Raised Intracranial Pressure Alters Cortical Vascular Function And Cephalic Allodynia.
Olivia Grech1, Eloisa Rubio-Beltran3, Emily C. Stanyer4, Alejandro Labastida-Ramirez3, Gareth G. Lavery5, Lisa J. Hill2, Philip R. Holland3, Alexandra J. Sinclair1
1Metabolism and Systems Science, 2Biomedical Sciences, University of Birmingham, 3Wolfson Sensory, Pain and Regeneration Centre, King's College London, 4Sleep and Circadian Neuroscience Institute, University of Oxford, 5Centre for Systems Health and Integrated Metabolic Research, Nottingham Trent University
Objective:
To evaluate the relationship between cephalic pain and altered cerebral hemodynamics in raised intracranial pressure (ICP). We investigated whether reducing ICP with a glucagon-like peptide-1 receptor agonist (GLP-1RA) could alleviate the cephalic pain and examined the role of calcitonin gene-related peptide (CGRP) associated with elevated ICP.
Background:
Cortical vascular changes, particularly spreading depolarization, signal altered excitability in neurological conditions with raised ICP. While raised ICP is linked to cephalic pain, the relationship between ICP, cortical neurovascular changes, and allodynia remains unclear.
Design/Methods:
In a rat model of raised ICP, mechanical thresholds were measured alongside steady-state potential and cerebral blood flow (CBF) responses to spreading depolarisation. Ex-vivo nuclear magnetic resonance spectroscopy evaluated energetic substrates. Daily injection of GLP-1RA and CGRP receptor antagonist were administered, and measurements were repeated.
Results:
Kaolin increased ICP [median (range) 15.96mmHg(8.97) n=8, controls:6.02mmHg(1.79) n=6 p=0.0007] and reduced mechanical thresholds (mean (SD) hind paw baseline:5.78g(2.81), day 7:3.34g(2.22) p<0.001, periorbital baseline:6.13g(2.07), day 7:2.35g(1.91) n=12 p<0.001). Spreading depolarisation responses were altered [repolarisation duration raised ICP:1824.26s(3499.54) n=12, controls:86.96s(140.05) n=9 p<0.0001] and CBF change was reduced (raised ICP:85.55%(30.84) n=9, controls:217.64%(37.70) n=8 p<0.0001). Substrates for cellular energetics were depleted in animals with raised ICP (ADP p=0.009, ATP p=0.018, NAD+ p=0.011).
GLP-1RA lowered ICP (GLP-1RA: 9.74mmHg(6.09) n=19, vehicle: 18.27mmHg(6.67) n=16 p=0.004) and rescued changes in mechanical thresholds. GLP-1RA recovered spreading depolarisation responses [repolarisation duration GLP-1RA: 177.55s(562.88) n=7, vehicle: 800.85s(1988.67) n=6 p=0.002]. In the setting of raised ICP, CGRP receptor antagonism prevented changes in periorbital mechanical thresholds.
Conclusions:
Animals with raised ICP showed disrupted neurovascular responses, lower pain thresholds, and depleted energy substrates. GLP-1RA reduced ICP, improving these measures, while CGRP receptor antagonism alleviated cephalic pain. These findings suggest that reducing ICP may relieve cephalic pain and targeting the CGRP pathway could be a therapeutic strategy for headache in raised ICP conditions.
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