Trigeminal Sensory Processing Research Articles

Compromised trigemino-coerulean coupling in migraine sensitization can be prevented by blocking beta-receptors in the locus coeruleus

BackgroundMigraine is a disabling neurological disorder, characterized by recurrent headaches. During migraine attacks, individuals often experience sensory symptoms such as cutaneous allodynia which indicates the presence of central sensitization. This sensitization is prevented by oral administration of propranolol, a common first-line medication for migraine prophylaxis, that also normalized the activation of the locus coeruleus (LC), considered as the main origin of descending noradrenergic pain controls. We hypothesized that the basal modulation of trigeminal sensory processing by the locus coeruleus is shifted towards more facilitation in migraineurs and that prophylactic action of propranolol may be attributed to a direct action in LC through beta-adrenergic receptors.MethodsWe used simultaneous in vivo extracellular recordings from the trigeminocervical complex (TCC) and LC of male Sprague–Dawley rats to characterize the relationship between these two areas following repeated meningeal inflammatory soup infusions. Von Frey Hairs and air-puff were used to test periorbital mechanical allodynia. RNAscope and patch-clamp recordings allowed us to examine the action mechanism of propranolol.ResultsWe found a strong synchronization between TCC and LC spontaneous activities, with a precession of the LC, suggesting the LC drives TCC excitability. Following repeated dural-evoked trigeminal activations, we observed a disruption in coupling of activity within LC and TCC. This suggested an involvement of the two regions’ interactions in the development of sensitization. Furthermore, we showed the co-expression of alpha-2A and beta-2 adrenergic receptors within LC neurons. Finally propranolol microinjections into the LC prevented trigeminal sensitization by desynchronizing and decreasing LC neuronal activity.ConclusionsAltogether these results suggest that trigemino-coerulean coupling plays a pivotal role in migraine progression, and that propranolol’s prophylactic effects involve, to some extent, the modulation of LC activity through beta-2 adrenergic receptors. This insight reveals new mechanistic aspects of LC control over sensory processing.

Chapter 5 - Migraine headache pathophysiology

In both episodic and chronic migraine, headache is the most disabling symptom that requires medical care. The migraine headache is the most well-studied symptom of migraine pathophysiology. The trigeminal system and the central processing of sensory information transmitted by the trigeminal system are of considerable importance in the pathophysiology of migraine headache. Glutamate is the main neurotransmitter that drives activation of the ascending trigeminal and trigeminothalamic pathways. The neuropeptide, calcitonin gene-related peptide (CGRP) that is released by the trigeminal system, plays a crucial role in the neurobiology of headache. Peripheral and central sensitizations associated with trigeminal sensory processing are neurobiologic states that contribute to both the development of headache during a migraine attack and the maintenance of chronic migraine.

Cortico-thalamic reciprocal circuit working for trigeminal sensory processing

Cortico-thalamic reciprocal circuit working for trigeminal sensory processing

Inflammation and Abnormal Trigeminal Sensory Processing in Obese Mice (S26.006)

Inflammation and Abnormal Trigeminal Sensory Processing in Obese Mice (S26.006)

Intraganglionic injection of a nitric oxide donator induces afferent mechanical sensitization that is attenuated by palmitoylethanolamide

The aim of this article is to investigate whether the nitric oxide (NO) donator diethylenetriamine/nitric oxide (DETA/NO) affects trigeminal sensory processing through the trigeminal ganglion in part by activating trigeminal satellite glial cells (SGCs) and whether this effect is attenuated by the anti-inflammatory compound palmitoylethanolamide (PEA). DETA/NO was administered to isolated rat trigeminal SGCs invitro, and injected into the rat trigeminal ganglion invivo, in the presence or absence of PEA. Administration of DETA/NO (1000 µM) increased the release of prostaglandin E2 by SGCs. PEA (1 and 10 µM) significantly attenuated prostaglandin E2 release. Two intraganglionic injections of DETA/NO (10 mM, 3 µl) or prostaglandin E2 at a 30-minute interval did not evoke discharge in trigeminal ganglion neurons that innervate the rat jaw-closer muscles, but did reduce the mechanical activation threshold of their peripheral endings by 30%-50%. Intravenous administration of PEA (1 mg/kg) or ketorolac (0.5 mg/kg) prevented DETA/NO-induced afferent mechanical sensitization. Elevation of NO in the trigeminal ganglion results in the sensitization of the peripheral endings of masticatory muscle nociceptors to mechanical stimulation through a mechanism that involves prostaglandin E2 release from SGCs. Attenuation of this sensitization by PEA suggests a possible option for acute management of craniofacial pain and headache.

TRPV1 receptor blockade is ineffective in different in vivo models of migraine

It has been proposed that TRPV1 receptors may play a role modulating trigeminal sensory processing. We used models of trigeminovascular nociceptive activation to study the involvement of TRPV1 receptors in the rat. Due to a possible role of TRPV1 receptors in cortical spreading depression (CSD), an experimental phenomenon sharing many features with migraine aura, we also utilized a model of mechanically induced CSD. Male Sprague Dawley rats (N = 39) were anesthetized and cannulated for monitoring and drug administration to study the effects of the TRPV1 receptor antagonist A-993610 (8 mg kg(-1) IV). Wide-dynamic-range neurons, responding to electrical stimulation of the middle meningeal artery (MMA)/dura mater were identified and recorded using electrophysiological techniques. Intravital microscopy was used to study neurogenic dural vasodilation (NDV) of the MMA comparing capsaicin and electrical stimulation, and the effect of A-993610 on mechanically induced CSD was examined. Administration of A-993610 had no significant effect on trigeminal firing of A- or C-fibers elicited by electrical stimulation of the MMA. It also showed no effect on NDV whilst blocking vasodilation due to intravenous capsaicin injection. The mechanically induced CSD response could not be altered by A-993610 administration. Although there is evidence that TRPV1 receptors play an important role in sensory processing in general, the new data do not support a role in the treatment of acute migraine.

