A nonpharmacological therapeutic intervention of TBI-induced facial allodynia/hyperalgesias in a rodent model

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The lack of understanding of the fundamental neurobiology that underlies the development and persistence of post-traumatic brain injury (TBI)-induced acute and chronic pain is currently unknown, further limiting our ability to develop appropriate treatments. Electro-acupuncture (EA) is a healing modality that has been in use for years. It's modes of action, however, are largely unknown, although there is increasing evidence that brain and spinal cord are primarily involved in the processing of acupuncture stimuli. The analgesic effects of acupuncture are well documented. In addition, acupuncture's powerful ability to modulate systemic inflammation during acute and chronic events has recently been documented in multiple disease conditions. However, there is not enough preclinical data using the procedure to initiate a clinical trial for TBI. The main objective of this proposal is to test the dose-dependent effectiveness and mechanism of action of EA treatment to alleviate pain/headache-like behavior in a clinically relevant rodent model of closed head traumatic brain injury (CH-TBI). This model closely resembles blunt trauma head injury seen in human injury situations involving head impact from automobile crashes, sports, and from blast injury received in battlefield situations. This CH-TBI rodent model exhibited comprehensive evidence of progressive and enduring orofacial and somatic pain/headache-like symptoms induced by non-painful stimulation. These pain/headache-like symptoms correlated with changes in several known pain signaling receptors and molecules along the trigeminal and spinothalamic neuronal pain pathways. Since post-TBI induced chronic pain and headache are major health issue in both military and civilian personnel, preclinical research aiming at the exploration of underlying neurobiology, and targeted therapy is vital. Therefore, the objective of two mechanism driven Specific Aims in this proposal is to enhance our understanding of the neurobiology of EA therapy-influenced changes in TBI-induced pain/headache-like behaviors tested as facial and somatic hyperalgesia/allodynia. Our recent studies using a mild CH impact acceleration TBI model in adult Sprague Dawley rats revealed significant and enduring trigeminal and plantar hyperalgesia using a state of the art operant orofacial and paw pain reward/conflict testing paradigm. Specific Aim 1 will evaluate the therapeutic potential of EA therapy on the progression of TBI-induced orofacial and paw allodynia/hyperalgesias at acute (immediate after TBI) and chronic (2 months) time points after TBI using 2 different durations (2-week vs. 4- week) of EA therapy. Specific Aim 2 will address TBI and therapy-induced changes in mechanisms of pain signaling in trigeminal and somatic pain pathways; these studies will quantitate of changes in a comprehensive array of MRI-based biomarkers, molecules, and receptors related to pain signaling and inflammation in the trigeminal and somatic pain pathways using quantitative MRI, and immunohistochemistry (IHC) based techniques. The investigators propose that EA treatment will produce a safe, significant reduction of orofacial and somatic allodynia/hypersensitivities; accordingly, this therapy has the potential for rapid clinical translation as significant drug free therapy to treat TBI-induced pain and headache. Investigators further propose that the EA treatment-induced significant reduction in orofacial and somatic pain sensitivity will be accompanied by significant reduction of inflammatory biomarkers, and pain signaling molecules/receptors in the facial and somatic pain pathways. MRI and IHC data will further identify details of the mechanisms of action. These studies have the potential to increase our understanding of the neurobiology of TBI-induced pain/headache and the mechanisms of benefits from EA, appropriate time of treatment initiation, duration of treatment, and further provide a platform for the development of TBI-induced pain/headache treatment in both genders. We do hypothesize that the effectiveness of EA will be maximal if it is administered acutely after injury before significant maladaptive plasticity in pain pathways happen. Moreover, 4 weeks treatment will produce significantly better outcomes compared to 2-week treatment due to stimuli-based enduring guided plasticity in the pain pathways.