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Journal of Neuroinflammation Nov 2019Microglial activation contributes to the development of chronic migraine (CM). The P2Y12 receptor (P2Y12R), a metabolic purinoceptor that is expressed on microglia in...
BACKGROUND
Microglial activation contributes to the development of chronic migraine (CM). The P2Y12 receptor (P2Y12R), a metabolic purinoceptor that is expressed on microglia in the central nervous system (CNS), has been indicated to play a critical role in the pathogenesis of chronic pain. However, whether it contributes to the mechanism of CM remains unknown. Thus, the present study investigated the precise details of microglial P2Y12R involvement in CM.
METHODS
Mice subjected to recurrent nitroglycerin (NTG) treatment were used as the CM model. Hyperalgesia were assessed by mechanical withdrawal threshold to electronic von Frey and thermal withdrawal latency to radiant heat. Western blot and immunohistochemical analyses were employed to detect the expression of P2Y12R, Iba-1, RhoA, and ROCK2 in the trigeminal nucleus caudalis (TNC). To confirm the role of P2Y12R and RhoA/ROCK in CM, we systemically administered P2Y12R antagonists (MRS2395 and clopidogrel) and a ROCK2 inhibitor (fasudil) and investigated their effects on microglial activation, c-fos, and calcitonin gene-related peptide (CGRP) expression in the TNC. To further confirm the effect of P2Y12R on microglial activation, we preincubated lipopolysaccharide (LPS)-treated BV-2 microglia with MRS2395 and clopidogrel. ELISA was used to evaluate the levels of inflammatory cytokines.
RESULTS
The protein levels of P2Y12R, GTP-RhoA, ROCK2, CGRP, c-fos, and inducible nitric oxide synthase (iNOS) in the TNC were increased after recurrent NTG injection. A double labeling study showed that P2Y12R was restricted to microglia in the TNC. MRS2395 and clopidogrel attenuated the development of tactile allodynia and suppressed the expression of CGRP, c-fos, and GTP-RhoA/ROCK2 in the TNC. Furthermore, fasudil also prevented hyperalgesia and suppressed the expression of CGRP in the TNC. In addition, inhibiting P2Y12R and ROCK2 activities suppressed NTG-induced microglial morphological changes (process retraction) and iNOS production in the TNC. In vitro, a double labeling study showed that P2Y12R was colocalized with BV-2 cells, and the levels of iNOS, IL-1β, and TNF-α in LPS-stimulated BV-2 microglia were reduced by P2Y12R inhibitors.
CONCLUSIONS
These data demonstrate that microglial P2Y12R in the TNC plays a critical role in the pathogenesis of CM by regulating microglial activation in the TNC via RhoA/ROCK pathway.
Topics: Adenine; Animals; Clopidogrel; Disease Models, Animal; Mice; Microglia; Migraine Disorders; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Signal Transduction; Trigeminal Nuclei; Valerates; rho-Associated Kinases; rhoA GTP-Binding Protein
PubMed: 31722730
DOI: 10.1186/s12974-019-1603-4 -
Diagnostic and Interventional Imaging Oct 2013Two different clinical entities, essential or secondary neuralgia, are associated with different pathologies. The pathways of CN V comprise the cervical spine, the... (Review)
Review
Two different clinical entities, essential or secondary neuralgia, are associated with different pathologies. The pathways of CN V comprise the cervical spine, the brainstem, the root of the nerve and the three peripheral branches: V1, V2 and V3. The lesions responsible for neuralgia are neoplastic, vascular, inflammatory, malformative or post-traumatic. The examination protocol should explore the set of CN V pathways. Neurovascular compression is the main cause of essential neuralgia. It is investigated by T2-weighted inframillimetric volume. Two conditions are necessary to diagnose a neurovascular compression: localised on the root entry zone [(REZ), 2-6mm from the emergence of the pons] and perpendicularly. In the absence of neurovascular compression, thin slices and a gadolinium injection are necessary.
