Headache - What's going on?

Pathogenesis of headache

Pharmacotherapy options for headache remain limited by a poor understanding of its pathogenesis. It is difficult to test hypotheses because headaches are transient and patients often experience severe discomfort and vomiting during attacks, making it difficult to participate in research. Creating an experimental model of headache in animals also faces a number of difficulties due to limited knowledge of the underlying mechanisms of headache and because headaches are often only part of a symptom complex, some components of which may develop 24 hours before the onset of the headache itself. The causes of headaches are extremely variable. In some patients, neuroimaging or other additional examination methods can identify structural or inflammatory changes that are the source of pain. In patients suffering from secondary headaches, treatment of the underlying disorder often eliminates the headache. However, the vast majority of patients suffer from primary forms of headache, such as migraine or tension headache, in which physical and additional examination methods do not reveal any abnormalities. Of the various primary forms of headache, the pathogenesis of migraine has been studied most actively. Traditional theories of migraine pathogenesis can be divided into two categories.

Vasogenic theory

In the late 1930s, Dr. Harold Wolff and his colleagues discovered that:

1. During a migraine attack, extracranial vessels in many patients stretch and pulsate, which may be important in the pathogenesis of headaches;
2. stimulation of intracranial vessels in an awake patient causes ipsilateral headache;
3. Vasoconstrictors, such as ergot alkaloids, stop the headache, while vasodilators (such as nitrates) provoke an attack.

Based on these observations, Wolff proposed that constriction of intracranial vessels may be responsible for the occurrence of migraine aura, and that headache results from rebound dilation and stretching of cranial vessels and activation of perivascular nociceptive endings.

Neurogenic theory

According to an alternative - neurogenic - theory, the generator of migraine is the brain, and individual sensitivity reflects the threshold inherent in this organ. Supporters of this theory argue that vascular changes that occur during a migraine attack are a consequence, not a cause of migraine. They draw attention to the fact that migraine attacks are often accompanied by a number of neurological symptoms that are either focal (aura) or vegetative (prodrome) and cannot be explained by vasoconstriction in the basin of any vessel.

It is possible that none of these hypotheses alone can explain the origin of migraine or other forms of primary headache. Headache, including migraine, probably results from the action of many factors (including genetic and acquired ones), some of which are related to brain function, others to blood vessels or circulating biologically active substances. For example, scientists have reported that familial hemiplegic migraine is caused by a point mutation in the gene encoding the alpha2-subunit of the calcium channel PQ.

Morphological substrate of headache

Modern ideas about the origin of headache have been formed in the last 60 years. The meninges, meningeal and cerebral vessels are the main intracranial structures that generate headache. In the late 1930s and 1940s, studies on awake patients undergoing craniotomy showed that electrical and mechanical stimulation of the blood vessels of the meninges causes intense piercing unilateral headache. Similar stimulation of the brain parenchyma did not cause pain. Small pseudounipolar branches of the trigeminal (V cranial) nerve and the upper cervical segments that innervate the meninges and meningeal vessels are the main source of somatosensory afferentation that creates the sensation of pain in the head. When these unmyelinated C fibers are activated, nociceptive information from the perivascular terminals passes through the trigeminal ganglion and synapses onto second-order neurons in the superficial plate of the caudal trigeminal nucleus in the medulla. These predominantly afferent neurons contain substance P, calcitonin gene-related peptide (CGRP), neurokinin A, and other neurotransmitters in the central and peripheral (i.e., sheath) portions of their axons.

The caudal trigeminal nucleus also receives input from more rostral trigeminal nuclei, the periaqueductal gray, the magnus raphe nucleus, and descending cortical inhibitory systems and is a key link in the regulation of headache. Little is known about the role of central trigeminal projections in the transmission of nociceptive information. However, it is believed that second-order neurons in the caudal trigeminal nucleus transmit nociceptive information to other brainstem and subcortical structures, including more rostral parts of the trogeminal complex, the brainstem reticular formation, the parabrachial nuclei, and the cerebellum. From the rostral nuclei, nociceptive information is transmitted to limbic areas that mediate emotional and autonomic responses to pain. Projections are also sent from the caudal trigeminal nucleus to the ventrobasal, posterior, and medial thalamus. From the ventrobasal thalamus, neurons send axonal projections to the somatosensory cortex, whose function is to determine the location and nature of pain. The medial thalamus projects to the frontal cortex, which provides an affective response to pain. However, according to available data, the medial thalamus can participate in the transmission of both affective and discriminative components of pain sensation. Modulation of nociceptive afferentation can occur at one or more levels - from the trigeminal nerve to the cerebral cortex, and each of these levels is a potential target for drug action.