Cardiovascular and Neuronal Responses to Head Stimulation Reflect Central Sensitization and Cutaneous Allodynia in a Rat Model of Migraine

Abstract

Reduction of the threshold of cardiovascular and neuronal responses to facial and intracranial stimulation reflects central sensitization and cutaneous allodynia in a rat model of migraine. Current theories propose that migraine pain is caused by chemical activation of meningeal perivascular fibers. We previously found that chemical irritation of the dura causes trigeminovascular fibers innervating the dura and central trigeminal neurons receiving convergent input from the dura and skin to respond to low-intensity mechanical and thermal stimuli that previously induced minimal or no responses. One conclusion of these studies was that when low- and high-intensity stimuli induce responses of similar magnitude in nociceptive neurons, low-intensity stimuli must be as painful as the high-intensity stimuli. The present study investigates in anesthetized rats the significance of the changes in the responses of central trigeminal neurons (i.e., in nucleus caudalis) by correlating them with the occurrence and type of the simultaneously recorded cardiovascular responses. Before chemical stimulation of the dura, simultaneous increases in neuronal firing rates and blood pressure were induced by dural indentation with forces >/= 2.35 g and by noxious cutaneous stimuli such as pinching the skin and warming > 46 degrees C. After chemical stimulation, similar neuronal responses and blood pressure increases were evoked by much smaller forces for dural indentation and by innocuous cutaneous stimuli such as brushing the skin and warming it to >/= 43 degrees C. The onsets of neuronal responses preceded the onsets of depressor responses by 1.7 s and pressor responses by 4.0 s. The duration of neuronal responses was 15 s, whereas the duration of depressor responses was shorter (5.8 s) and pressor responses longer (22.7 s) than the neuronal responses. We conclude that the facilitated cardiovascular and central trigeminal neuronal responses to innocuous stimulation of the skin indicate that when dural stimulation induces central sensitization, innocuous stimuli are as nociceptive as noxious stimuli had been before dural stimulation and that a similar process might occur during the development of cutaneous allodynia during migraine.

A neurohistochemical blueprint for pain-induced loss of appetite

“…This paradigm was developed on the basis of our electrophysiological evidence that chemical stimulation of the dura activates and sensitizes meningeal-nociceptors in the trigeminal ganglion and nociceptive neurons in the medullary dorsal horn, and that mechanical dural stimulation further enhances the firing rate of these neurons (6,7). The noxious nature of these dural stimuli was determined not only by their ability to activate and sensitize peripheral and central nociceptive neurons but also by their ability to induce pressor responses (i.e., acute increases in blood pressure) (8), because pressor responses are induced by visceral and cutaneous stimuli which damage tissue and cause pain (9)(10)(11).…”

“…It also produces acute increases in mean arterial pressure, or pressor responses (8), which, in humans, are usually associated with pain perception. Finally, chemical stimulation renders the dura hypersensitive to mild mechanical stimuli because it potentiates large neuronal and pressor responses to otherwise subthreshold mechanical stimuli (7,8).…”

“…It also produces acute increases in mean arterial pressure, or pressor responses (8), which, in humans, are usually associated with pain perception. Finally, chemical stimulation renders the dura hypersensitive to mild mechanical stimuli because it potentiates large neuronal and pressor responses to otherwise subthreshold mechanical stimuli (7,8). It was therefore necessary in the present study to verify that dural stimulation with chemical and mechanical stimuli indeed produced robust Fos expression in the same ventrolateral areas of spV laminae I and V. In the discussion below, we shall consider the possibility of our nociceptive stimuli being stressful as well.…”

Pain Threshold in Migraine and Tension-Type Headache by Pressure Algometry in Craniocervical Muscles and Peripheral Nerves in Both Genders

“…This inflammatory state probably sensitizes cranial nociceptors and subsequently decreases its activation threshold expanding their receptors [15]. Second-other and third-order neurons become activated and exposure to repeated episodes of pain eventually results in decreased pain threshold [16] reaching up to 79% of patients with cutaneous allodynia [17].…”

Pathophysiologie der Migräne

“…Dort liegt die zentrale Verschaltungsstelle auf postsynaptische Neurone, die nicht nur der Fortleitung der Aktivität dient, sondern auch selbst einer zentralen Sensibilisierung unterliegen kann, d. h. eine weitere Signalverstärkung erzeugt. Für Hirnstammneurone mit Einstrom von der Dura wurde die zentrale Sensibilisierung durch elektrophysiologische Ableitungen tierexperimentell gezeigt [53]. Damit ist auch eine Ausdehnung der rezeptiven Felder in der Peripherie verbunden.…”