Topics: Cranial Nerve Neoplasms; Diagnosis, Differential; Humans; Image Enhancement; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Nerve Compression Syndromes; Neural Pathways; Neurologic Examination; Sensitivity and Specificity; Trigeminal Nerve; Trigeminal Nerve Diseases; Trigeminal Nerve Injuries; Trigeminal Neuralgia; Trigeminal Nuclei
PubMed: 24007773
DOI: 10.1016/j.diii.2013.08.002 -
Journal of Oral & Maxillofacial Research Jan 2013The aim of present paper was to discuss issues related to trigeminal neuralgia with strong emphasis on the aetiology and pathogenesis of this problem. (Review)
Review
OBJECTIVES
The aim of present paper was to discuss issues related to trigeminal neuralgia with strong emphasis on the aetiology and pathogenesis of this problem.
MATERIAL AND METHODS
An electronic search of 5 databases (1965 - Oct 2012) and a hand search of peer-reviewed journals for relevant articles were performed. In addition, experience acquired from treating 3263 patients in the Department of Maxillofacial Surgery, Lithuanian University of Health Sciences, were also summarized.
RESULTS
Generally, aetiological factors can be classified into 3 most popular theories that were based on: 1) Related to other disease, 2) Direct injury to the trigeminal nerve, and 3) Propagates the polyetiologic origin of the disease. In addition, two pathogenesis mechanisms of trigeminal neuralgia were proposed. First: the peripheral pathogenetic mechanism that is often induced by progressive dystrophy around the peripheral branches of the trigeminal nerve. Second, central pathogenetic mechanism which often triggered by peripheral pathogen that causes long-lasting afferent impulsation and the formation of a stable pathologic paroxysmal type irritation focus on the central nerve system (CNS).
CONCLUSIONS
Patients with susceptive trigeminal neuralgia should be examined carefully by specialists who have expertise in assessing and diagnosing of possible pathological processes and be able to eliminate the contributing factors so the trigeminal neuralgia can be properly managed.
PubMed: 24422020
DOI: 10.5037/jomr.2012.3402 -
Experimental Neurology Jan 2016
Topics: Animals; Animals, Newborn; Female; Humans; Infant, Newborn; Neuronal Plasticity; Peripheral Nerve Injuries; Pregnancy; Sensory Receptor Cells; Synapses; Trigeminal Nuclei
PubMed: 26689323
DOI: 10.1016/j.expneurol.2015.07.007 -
Journal of Vestibular Research :... 2011The cardinal symptom of migraine is headache pain. In this paper we review the neurobiology of this pain as it is currently understood. In recent years, we discovered... (Review)
Review
The cardinal symptom of migraine is headache pain. In this paper we review the neurobiology of this pain as it is currently understood. In recent years, we discovered that the network of neurons that sense pain signals from the dura changes rapidly during the course of a single migraine attack and that the treatment of an attack is a moving target. We found that if the pain is not stopped within 10-20 minutes after it starts, the first set of neurons in the network, those located in the trigeminal ganglion, undergo molecular changes that make them hypersensitive to the changing pressure inside the head, which explains why migraine headache throbs and is worsened by bending over and sneezing. We found that if the pain is not stopped within 60-120 minutes, the second group of neurons in the network, those located in the spinal trigeminal nucleus, undergoes molecular changes that convert them from being dependent on sensory signals they receive from the dura by the first set of neurons, into an independent state in which they themselves become the pain generator of the headache. When this happens, patients notice that brushing their hair, taking a shower, touching their periorbital skin, shaving, wearing earrings, etc become painful, a condition called cutaneous allodynia. Based on this scenario, we showed recently that the success rate of rendering migraine patients pain-free increased dramatically if medication was given before the establishment of cutaneous allodynia and central sensitization. The molecular shift from activity-dependent to activity-independent central sensitization together with our recent conclusion that triptans have the ability to disrupt communications between peripheral and central trigeminovascular neurons (rather than inhibiting directly peripheral or central neurons) explain their clinical effects. Both our clinical and pre-clinical findings of the last five years point to possible short- and long-term advantages in using an early-treatment approach in the treatment of acute migraine attacks.
