Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model

Abstract

Introduction: Posttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying PTH. To address these shortcomings, we previously characterized the development of PTH-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further develop this preclinical model by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral CGRP signaling by testing the effect of systemic anti-CGRP monoclonal antibody (anti-CGRP mAb).Methods: Adult male Sprague Dawley rats (total n=138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: a single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of headache-related cephalic and extracephalic mechanical pain hypersensitivity were assessed up to 42 days post head trauma. Treatment included systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody (30 mg/kg.).Results: Rats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic and extracephalic mechanical pain hypersensitivity that resolved by 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as prolonged cephalic and extracephalic mechanical pain hypersensitivity. Early and prolonged anti-CGRP mAb treatment inhibited the development of the cephalic, but not extracephalic pain hypersensitivities in both the severe and repetitive subconcussive head impact models. Conclusions:When compared to the data obtained from male rats in the previous study, a more severe head injury gives rise to a prolonged state of cephalic and extracephalic hyperalgesia. Such enhanced headache-like behaviors also occur following repetitive, subconcussive head impacts.Extended headache-like behaviors following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-CGRP mAb treatment, suggesting a mechanism linked to peripheral CGRP signaling.

Post-traumatic headache due to mild traumatic brain injury: Current knowledge and future directions

“…Finally, neurogenic inflammation after mTBI, including the release of calcitonin gene-related peptide (CGRP), might contribute to the initial development of PTH as well as the development of trigeminal and extratrigeminal sensitization, which facilitate PTH persistence (42,43). Preclinical studies that block CGRP have demonstrated benefits for reducing post-TBI pain behaviors, early sensitization, late latent sensitization, and photophobia (44)(45)(46). Preclinical and human studies suggest that CGRP might play more of a role early after TBI and PTH onset, with a diminished role after PTH has become persistent (45,47).…”

Subconcussion, Concussion, and Cognitive Decline: The Impact of Sports Related Collisions

“…Understanding the mechanism of injury and the tolerance within humans in regard to repetitive subconcussive injuries is vital in developing diagnosis and treatment models. A relationship between repetitive subconcussive injuries and the resulting insidious behavioral and pathological outcomes has yet to be defined in a study that translates to human physiology and subconcussive biomechanical characteristics [115][116][117][118]. Much of the human studies literature is subject to significant variability, particularly in frequency and magnitude of subconcussive impacts.…”