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Principal Investigator: Mohab M Ibrahim
Organization: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
Mild traumatic brain injury (mTBI) is the most common traumatic brain injury affecting military personnel. mTBI
is associated with several neurological symptoms that correlate with neuroinflammation. One of the neurological
symptoms associated with mTBI is pain. mTBI-induced pain may be challenging to manage in some cases.
Therefore, opioids may be used to control such pain. However, opioids have significant side effects, especially
when used chronically, which may lead to substance misuse. The opioid crisis has demonstrated the need for
complementary methods for pain control. Because of the association between mTBI and substance misuse,
there is a significant need for alternative/complementary approaches to opioids to treat pain, especially in treating
the pain associated with mTBI.
mTBI induces inflammation as manifested by increased inflammatory cytokines such as IL-6 and TNF-α in the
central nervous system (CNS) and plasma. Two sources for these cytokines are microglia and astrocytes, both
of which become activated after mTBI, contributing to the development of pain. Decreasing the levels of pro-
inflammatory cytokines and increasing the levels of anti-inflammatory cytokines may promote decreased mTBI-
induced pain. A therapy that reduces microglia and astrocytes' activation and decreases the neuroinflammatory
environment would be ideal for both military personnel and veterans.
Phototherapy is used for multiple medical conditions, but few studies investigated the effects of phototherapy on
pain. We have shown that green light exposure (GLED) was antinociceptive by reversing thermal and mechanical
hypersensitivity in rats. In humans, we have demonstrated that GLED decreased chronic pain and sleep
disturbances in fibromyalgia and migraine, suggesting that GLED therapy applies to humans despite differences
in the visual systems between rodents and humans. Furthermore, we have shown that GLED reversed the
hypersensitivity associated with mTBI in two different TBI mice models. We also demonstrated that GLED
reversed postsurgical thermal and mechanical hypersensitivity by increasing anti-inflammatory IL-10 levels in
the cerebrospinal fluid (CSF) while decreasing pro-inflammatory IL-6. GLED reversal of thermal and mechanical
hypersensitivities was attenuated when the periaqueductal gray (PAG), a crucial pain-modulating center, was
blocked, suggesting that GLED may be inhibiting the descending pain-facilitatory pathway.
Therefore, it is reasonable to postulate our hypothesis that GLED visual exposure will attenuate mTBI-
induced hypersensitivity by inhibiting the descending pain-facilitatory pathway.
We will use three specific aims (SA) to investigate our hypothesis. SA1 will explore the potential translation of
GLED therapy by exploring its ability to reverse the mTBI-induced thermal and mechanical hypersensitivities in
multiple rodent sexes and species. SA2 will evaluate the effects of GLED on modulating glial cells and the effects
on neuroinflammation while assessing the contribution of microglia and astrocytes to the development of mTBI-
induced hypersensitivities. SA3 will elucidate how GLED interacts with the descending pain-facilitatory pathway
Short-term benefits of completing our proposed studies include elucidating the neuronal circuitry mediating the
effects of GLED and characterizing the effects of GLED on the PAG, which may bring GLED therapy a step
closer to clinical implementation. The long-term benefits include the innovative development of a regenerative
medicine approach using the minimally invasive and affordable GLED therapy for mTBI and other conditions that
involve CNS inflammation and decreasing the need for opioids.
