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

Cephalalgia ◽  
2020 ◽  
Vol 40 (7) ◽  
pp. 748-760 ◽  
Author(s):  
Dara Bree ◽  
Kimberly Mackenzie ◽  
Jennifer Stratton ◽  
Dan Levy
Keyword(s):  
Monoclonal Antibody ◽  
Head Injury ◽  
Closed Head Injury ◽  
Calcitonin Gene Related Peptide ◽  
Female Rats ◽  
Related Peptide ◽  
Increased Risk ◽  
Calcitonin Gene ◽  
Closed Head ◽  
Post Traumatic

Introduction Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated the development of post-traumatic headache-like pain behaviors in a male 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 conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. Methods Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). 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 intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). Results Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which 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-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. Conclusions Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, 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-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

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

2019 ◽  
Author(s):  
Dara Bree ◽  
Kimberly Mackenzie ◽  
Jennifer Stratton ◽  
Dan Levy
Keyword(s):  
Monoclonal Antibody ◽  
Head Injury ◽  
Closed Head Injury ◽  
Calcitonin Gene Related Peptide ◽  
Systemic Administration ◽  
Female Rats ◽  
Related Peptide ◽  
Increased Risk ◽  
Calcitonin Gene ◽  
Closed Head

AbstractIntroductionFemales 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.

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

Cephalalgia ◽  
2020 ◽  
Vol 40 (11) ◽  
pp. 1224-1239
Author(s):  
Dara Bree ◽  
Jennifer Stratton ◽  
Dan Levy
Keyword(s):  
Head Injury ◽  
Closed Head Injury ◽  
Calcitonin Gene Related Peptide ◽  
Posttraumatic Headache ◽  
Pain Hypersensitivity ◽  
Head Impacts ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Closed Head ◽  
Weight Drop

Introduction Posttraumatic headache 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 posttraumatic headache. To address these shortcomings, we previously characterized the development of posttraumatic headache-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 extend the preclinical research toolbox for studying posttraumatic headache 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 calcitonin gene-related peptide signaling by testing the effect of systemic treatment with an anti-calcitonin gene-related peptide monoclonal antibody (anti-calcitonin gene-related peptide 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 cephalic and extracephalic tactile pain hypersensitivity were assessed up to 42 days post head trauma. Systemic administration of the anti-calcitonin gene-related peptide mAb or its control IgG (30 mg/kg) began immediately after the 450 g injury or the third 150 g weight drop with additional doses given every 6 days subsequently. Results Rats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Injured animals also displayed delayed and prolonged extracephalic tactile pain hypersensitivity that remained present at 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 cephalic and extracephalic tactile pain hypersensitivity that resolved by 6 weeks post-injury. Early and prolonged anti-calcitonin gene-related peptide mAb treatment inhibited the development of the cephalic tactile pain hypersensitivity in both the severe and repetitive subconcussive head impact models. Conclusions Severe head injury gives rise to a prolonged state of cephalic and extracephalic tactile pain hypersensitivity. These pain behaviors also develop following repetitive, subconcussive head impacts. Extended cephalic tactile pain hypersensitivity following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-calcitonin gene-related peptide mAb treatment, suggesting a mechanism linked to calcitonin gene-related peptide signaling, potentially of trigeminal origin.

Galcanezumab for the prevention of migraine

2020 ◽  
Author(s):  
Lindsay M Frerichs ◽  
Deborah I Friedman
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Efficacy ◽  
Preventive Treatment ◽  
Calcitonin Gene Related Peptide ◽  
Efficacy And Safety ◽  
Related Peptide ◽  
Calcitonin Gene

Migraine is a common and disabling disorder affecting approximately 1.02 billion people worldwide. Calcitonin gene-related peptide (CGRP) has been identified as playing an important role in the pathophysiology of migraine and several migraine-specific therapies targeting the CGRP ligand or its receptor have been approved since 2018 for the acute and preventive treatment of migraine. This review focuses on the pharmacology, clinical efficacy and safety/tolerability of galcanezumab, an anti-CGRP monoclonal antibody approved for the prevention of migraine.

CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice

Cephalalgia ◽  
2019 ◽  
Vol 39 (14) ◽  
pp. 1762-1775 ◽  
Author(s):  
Edita Navratilova ◽  
Jill Rau ◽  
Janice Oyarzo ◽  
Jason Tien ◽  
Kimberly Mackenzie ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mild Traumatic Brain Injury ◽  
Light Stress ◽  
Bright Light ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Cutaneous Allodynia ◽  
Calcitonin Gene ◽  
Post Traumatic

Background Acute and persistent post-traumatic headache are often debilitating consequences of traumatic brain injury. Underlying physiological mechanisms of post-traumatic headache and its persistence remain unknown, and there are currently no approved therapies for these conditions. Post-traumatic headache often presents with a migraine-like phenotype. As calcitonin-gene related peptide promotes migraine headache, we explored the efficacy and timing of intervention with an anti- calcitonin-gene related peptide monoclonal antibody in novel preclinical models of acute post-traumatic headache and persistent post-traumatic headache following a mild traumatic brain injury event in mice. Methods Male, C57Bl/6 J mice received a sham procedure or mild traumatic brain injury resulting from a weight drop that allowed free head rotation while under minimal anesthesia. Periorbital and hindpaw tactile stimulation were used to assess mild traumatic brain injury-induced cutaneous allodynia. Two weeks after the injury, mice were challenged with stress, a common aggravator of migraine and post-traumatic headache, by exposure to bright lights (i.e. bright light stress) and cutaneous allodynia was measured hourly for 5 hours. A murine anti- calcitonin-gene related peptide monoclonal antibody was administered after mild traumatic brain injury at different time points to allow evaluation of the consequences of either early and sustained calcitonin-gene related peptide sequestration or late administration only prior to bright light stress. Results Mice with mild traumatic brain injury, but not a sham procedure, exhibited both periorbital and hindpaw cutaneous allodynia that resolved by post-injury day 13. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-instated periorbital and hindpaw cutaneous allodynia in injured, but not sham mice. Repeated administration of anti-calcitonin-gene related peptide monoclonal antibody at 2 hours, 7 and 14 days post mild traumatic brain injury significantly attenuated the expression of cutaneous allodynia when evaluated over the 14-day post injury time course and also prevented bright light stress-induced cutaneous allodynia in injured mice. Administration of anti-calcitonin-gene related peptide monoclonal antibody only at 2 hours and 7 days after mild traumatic brain injury blocked injury-induced cutaneous allodynia and partially prevented bright light stress-induced cutaneous allodynia. A single administration of anti-calcitonin-gene related peptide monoclonal antibody after the resolution of the peak injury-induced cutaneous allodynia, but prior to bright light stress challenge, did not prevent bright light stress-induced cutaneous allodynia. Conclusions We used a clinically relevant mild traumatic brain injury event in mice along with a provocative stimulus as novel models of acute post-traumatic headache and persistent post-traumatic headache. Following mild traumatic brain injury, mice demonstrated transient periorbital and hindpaw cutaneous allodynia suggestive of post-traumatic headache-related pain and establishment of central sensitization. Following resolution of injury-induced cutaneous allodynia, exposure to bright light stress re-established cutaneous allodynia, suggestive of persistent post-traumatic headache-related pain. Continuous early sequestration of calcitonin-gene related peptide prevented both acute post-traumatic headache and persistent post-traumatic headache. In contrast, delayed anti-calcitonin-gene related peptide monoclonal antibody treatment following establishment of central sensitization was ineffective in preventing persistent post-traumatic headache. These observations suggest that mechanisms involving calcitonin-gene related peptide underlie the expression of acute post-traumatic headache, and drive the development of central sensitization, increasing vulnerability to headache triggers and promoting persistent post-traumatic headache. Early and continuous calcitonin-gene related peptide blockade following mild traumatic brain injury may represent a viable treatment option for post-traumatic headache and for the prevention of post-traumatic headache persistence. Abbreviations CA Cutaneous allodynia CGRP Calcitonin gene-related peptide mTBI Mild traumatic brain injury PTH Post-traumatic headache APTH Acute post-traumatic headache PPTH Persistent post-traumatic headache

Post-traumatic headache: emphasis on chronic types following mild closed head injury

2007 ◽  
Vol 28 (S2) ◽  
pp. S203-S207 ◽  
Author(s):  
F. D. Sheftell ◽  
S. J. Tepper ◽  
C. L. Lay ◽  
M. E. Bigal
Keyword(s):  
Head Injury ◽  
Closed Head Injury ◽  
Closed Head ◽  
Post Traumatic

Predicting clearing of post-traumatic amnesia following closed-head injury

Brain Injury ◽  
1992 ◽  
Vol 6 (2) ◽  
pp. 167-174 ◽  
Author(s):  
Deborah L. Saneda ◽  
John D. Corrigan
Keyword(s):  
Head Injury ◽  
Closed Head Injury ◽  
Traumatic Amnesia ◽  
Closed Head ◽  
Post Traumatic
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