Topics: Afferent Pathways; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Central Nervous System Sensitization; Cortical Spreading Depression; Drug Administration Schedule; Humans; Hyperalgesia; Inflammation; Intracranial Pressure; Ion Channels; Meninges; Migraine Disorders; Nerve Net; Nociceptors; Pain; Pain Threshold; Posterior Horn Cells; Rats; Serotonin 5-HT1 Receptor Agonists; Trigeminal Ganglion; Trigeminal Nuclei; Vasodilation
PubMed: 22348935
DOI: 10.3233/VES-2012-0433 -
Nature Reviews. Neuroscience Apr 2010The facial somatosensory map in the cortex is derived from facial representations that are first established at the brainstem level and then serially 'copied' at each... (Review)
Review
The facial somatosensory map in the cortex is derived from facial representations that are first established at the brainstem level and then serially 'copied' at each stage of the somatosensory pathway. Recent studies have provided insights into the molecular mechanisms involved in the development of somatotopic maps of the face and whiskers in the trigeminal nuclei of the mouse brainstem. This work has revealed that early molecular regionalization and positional patterning of trigeminal ganglion and brainstem target neurons are established by homeodomain transcription factors, the expression of which is induced and maintained by signals from the brain and face. Such position-dependent information is fundamental in transforming the early spatial layout of sensory receptors into a topographic connectivity map that is conferred to higher brain levels.
Topics: Afferent Pathways; Animals; Body Patterning; Brain; Brain Mapping; Brain Stem; Face; Homeodomain Proteins; Mice; Neurons; Sensation; Sensory Receptor Cells; Signal Transduction; Transcription Factors; Trigeminal Ganglion; Trigeminal Nuclei; Vibrissae
PubMed: 20179712
DOI: 10.1038/nrn2804 -
Cephalalgia : An International Journal... May 2023The human in-vivo functional somatotopy of the three branches of the trigeminal (V1, V2, V3) and greater occipital nerve in brainstem and also in thalamus and insula is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The human in-vivo functional somatotopy of the three branches of the trigeminal (V1, V2, V3) and greater occipital nerve in brainstem and also in thalamus and insula is still not well understood.
METHODS
After preregistration (clinicaltrials.gov: NCT03999060), we mapped the functional representations of this trigemino-cervical complex non-invasively in 87 humans using high-resolution protocols for functional magnetic resonance imaging during painful electrical stimulation in two separate experiments. The imaging protocol and analysis was optimized for the lower brainstem and upper spinal cord, to identify activation of the spinal trigeminal nuclei. The stimulation protocol involved four electrodes which were positioned on the left side according to the three branches of the trigeminal nerve and the greater occipital nerve. The stimulation site was randomized and each site was repeated 10 times per session. The participants partook in three sessions resulting in 30 trials per stimulation site.
RESULTS
We show a large overlap of peripheral dermatomes on brainstem representations and a somatotopic arrangement of the three branches of the trigeminal nerve along the perioral-periauricular axis and for the greater occipital nerve in brainstem below pons, as well as in thalamus, insula and cerebellum. The co-localization of greater occipital nerve with V1 along the lower part of brainstem is of particular interest since some headache patients profit from an anesthetic block of the greater occipital nerve.
CONCLUSION
Our data provide anatomical evidence for a functional inter-inhibitory network between the trigeminal branches and greater occipital nerve in healthy humans as postulated in animal work. We further show that functional trigeminal representations intermingle perioral and periauricular facial dermatomes with individual branches of the trigeminal nerve in an onion shaped manner and overlap in a typical within-body-part somatotopic arrangement.Trial registration: clinicaltrials.gov: NCT03999060.
Topics: Animals; Humans; Brain Stem; Headache; Pain; Trigeminal Nerve; Trigeminal Nucleus, Spinal
PubMed: 37203351
DOI: 10.1177/03331024231174862 -
Journal of Cerebral Blood Flow and... Apr 2019Vascular theories of migraine and cluster headache have dominated for many years the pathobiological concept of these disorders. This view is supported by observations... (Review)
Review
Vascular theories of migraine and cluster headache have dominated for many years the pathobiological concept of these disorders. This view is supported by observations that trigeminal activation induces a vascular response and that several vasodilating molecules trigger acute attacks of migraine and cluster headache in susceptible individuals. Over the past 30 years, this rationale has been questioned as it became clear that the actions of some of these molecules, in particular, calcitonin gene-related peptide and pituitary adenylate cyclase-activating peptide, extend far beyond the vasoactive effects, as they possess the ability to modulate nociceptive neuronal activity in several key regions of the trigeminovascular system. These findings have shifted our understanding of these disorders to a primarily neuronal origin with the vascular manifestations being the consequence rather than the origin of trigeminal activation. Nevertheless, the neurovascular component, or coupling, seems to be far more complex than initially thought, being involved in several accompanying features. The review will discuss in detail the anatomical basis and the functional role of the neurovascular mechanisms relevant to migraine and cluster headache.