Terms: <(TNF)-α><Actinotherapy><Acute Pain><Address><Affect><Afghanistan><Age><Allergy><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Armed Forces Personnel><Astrocytes><Astrocytus><Astroglia><Attenuated><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Behavior><Blood Plasma><Brain><Brain Nervous System><Brain Trauma><CNS Nervous System><CSIF><CSIF-10><Cachectin><Cause of Death><Cell Body><Cells><Central Nervous System><Cephalalgia><Cephalgia><Cephalodynia><Cerebrospinal Fluid><Chronic><Clinical Trials><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Common Rat Strains><Coupled><Cranial Pain><Cytokine Synthesis Inhibitory Factor><Development><Diffuse><Diffuse Myofascial Pain Syndrome><Disturbance in cognition><Drops><Drugs><Encephalon><Environment><Exposure to><Female><Fibromyalgia><Fibromyositis-Fibromyalgia Syndrome><Fibrositis><Freedom><Glia><Glial Cells><HPGF><Head Pain><Headache><Hepatocyte-Stimulating Factor><Hortega cell><Human><Human Resources><Hybridoma Growth Factor><Hypersensitivity><IFN-beta 2><IFNB2><IL-10><IL-6><IL10><IL10A><IL6 Protein><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impaired cognition><Individual><Inflammation><Inflammatory><Infumorph><Interleukin 10 Precursor><Interleukin-10><Interleukin-6><Iraq><Kadian><Knowledge><Kolliker's reticulum><Lateral><Lateral Geniculate Body><Liberty><Lidocaine><Light><Light Therapy><Lignocaine><MGI-2><MPD syndrome><MS Contin><MSir><MTBI><Macrophage-Derived TNF><Manpower><Mechanics><Mediating><Medical><Medication><Medulla Spinalis><Mesencephalic Central Gray><Methods><Mice><Mice Mammals><Microglia><Midbrain Central Gray><Migraine><Migraine Headache><Military><Military Personnel><Modeling><Modern Man><Monocyte-Derived TNF><Morphia><Morphine><Murine><Mus><Muscular Rheumatism><Myeloid Differentiation-Inducing Protein><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and Symptoms><Neurons><Non-neuronal cell><Nonneuronal cell><North America><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Oramorph><Oramorph SR><Pain><Pain Centers><Pain Clinics><Pain Control><Pain Relief Units><Pain Therapy><Pain management><Painful><Pathway interactions><Patients><Periaqueductal Gray><Pharmaceutical Preparations><Photic Stimulation><Photoradiation><Photoradiation Therapy><Phototherapy><Plasma><Plasma Serum><Plasmacytoma Growth Factor><Rat><Rats Mammals><Rattus><Recommendation><Recovery><Regenerative Medicine><Reporting><Reticuloendothelial System, Serum, Plasma><Retina><Risk><Rodent><Rodentia><Rodents Mammals><Role><Roxanol><Sedation procedure><Sleep disturbances><Source><Spinal Cord><Statex SR><Symptoms><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Traumatic Brain Injury><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Veterans><Visual><Visual Stimulation><Visual System><Weight><aberrant sleep><active duty><active service><ages><annulus of the aqueduct><antinociception><antinociceptive><associated symptom><astrocytic glia><attenuate><attenuates><cerebral spinal fluid><chronic pain><chronic pain condition><chronic pain disorder><chronic painful condition><clinical implementation><clinical translation><clinically translatable><co-morbid><co-morbid symptom><co-morbidity><co-occuring symptom><cognitive dysfunction><cognitive loss><comorbid symptom><comorbidity><concurrent symptom><cooccuring symptom><cytokine><developmental><disrupted sleep><disturbed sleep><drug/agent><experiment><experimental research><experimental study><experiments><fibromyalgia syndrome><gitter cell><head ache><high risk><impaired sleep><improved><innovate><innovation><innovative><interferon beta 2><irregular sleep><lateral geniculate><lateral geniculate nucleus><light intervention><light treatment><male><mechanic><mechanical><mesoglia><microglial cell><microgliocyte><midbrain central gray substance><mild TBI><mild brain trauma><mild traumatic brain injury><military population><military veteran><minimally invasive><mouse model><murine model><myofascial pain dysfunction syndrome><nerve cement><neural inflammation><neural manifestation><neuroinflammation><neuroinflammatory><neuronal><neuronal circuit><neuronal circuitry><operation><operations><opiate consumption><opiate crisis><opiate drug use><opiate intake><opiate use><opioid addiction><opioid consumption><opioid crisis><opioid dependence><opioid dependent><opioid drug use><opioid epidemic><opioid intake><opioid use><pain treatment><pathway><periaqueductal gray matter><perivascular glial cell><personnel><regenerative><response><sedation><sex><side effect><sleep disruption><sleep dysregulation><social role><spinal fluid><substance misuse><symptom association><symptom comorbidity><translational opportunities><translational potential><traumatic brain damage><veteran population><weights>