Nearly 2 million people in the United States sustain traumatic brain injury(TBI) every year and mild TBI(mTBI) is considered a ?signature injury? of those involved in Iraq and Afghanistan conflicts. Pain after such injury occurs in >50% of the time, worsens clinical course, interferes with community integration, and dramatically increases the costs of treatment. Despite pain being considered an important public health issue, the pathophysiology of pain in mTBI is currently unknown, which limits development of novel and effective treatments. The long-term goal of this research is to determine biological markers for the increased pain vulnerability after traumatic brain injury that can be used to improve chronic pain prevention and treatments in our Veterans. The immediate goals of this revised application are to examine the role of opioidergic transmission and circuitry in the increased pain vulnerability in Veterans who sustained mTBI during combat. Our central hypothesis is that brain Mu (?)-opioid receptor (MOR) availability will show regional variability in Veterans with combat mTBI with and without chronic pain, with most decrease observed in the co-morbid pain and mTBI group. We will use novel hybrid Positron Emission Tomography and Magnetic Resonance Imaging (PET-MRI) platform that provides complementary and simultaneous information about the hemodynamic response and neurotransmitter activation and thus allows direct classification of function of the endogenous pain control in individuals who has pain and mTBI. This work will allow determination of behavioral, microstructural, functional and molecular integrity of the opioidergic circuitry and its relationship to clinical pain behaviors and quality of life. Guided by strong preliminary data the central hypothesis will be tested by pursuing two specific aims: 1) To examine the complementary impact of mTBI and chronic pain on the integrity of pain modulatory systems; 2) To distinguish the complementary impact of mTBI and chronic pain on the capability of pain modulatory systems. This work is significant since it will provide: 1) a mechanism for pain and enhanced pain vulnerability following mTBI; and 2) better imaging tool to detect pain after mTBI. Veterans are often prescribed opioids for pain. These drugs have a high potential for abuse and changes in the endogenous opioid system may contribute to alterations in the rewarding effects of these drugs; thus mTBI individuals may be particularly vulnerable to exogenous opioids. The current proposal fills an important gap in understanding how MOR mediated neurotransmission, the primary target of opioid medications, is affected in pain and mTBI. !
Pain worsens well-being and functioning, interferes with rehabilitative care and community integration, and contributes significantly to poorer health outcomes in Veterans with mild Traumatic Brain Injury (mTBI). The pathophysiology of pain in mTBI is currently unknown and current pharmacological treatments often lead to unwanted and debilitating side-effects. Identifying dysfunctional neurotransmitter systems as a mechanism for predisposing Veterans with mTBI for increased pain will lead to the development of novel, scientifically based, therapeutic approaches for treating co-occurring pain in this treatment resistant population. The proposed research is relevant to Veterans health since it aims to lessen suffering and morbidity associated with pain in Veterans with mTBI and decrease the total cost of treatment for the Veteran population.