Preclinical Studies of Posttraumatic Headache and the Potential Therapeutics

Abstract

Posttraumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache developed within 7 days after head injury, and in a substantial number of patients PTH becomes chronic and lasts for more than 3 months. Current medications are almost entirely relied on the treatment of primary headache such as migraine, due to its migraine-like phenotype and the limited understanding on the PTH pathogenic mechanisms. To this end, increasing preclinical studies have been conducted in the last decade. We focus in this review on the trigeminovascular system from the animal studies since it provides the primary nociceptive sensory afferents innervating the head and face region, and the pathological changes in the trigeminal pathway are thought to play a key role in the development of PTH. In addition to the pathologies, PTH-like behaviors induced by TBI and further exacerbated by nitroglycerin, a general headache inducer through vasodilation are reviewed. We will overview the current pharmacotherapies including calcitonin gene-related peptide (CGRP) monoclonal antibody and sumatriptan in the PTH animal models. Given that modulation of the endocannabinoid (eCB) system has been well-documented in the treatment of migraine and TBI, the therapeutic potential of eCB in PTH will also be discussed.

Keywords: CGRP; endocannabinoids; migraine; posttraumatic headache; traumatic brain injury; trigeminovascular system.

Figure 1

Schematic signal transduction pathways of TG neurons. There are mainly three modulatory regions that are important in nociceptive regulation of TG neurons; peripheral end terminal on the meningeal blood vessels, TG regions associating with satellite glial cells, and central terminal connecting to the second order neurons in TNC. Aδ fiber and C fiber neurons have distinct gene regulations, for instance CGRP and its receptors expression. CGRP plays a critical role in vasodilation as well as TG neuronal activity through induction of NO and cytokine/chemokine production, that can in turn trigger more CGRP release and nociception.

Figure 2

Hypothetical eCB mediated pain modulation in the PTH model. ECB signaling modulates nociceptive activation raised in TG neurons at (1) meninges by mast cells, macrophages and vascular cells, (2) TG with associated satellite glia cells, and (3) TNC. Nociceptive information ascends via the second order neurons innervating to (4) neurons in thalamus, amygdala, and other brainstem regions such as PAG where pain sensation was altered by CB receptor agonist or antagonist microinjection. Subsequently it is transited to (5) cortical regions such as mPFC and insular cortex. It is possible that eCB signaling has a substantial modulatory function, for instance through amygdala-mPFC-PAG pathway. In descending pathway, eCB system is deeply involved in the modulation via (6) PAG and RVM, and in (3) TNC. These brainstem regions integrate and process both ascending and descending pain signals via eCB system modulation.