CGRP antibody rescues tactile sensitization induced by mild traumatic brain injury in mice

Post-traumatic headache (PTH) after mild traumatic brain injury (mTBI) is debilitating and hard to diagnose. Unfortunately, PTH is highly prevalent in active duty personnel, Veterans, as well as sport athletes. The high incidence and chronic nature of PTH underscores the need to study these problems in animal models in order to develop new and effective treatments. Patients suffering from PTH often present the same symptoms as migraine patients, which can be studied in mice. We explored hypersensitivity to a tactile stimulation of the periorbital facial and plantar paw areas in a model of mTBI in mice using von Frey filaments. This mild closed head impact (mCHI) is induced by a weight (30 g) dropped onto the intact skull once a day over 3 consecutive days, after which mice develop a transient cephalic hypersensitivity between day 1 and day 5 after the injury, and then recover to normal thresholds. Additionally, after mice recover from this transient cephalic hypersensitivity, an injection of normally non-noxious triggers such as a low dose of calcitonin gene-related peptide (CGRP) or a low dose of sodium nitroprusside (SNP, a nitric oxide donor) can induce tactile hypersensitivity. This can last for at least 13 weeks after injury. Treatment with a CGRP-blocking monoclonal antibody after injury, but prior to CGRP or SNP administration can alleviate this sensitization. Preliminary data indicate that after injuries, administration of CGRP is also able to induce light aversion at usually non-noxious dim light intensities. In summary, we report that mice are primed by a mild TBI that sensitizes them to subsequent migraine triggers in a CGRP-dependent manner. Dept. Defense W81XWH-16-1-0071, W81XWH-16-1-0211 to AFR; VA-ORD (RR&D) 1IO1RX002101 and C6810-C to AFR; IHA Research Award and Pilot Grant from Iowa City VA Center for the Prevention and Treatment of Visual Loss to ASW.