Migraine: An Endemic Disease Inside the Blood–Brain Barrier

Migraine is a complex neurological disorder that in recent years has received more and more attention. Knowledge regarding this primary headache has increased substantially, both with respect to its pathogenesis and how to effectively treat its symptoms. Over the years, the proposed location of the onset of migraine has moved from the periphery of the nervous system toward deeper parts of the brain. Migraine can be viewed as an inherited failure of trigeminal sensory processing with abnormal neuronal excitability in the trigeminal nucleus caudalis, which, in turn, causes central sensitization and amplification of the pain. Increased activation of the trigeminal nerve during a migraine attack causes release of the calcitonin gene-related peptide (CGRP) inside and outside the BBB. Within the CNS, CGRP promotes trigeminal sensory input and facilitates central sensitization. The future introduction of CGRP antagonists in clinical practice could represent significant progress for acute migraine therapy.

A Role For Wind-Up in Trigeminal Sensory Processing: Intensity Coding of Nociceptive Stimuli in the Rat

Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres. The correlate of wind-up in humans is temporal summation, which is an increase in pain perception to repetitive constant nociceptive stimulation. Although wind-up is widely used as a tool for studying the processing of nociceptive information, including central sensitization, its actual role is still unknown. Here, we recorded from trigeminal WDR neurons using in vivo electrophysiological techniques in rats and assessed the wind-up phenomenon in response to stimuli of different intensities and frequencies. First, we found that the amplitude of C-evoked responses of WDR neurons to repetitive stimulation increased progressively to reach a peak, then consistently showed a stable or slightly decreasing plateau phase. Only the first phase of this time course fitted in with the wind-up description. Therefore, to assess wind-up, we measured a limited number of initial responses. Second, we showed that wind-up, i.e. the slope of the frequency-dependent increase in the response to C-fibre stimulation, was linearly correlated to the stimulus intensity. Intensities of brief C-fibre inputs were thus coded into frequencies of action potentials by second-order neurons through frequency-dependent potentiation of the evoked responses. Third, wind-up also occurred at stimulation intensities below the threshold for C-evoked responses in WDR neurons, suggesting that wind-up can amplify subthreshold C-fibre inputs to WDR neurons. This might account for the observation that sparse, subliminal, neuronal activity in nociceptors can become painful via central integration of neural responses. Altogether, the present results show that wind-up can provide trigeminal WDR neurons with the capability to encode the intensity of short-duration orofacial nociceptive stimuli and to detect subthreshold nociceptive input. Thus, not only may wind-up play a physiological role in trigeminal sensory processing, but its enhancement may also underlie the pathophysiology of chronic orofacial pain conditions.

Acute migraine headache: possible sensitization of neurons in the spinal trigeminal nucleus?

Neurology. 2002;58:1234‐1238.OBJECTIVE: To investigate trigeminal sensory processing in patients with migraine using a novel “nociception‐specific” blink reflex. METHODS: Seventeen patients with unilateral migraine headache were studied within 6 hours of onset. Blink reflexes were elicited with a standard stimulating electrode (standard blink reflex) and concentric stimulating electrode (nociception‐specific blink reflex) during the acute migraine attack, after treatment with IV lysine acetylsalicylate (1,000 mg) or oral zolmitriptan (5 mg) and interictally. RESULTS: After standard stimulation, no differences were detected for the R1 and R2 onset latencies and areas under the curve (AUC) between the different time points and the headache and nonheadache side. Nociception‐specific stimulation revealed a shortening of R2 onset latencies (44.3 ± 5.4 ms for headache side vs 48.9 ± 5.8 ms for nonheadache side) during the acute migraine attack compared with the headache‐free interval (49.8 ± 5.3 vs 49.8 ± 4.5 ms). The AUC of the R2 increased on the headache side by 680% and on the nonheadache side by 230% compared with the headache‐free interval. Drug treatment parallel to pain relief increased the onset latencies (zolmitriptan: 48.0 ± 8.2 ms for headache side vs 52.3 ± 7.6 ms for nonheadache side; lysine acetylsalicylate: 48.0 ± 5.0 ms for headache side vs 51.2 ± 5.6 ms for nonheadache side) and reduced the AUC of R2 (zolmitriptan by 45% and lysine acetylsalicylate by 48%). CONCLUSION: The data suggest temporary sensitization of central trigeminal neurons during acute migraine attacks. Comment: This abstract from Dr. Chris Diener's group reports large changes in the AUC for onset latencies between headache affected and nonaffected sides. Drug treatment effects were small. No statistical comparisons were reported. This noninvasive technique may be useful in further exploring the mechanisms which underlie the temporary sensitization of central trigeminal neurons during acute migraine attacks. DSM

The electrophysiology of migraine.

Migraine is currently regarded as a neurovascular disorder of trigeminal sensory processing, generated centrally, probably at the level of the brainstem. In the past, electrophysiological techniques have drawn no definite conclusions on either interictal or ictal changes in migraineurs compared with controls, largely because of methodological differences. Recently, two findings have been shown consistently: an interictal increasing lack of habituation of evoked potentials with a normalization at the start of the attack and strong intensity dependence of auditory evoked potentials. These findings substantiate migraine sufferers as having an abnormal trait interictally, with the attack characterized by a change in the state of central processing. Exploitation of these differences may be a useful tool to study the mechanism of action of drugs used for the treatment of migraine.