Biology subjects

Stratton, J.

Publications and source records attributed to Stratton, J..

2 recordsLinked to original sources

bioRxiv2020

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

IntroductionPosttraumatic 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). MethodsAdult 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.). ResultsRats 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. ConclusionsWhen 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.

neuroscience↗

bioRxiv2019

Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury

IntroductionFemales are thought to have increased risk of developing posttraumatic headache (PTH) following a traumatic head injury, or concussion. However, the processes underlying this susceptibility remain unclear. We previously explored the development of PTH-like pain behaviors in a novel rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we explored the development of PTH-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. MethodsAdult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device. Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of systemic administration of a low-dose of glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and repeated systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody. Serum levels of calcitonin-gene-related peptide were measured at various time points in females and males after the head injury. ResultsFemale rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, that was limited to the cephalic region, and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan, but was resistant to an early and prolonged treatment with the anti-CGRP monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-CGRP treatment. CGRP serum levels were elevated in females but not in males at 7 days post head injury. ConclusionsDevelopment of PTH-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to males, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-CGRP treatment. The increased risk of females to develop PTH may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral CGRP signaling.

neuroscience↗