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International Journal of Molecular... Mar 2022Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying... (Review)
Review
Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.
Topics: Animals; Facial Pain; Humans; Multiple Sclerosis; Neuralgia; Trigeminal Nerve; Trigeminal Neuralgia
PubMed: 35408959
DOI: 10.3390/ijms23073604 -
Neuron Jun 2022Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes...
Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes that are involved remain unclear. We thus developed a cell atlas in which human and mouse trigeminal ganglia are transcriptionally and epigenomically profiled at single-cell resolution. These data describe evolutionarily conserved and human-specific gene expression patterns within each trigeminal ganglion cell type, as well as the transcription factors and gene regulatory elements that contribute to cell-type-specific gene expression. We then leveraged these data to identify trigeminal ganglion cell types that are implicated both by human genetic variation associated with migraine and two mouse models of headache. This trigeminal ganglion cell atlas improves our understanding of the cell types, genes, and epigenomic features involved in headache pathophysiology and establishes a rich resource of cell-type-specific molecular features to guide the development of more selective treatments for headache and facial pain.
Topics: Animals; Disease Models, Animal; Headache; Humans; Mice; Migraine Disorders; Neurons; Trigeminal Ganglion
PubMed: 35349784
DOI: 10.1016/j.neuron.2022.03.003 -
The Journal of Headache and Pain Jun 2020Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to... (Review)
Review
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT receptors. The discovery that the serotonin 1F (5-HT) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT receptors, the activation of 5-HT receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
Topics: Animals; Benzamides; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neurons; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines; Vasoconstriction; Receptor, Serotonin, 5-HT1F
PubMed: 32522164
DOI: 10.1186/s10194-020-01132-3 -
Oral Diseases Nov 2019The natural history of oral herpes simplex virus type 1 (HSV-1) infection in the immunocompetent host is complex and rich in controversial phenomena, namely the role of... (Review)
Review
The natural history of oral herpes simplex virus type 1 (HSV-1) infection in the immunocompetent host is complex and rich in controversial phenomena, namely the role of unapparent transmission in primary infection acquisition, the high frequency of asymptomatic primary and recurrent infections, the lack of immunogenicity of HSV-1 internalized in the soma (cell body) of the sensory neurons of the trigeminal ganglion, the lytic activity of HSV-1 in the soma of neurons that is inhibited in the sensory neurons of the trigeminal ganglion and often uncontrolled in the other neurons, the role of keratin in promoting the development of recurrence episodes in immunocompetent hosts, the virus-host Nash equilibrium, the paradoxical HSV-1-seronegative individuals who shed HSV-1 through saliva, the limited efficacy of anti-HSV vaccines, and why the oral route of infection is the least likely to produce severe complications. The natural history of oral HSV-1 infection is also a history of symbiosis between humans and virus that may switch from mutualism to parasitism and vice versa. This balance is typical of microorganisms that are highly coevolved with humans, and its knowledge is essential to oral healthcare providers to perform adequate diagnosis and provide proper individual-based HSV-1 infection therapy.
Topics: Herpes Labialis; Herpes Simplex; Herpesvirus 1, Human; Humans; Stomatitis, Herpetic; Trigeminal Ganglion
PubMed: 31733122
DOI: 10.1111/odi.13234 -
Neuron Mar 2022Self-grooming is a complex behavior with important biological functions and pathological relevance. How the brain coordinates with the spinal cord to generate the...
Self-grooming is a complex behavior with important biological functions and pathological relevance. How the brain coordinates with the spinal cord to generate the repetitive movements of self-grooming remains largely unknown. Here, we report that in the caudal part of the spinal trigeminal nucleus (Sp5C), neurons that express Cerebellin-2 (Cbln2) form a neural circuit to the cervical spinal cord to maintain repetitive orofacial self-grooming. Inactivation of Cbln2 Sp5C neurons blocked both sensory-evoked and stress-induced repetitive orofacial self-grooming. Activation of these neurons triggered short-latency repetitive forelimb movements that resembled orofacial self-grooming. The Cbln2 Sp5C neurons were monosynaptically innervated by both somatosensory neurons in the trigeminal ganglion and paraventricular hypothalamic neurons. Among the divergent projections of Cbln2 Sp5C neurons, a descending pathway that innervated motor neurons and interneurons in the cervical spinal cord was necessary and sufficient for repetitive orofacial self-grooming. These data reveal a brain-to-spinal sensorimotor loop for repetitive self-grooming in mice.