Topics: Animals; Calcitonin Gene-Related Peptide; Cluster Headache; Humans; Migraine Disorders; Neurovascular Coupling; Pituitary Adenylate Cyclase-Activating Polypeptide; Trigeminal Nuclei
PubMed: 28948863
DOI: 10.1177/0271678X17733655 -
Molecular Brain May 2020The linear nucleus (Li) was identified in 1978 from its projections to the cerebellum. However, there is no systematic study of its connections with other areas of the...
The linear nucleus (Li) was identified in 1978 from its projections to the cerebellum. However, there is no systematic study of its connections with other areas of the central nervous system possibly due to the challenge of injecting retrograde tracers into this nucleus. The present study examines its afferents from some nuclei involved in motor and cardiovascular control with anterograde tracer injections. BDA injections into the central amygdaloid nucleus result in labeled fibers to the ipsilateral Li. Bilateral projections with an ipsilateral dominance were observed after injections in a) jointly the paralemniscal nucleus, the noradrenergic group 7/ Köllike -Fuse nucleus/subcoeruleus nucleus, b) the gigantocellular reticular nucleus, c) and the solitary nucleus/the parvicellular/intermediate reticular nucleus. Retrogradely labeled neurons were observed in Li after BDA injections into all these nuclei except the central amygdaloid and the paralemniscal nuclei. Our results suggest that Li is involved in a variety of physiological functions apart from motor and balance control it may exert via its cerebellar projections.
Topics: Afferent Pathways; Amygdala; Animals; Biotin; Cerebellum; Dextrans; Dorsal Raphe Nucleus; Medulla Oblongata; Mice; Mice, Inbred C57BL; Neural Pathways; Neurons; Pontine Tegmentum; Trigeminal Nuclei; Vestibular Nuclei
PubMed: 32370769
DOI: 10.1186/s13041-020-00602-8 -
The Journal of Headache and Pain Apr 2022Adenosine is a purinergic signaling molecule with a wide range of physiological functions including anti- and pronociceptive properties. Adenosine receptors are... (Review)
Review
BACKGROUND
Adenosine is a purinergic signaling molecule with a wide range of physiological functions including anti- and pronociceptive properties. Adenosine receptors are expressed in the trigeminovascular system, and adenosine receptor antagonist, caffeine, relieves migraine headache. We performed a systematic review of the literature of preclinical data addressing the role of adenosine in migraine pathophysiology.
METHODS
PubMed and EMBASE were searched for pre-clinical studies on the role of adenosine in migraine pathophysiology on September 5, 2021.
RESULTS
A total of 2510 studies were screened by title and abstract. Of these, thirteen pre-clinical studies evaluating adenosine, adenosine A1, A2A and A3 receptors were included. These studies showed that adenosine signaling pathway is involved in controlling vascular tone. Furthermore, electrical stimulation of the trigeminal ganglion modulates the expression of adenosine A and A receptors in the trigeminal ganglion and trigeminal nucleus caudalis implicating adenosine signaling pathway in pain transmission.
CONCLUSION
Preclinical studies showed that adenosine has a dual effect on vasodilation and trigeminal pain pathway due to different receptor activation, suggesting a possible role of adenosine in migraine pathophysiology. Studies investigating pharmacological characteristics of subtypes of adenosine receptors are needed to further elucidate their role as a potential target for migraine treatment.
Topics: Adenosine; Humans; Migraine Disorders; Signal Transduction; Trigeminal Ganglion; Trigeminal Nuclei
PubMed: 35382738
DOI: 10.1186/s10194-022-01412-0