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Review
. 2024 May;28(5):439-451.
doi: 10.1007/s11916-024-01238-2. Epub 2024 Mar 19.

Research Progress on the Experimental Model and Underlying Mechanistic Studies of Tension-Type Headaches

Guo-Jing Fu #  1 , Liu-Ding Wang #  1 , Xian-Su Chi  1 , Xiao Liang  1 , Jing-Jing Wei  1 , Zhi-Hong Huang  2 , Wei Shen  3 , Yun-Ling Zhang  4
Affiliations
Review

Research Progress on the Experimental Model and Underlying Mechanistic Studies of Tension-Type Headaches

Guo-Jing Fu et al. Curr Pain Headache Rep. 2024 May.

Abstract

Purpose of review: Tension-type headaches (TTH) significantly diminish patients' quality of life and increase absenteeism, thereby imposing a substantial economic burden. Animal models are essential tools for studying disease mechanisms and drug development. However, until now, little focus has been placed on summarizing the animal models of TTH and associated mechanistic studies. This narrative review discusses the current animal models of TTH and related mechanistic studies to provide insights into the pathophysiological mechanisms of and treatments for TTH.

Recent findings: The primary method for constructing an animal model of TTH involves injecting a solution of pain relievers, such as adenosine triphosphate, nerve growth factor, or a high concentration of salt solution, into the neck to initiate harmful cervical muscle responses. This model enables the examination of the interaction between peripheral muscles and central sensitization, which is crucial for understanding the pathophysiology of TTH. Mechanistic studies based on this model have investigated the effect of the P2X receptor antagonist, P2X7 receptor blockade, the P2Y1 receptor agonist 2-MESADP, P2Y1 receptor antagonist MRS2179, nitric oxide synthase inhibitors, and acetylsalicylic acid. Despite notable advancements, the current model of TTH has limitations, including surgical complexity and the inability to replicate chronic tension-type headache (CTTH). To gain a more comprehensive understanding and develop more effective treatment methods, future studies should focus on simplifying surgical procedures, examining other predisposing factors, and establishing a model for chronic TTH. This will offer a deeper insight into the pathophysiological mechanism of TTH and pave the way for improved treatment approaches.

Keywords: Adenosine triphosphate; Animal model; Nerve growth factor; Pathophysiology; Tension-type headache.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Pathophysiological model of tension-type headache (TTH). A Muscle overuse, mechanical overload, psychological stress, ischemia, and inflammation, along with the release of various chemical mediators due to local pathological conditions, activate and sensitize muscle nociceptors, and peripheral sensory afferent fibers. B The trigeminal nerve and C1–C4 dorsal root ganglia receive nociceptive information from the periphery via C fibers, Aδ fibers, and Aβ fibers. C Increased peripheral noxious input leads to the sensitization of secondary neurons in the spinal trigeminal nucleus and dorsal horns at the C3–C4 level. D The heightened nociceptive input from the spinal trigeminal nucleus and dorsal horns results in the sensitization of supraspinal neurons. Pathways A, B, C, and D (highlighted in red) illustrate the regulatory process of ascending pain conduction. E Enhanced nociceptive activation of supraspinal structures may result in increased facilitation (via RVM) and decreased inhibition (via PAG) of pain transmission at the level of the spinal dorsal horn/trigeminal nucleus. F The heightened nociceptive activation of supraspinal structures enables descending inputs from the motor cortex to regulate motor neurons. This regulation leads to increased pericranial muscle activity, which manifests as increased muscle contraction or heightened muscle rigidity. Pathways E and F (highlighted in green) depict the control process of pain perception through descending input, triggered by increased stimulation of spinal cord structures. G Schematic representation of the molecular mechanisms underlying central sensitization [35]. This process mainly pertains to the sensitization of second-order neurons in the spinal dorsal horn/trigeminal nucleus, as well as sensitization of supraspinal structures. Neurotransmitters such as substance P, glutamic acid, and procalcitonin may contribute to the development of central sensitization. Normally dormant postsynaptic receptors, including NMDA receptors, mGluR receptors, and NK1R receptors, may be activated by the release of these neurotransmitters. The activation of these receptors induces an increase in calcium influx, which in turn triggers PKA, PKC, CaMKII, and ERK. This catalyzes a series of biochemical processes, including the increase of nitric oxide, prostaglandins, protein kinases, and immediate early gene protein products
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