Topics: Animals; Brain; Grooming; Hypothalamus; Mice; Neurons; Spinal Cord
PubMed: 34932943
DOI: 10.1016/j.neuron.2021.11.028 -
The Journal of Headache and Pain Apr 2023The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as mediators of migraine... (Review)
Review
The neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have emerged as mediators of migraine pathogenesis. Both are vasodilatory peptides that can cause migraine-like attacks when infused into people and migraine-like symptoms when injected into rodents. In this narrative review, we compare the similarities and differences between the peptides in both their clinical and preclinical migraine actions. A notable clinical difference is that PACAP, but not CGRP, causes premonitory-like symptoms in patients. Both peptides are found in distinct, but overlapping areas relevant to migraine, most notably with the prevalence of CGRP in trigeminal ganglia and PACAP in sphenopalatine ganglia. In rodents, the two peptides share activities, including vasodilation, neurogenic inflammation, and nociception. Most strikingly, CGRP and PACAP cause similar migraine-like symptoms in rodents that are manifested as light aversion and tactile allodynia. Yet, the peptides appear to act by independent mechanisms possibly by distinct intracellular signaling pathways. The complexity of these signaling pathways is magnified by the existence of multiple CGRP and PACAP receptors that may contribute to migraine pathogenesis. Based on these differences, we suggest PACAP and its receptors provide a rich set of targets to complement and augment the current CGRP-based migraine therapeutics.
Topics: Humans; Pituitary Adenylate Cyclase-Activating Polypeptide; Calcitonin Gene-Related Peptide; Migraine Disorders; Trigeminal Ganglion; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
PubMed: 37009867
DOI: 10.1186/s10194-023-01569-2 -
BioRxiv : the Preprint Server For... Jul 2023Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including...
Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory ganglia cell types in rodents, non-human primates, and humans, but it remains difficult to compare transcriptomically defined cell types across studies and species. Here, we built cross-species harmonized atlases of DRG and TG cell types that describe 18 neuronal and 11 non-neuronal cell types across 6 species and 19 studies. We then demonstrate the utility of this harmonized reference atlas by using it to annotate newly profiled DRG nuclei/cells from both human and the highly regenerative axolotl. We observe that the transcriptomic profiles of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The new resources and data presented here can guide future studies in comparative transcriptomics, simplify cell type nomenclature differences across studies, and help prioritize targets for future pain therapy development.
PubMed: 37461736
DOI: 10.1101/2023.07.04.547740 -
Journal of the Royal Society, Interface Sep 2019Birds can use two kinds of information from the geomagnetic field for navigation: the direction of the field lines as a compass and probably magnetic intensity as a... (Review)
Review
Birds can use two kinds of information from the geomagnetic field for navigation: the direction of the field lines as a compass and probably magnetic intensity as a component of the navigational 'map'. The direction of the magnetic field appears to be sensed via radical pair processes in the eyes, with the crucial radical pairs formed by cryptochrome. It is transmitted by the optic nerve to the brain, where parts of the visual system seem to process the respective information. Magnetic intensity appears to be perceived by magnetite-based receptors in the beak region; the information is transmitted by the ophthalmic branch of the trigeminal nerve to the trigeminal ganglion and the trigeminal brainstem nuclei. Yet in spite of considerable progress in recent years, many details are still unclear, among them details of the radical pair processes and their transformation into a nervous signal, the precise location of the magnetite-based receptors and the centres in the brain where magnetic information is combined with other navigational information for the navigational processes.
Topics: Animal Migration; Animals; Birds; Cryptochromes; Magnetic Fields; Orientation; Perception
PubMed: 31480921
DOI: 10.1098/rsif.2019.0295 -
International Journal of Molecular... May 2020Piezo channels are mechanosensitive ion channels. Piezo1 is primarily expressed in nonsensory tissues, whereas Piezo2 is predominantly found in sensory tissues,...
Piezo channels are mechanosensitive ion channels. Piezo1 is primarily expressed in nonsensory tissues, whereas Piezo2 is predominantly found in sensory tissues, including dorsal root ganglion (DRG) neurons. However, a recent study demonstrated the intracellular calcium response to Yoda1, a selective Piezo1 agonist, in trigeminal ganglion (TG) neurons. Herein, we investigate the expression of mRNA and protein in mouse and human DRG neurons and the activation of Piezo1 via calcium influx by Yoda1. Yoda1 induces inward currents mainly in small- (< 25 μm) and medium-sized (25-35 μm) mouse DRG neurons. The Yoda1-induced Ca response is inhibited by cationic channel blocker, ruthenium red and cationic mechanosensitive channel blocker, GsMTx4. To confirm the specific inhibition of Piezo1, we performed an adeno-associated virus serotype 2/5 (AAV2/5)-mediated delivery of short hairpin RNA (shRNA) into mouse DRG neurons. AAV2/5 transfection downregulates mRNA expression and reduces Ca response by Yoda1. Piezo1 also shows physiological functions with transient receptor potential vanilloid 1 (TRPV1) in the same DRG neurons and is regulated by the activation of TRPV1 in mouse DRG sensory neurons. Overall, we found that Piezo1 has physiological functions in DRG neurons and that TRPV1 activation inhibits an inward current induced by Yoda1.
Topics: Animals; Calcium; Cells, Cultured; Dependovirus; Female; Ganglia, Spinal; Gene Expression Regulation; Humans; Ion Channels; Male; Mechanotransduction, Cellular; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Pyrazines; RNA, Small Interfering; Sensory Receptor Cells; TRPV Cation Channels; Thiadiazoles; Trigeminal Ganglion
PubMed: 32481599
DOI: 10.3390/ijms21113834