Glymphatic function restored by α 1-noradrenergic antagonism alleviates headache allodynia in mice

Abstract Mild traumatic brain injury (mTBI) often leads to migraine-like post-traumatic headache (PTH), yet effective treatments are limited. Clinical and preclinical studies have shown that mTBI disrupts glymphatic transport of cerebrospinal fluid in the brain. We hypothesized that altered glymphatic transport might underlie facial allodynia commonly associated with migraine and PTH. A closed-head impact model was used to induce mTBI in mice. Facial allodynia, a symptom of PTH and migraine, was evaluated using periorbital von Frey testing. Glymphatic influx was assessed using slice-based imaging of a fluorescent tracer injected into the cisterna magna. Here we show that prazosin (PZN), an α1-noradrenergic receptor antagonist, restores glymphatic function and treats facial allodynia induced by calcitonin gene-related peptide (CGRP) and a nitric oxide donor in mice. In contrast, propranolol, a β-noradrenergic receptor antagonist, was ineffective. Even in the absence of mTBI, CGRP reduced glymphatic function and PZN was able to restore glymphatic function in the dorsal cortex. Importantly, the role of glymphatic function was confirmed by the lack of PZN efficacy in aquaporin-4 knockout mice. These findings indicate that targeting α1-noradrenergic receptors to enhance glymphatic transport may offer a therapeutic strategy for treating migraine and PTH. Competing Interest Statement ADP serves as a consultant for Delphian Therapeutics. AK serves as a consultant for Vedana Therapeutics. AFR serves as a consultant and/or on scientific advisory boards for Lundbeck, AbbVie, Pfizer, Vedana Therapeutics, Arrowhead Pharmaceuticals, Delphian Therapeutics, Solros Therapeutics, Numab Therapeutics, Forbian, Evommune. He receives grant support from NINDS, NIDA, VAHCS, Vedana Therapeutics, Pfizer. JJI serves as the Chair for the Scientific Advisory Board for Applied Cognition, from which he received compensation and stock options. He serves as a consultant to Tonix Pharmaceuticals, Orbit Technologies, Medical Microsintruments Inc, and huMannity Medtech.