Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2024 Jun 27

PMID 38931882

Authors

Vimala N Bharadwaj

Michael Klukinov

Robert Paul Cowan

Nazanin Mahinparvar

David John Clark

David Clifford Yeomans

Affiliations

Soon will be listed here.

Abstract

Objective: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH.

Methods: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia.

Results: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist.

Conclusion: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.

References

. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018; 38(1):1-211. DOI: 10.1177/0333102417738202. View

Sahbaie P, Irvine K, Liang D, Shi X, Clark J . Mild Traumatic Brain Injury Causes Nociceptive Sensitization through Spinal Chemokine Upregulation. Sci Rep. 2019; 9(1):19500. PMC: 6925232. DOI: 10.1038/s41598-019-55739-x. View

Benromano T, Defrin R, Ahn A, Zhao J, Pick C, Levy D . Mild closed head injury promotes a selective trigeminal hypernociception: implications for the acute emergence of post-traumatic headache. Eur J Pain. 2014; 19(5):621-8. PMC: 4345163. DOI: 10.1002/ejp.583. View

Fraser F, Matsuzawa Y, Lee Y, Minen M . Behavioral Treatments for Post-Traumatic Headache. Curr Pain Headache Rep. 2017; 21(5):22. DOI: 10.1007/s11916-017-0624-x. View

Vargas B, Dodick D . Posttraumatic headache. Curr Opin Neurol. 2012; 25(3):284-9. DOI: 10.1097/WCO.0b013e3283535bf5. View

Bree D, Levy D . Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia. 2016; 38(2):246-258. PMC: 6454269. DOI: 10.1177/0333102416681571. View

Brown A, Watanabe T, Hoffman J, Bell K, Lucas S, Dikmen S . Headache after traumatic brain injury: a national survey of clinical practices and treatment approaches. PM R. 2014; 7(1):3-8. DOI: 10.1016/j.pmrj.2014.06.016. View

Sanu O, Lamont R . Critical appraisal and clinical utility of atosiban in the management of preterm labor. Ther Clin Risk Manag. 2010; 6:191-9. PMC: 2861440. DOI: 10.2147/tcrm.s9378. View

Burstein R, Blake P, Schain A, Perry C . Extracranial origin of headache. Curr Opin Neurol. 2017; 30(3):263-271. PMC: 6051727. DOI: 10.1097/WCO.0000000000000437. View

10.

Tzabazis A, Mechanic J, Miller J, Klukinov M, Pascual C, Manering N . Oxytocin receptor: Expression in the trigeminal nociceptive system and potential role in the treatment of headache disorders. Cephalalgia. 2015; 36(10):943-50. DOI: 10.1177/0333102415618615. View

11.

Gfrerer L, Xu W, Austen W, Ashina S, Melo-Carrillo A, Longhi M . OnabotulinumtoxinA alters inflammatory gene expression and immune cells in chronic headache patients. Brain. 2021; 145(7):2436-2449. PMC: 9337807. DOI: 10.1093/brain/awab461. View

12.

Kopruszinski C, Navratilova E, Swiokla J, Dodick D, Chessell I, Porreca F . A novel, injury-free rodent model of vulnerability for assessment of acute and preventive therapies reveals temporal contributions of CGRP-receptor activation in migraine-like pain. Cephalalgia. 2020; 41(3):305-317. PMC: 7995998. DOI: 10.1177/0333102420959794. View

13.

Sahbaie P, Tajerian M, Yang P, Irvine K, Huang T, Luo J . Nociceptive and Cognitive Changes in a Murine Model of Polytrauma. J Pain. 2018; 19(12):1392-1405. DOI: 10.1016/j.jpain.2018.06.004. View

14.

Navratilova E, Rau J, Oyarzo J, Tien J, Mackenzie K, Stratton J . CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice. Cephalalgia. 2019; 39(14):1762-1775. DOI: 10.1177/0333102419877662. View

15.

Kosaras B, Jakubowski M, Kainz V, Burstein R . Sensory innervation of the calvarial bones of the mouse. J Comp Neurol. 2009; 515(3):331-48. PMC: 2710390. DOI: 10.1002/cne.22049. View

16.

Meidahl A, Eisenried A, Klukinov M, Cao L, Tzabazis A, Yeomans D . Intranasal Oxytocin Attenuates Reactive and Ongoing, Chronic Pain in a Model of Mild Traumatic Brain Injury. Headache. 2017; 58(4):545-558. DOI: 10.1111/head.13248. View

17.

Kubo A, Shinoda M, Katagiri A, Takeda M, Suzuki T, Asaka J . Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia. Pain. 2017; 158(4):649-659. DOI: 10.1097/j.pain.0000000000000808. View

18.

Zhao J, Levy D . The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior. Pain. 2014; 155(7):1392-1400. PMC: 4058402. DOI: 10.1016/j.pain.2014.04.019. View

19.

Bharadwaj V, Meyerowitz J, Zou B, Klukinov M, Yan N, Sharma K . Impact of Magnesium on Oxytocin Receptor Function. Pharmaceutics. 2022; 14(5). PMC: 9144867. DOI: 10.3390/pharmaceutics14051105. View

20.

Loder E, Burch R, Rizzoli P . The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012; 52(6):930-45. DOI: 10.1111/j.1526-4610.2012.02185.x. View