-cephalic (paw) mechanical allodynia have been

reported in rodent models of TBI, which may persist for weeks after

injury. However, there has been little research devoted to under-

standing the pathobiology to such hyperesthesia. The present study

characterized post-TBI sensory changes in mice with mild, moderate

or severe controlled cortical impact injury (CCI) by testing mechan-

ical/thermal allodynia, as well as presence of spontaneously face pain.

C57BL/6 male mice were subjected to mild, moderate, or severe CCI

and mechanical/thermal allodynia as well as mouse grimace scale

(MGS) test, a measure of spontaneous pain, were evaluated before

and after TBI. The von Frey hair force was significantly decreased on

the left hindpaw of mice subjected to moderate or severe TBI when

compared to sham operated mice. On the right hindpaw, a significant

decreased force was observed in the mice with moderate TBI. The

threshold for hot plate temperature was decreased in a severity-de-

pendent manner. The threshold for cold plate was significantly in-

creased in the mice subjected to all grades of TBI severity at early

time points (week 1 and 2) but returned to baseline level at 4 weeks

post-injury. MGS based on ear position, orbital tightening, and nose

bulge was transiently increased at post- TBI day 1 for all groups.

Sham and mild TBI group returns to the baseline level at week 1.

However, moderate and severe TBI mice showed extended increases

of MGS. The present study characterizes the time course of hyper-

esthesia after TBI of varying severity. These observations indicate that

more generalized hyperesthesia and pain, as well as vascular-like

headaches, may occur after TBI, and may serve as a model to char-

acterize the pathobiology and potential therapies for such pain.

Keywords: traumatic brain injury, hyperesthesia, mechanical/ther-

mal stimulation, the mouse grimace scale, pain

C5-03

CELL CYCLE ACTIVATION CONTRIBUTES TO DEVELOP-

MENT AND MAINTENANCE OF NEUROPATHIC PAIN

FOLLOWING SPINAL CORD INJURY

Junfang Wu

, Zaorui Zhao, Shuxin Zhao, Nicole Ward, Xiya Zhu,

Alan Faden

University of Maryland, School of Medicine, Anesthesiology, Balti-

more, USA

In addition to causing sensorimotor deficits, spinal cord injury (SCI)

also results in posttraumatic neuropathic pain in a majority of patients.

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