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Cephalalgia : An International Journal... Feb 2023OnabotulinumtoxinA (onabotA) is approved globally for prevention of chronic migraine; however, the classical mechanism of action of onabotA in motor and autonomic...
BACKGROUND
OnabotulinumtoxinA (onabotA) is approved globally for prevention of chronic migraine; however, the classical mechanism of action of onabotA in motor and autonomic neurons cannot fully explain the effectiveness of onabotulinumtoxinA in this sensory neurological disease. We sought to explore the direct effects of onabotulinumtoxinA on mouse trigeminal ganglion sensory neurons using an inflammatory soup-based model of sensitization.
METHODS
Primary cultured trigeminal ganglion neurons were pre-treated with inflammatory soup, then treated with onabotulinumtoxinA (2.75 pM). Treated neurons were used to examine transient receptor potential vanilloid subtype 1 and transient receptor potential ankyrin 1 cell-surface expression, calcium influx, and neuropeptide release.
RESULTS
We found that onabotulinumtoxinA cleaved synaptosomal-associated protein-25 kDa in cultured trigeminal ganglion neurons; synaptosomal-associated protein-25 kDa cleavage was enhanced by inflammatory soup pre-treatment, suggesting greater uptake of toxin under sensitized conditions. OnabotulinumtoxinA also prevented inflammatory soup-mediated increases in TRPV1 and TRPA1 cell-surface expression, without significantly altering TRPV1 or TRPA1 protein expression in unsensitized conditions. We observed similar inhibitory effects of onabotulinumtoxinA on TRP-mediated calcium influx and TRPV1- and TRPA1-mediated release of calcitonin gene-related peptide and prostaglandin 2 under sensitized, but not unsensitized control, conditions.
CONCLUSIONS
Our data deepen the understanding of the sensory mechanism of action of onabotulinumtoxinA and support the notion that, once endocytosed, the cytosolic light chain of onabotulinumtoxinA cleaves synaptosomal-associated protein-25 kDa to prevent soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated processes more generally in motor, autonomic, sensory neurons.
Topics: Mice; Animals; Nociceptors; Transient Receptor Potential Channels; Botulinum Toxins, Type A; Calcium; Sensory Receptor Cells; Trigeminal Ganglion; TRPV Cation Channels; TRPA1 Cation Channel
PubMed: 36751871
DOI: 10.1177/03331024221141683 -
The Journal of Headache and Pain Nov 2022Excruciating trigeminal neuralgia (TN) management is very difficult and severely affects the patient's quality of life. Earlier studies have shown that the trigeminal... (Review)
Review
Excruciating trigeminal neuralgia (TN) management is very difficult and severely affects the patient's quality of life. Earlier studies have shown that the trigeminal ganglion (TG) comprises several receptors and signal molecules that are involved in the process of peripheral sensitization, which influences the development and persistence of neuropathic pain. Targeting TG can modulate this sensitization pathway and mediate the pain-relieving effect. So far,there are few studies in which modulation approaches to TG itself have been suggested so far. "Trigeminal ganglion modulation" and "trigeminal neuralgia" were used as search phrases in the Scopus Index and PubMed databases to discover articles that were pertinent to the topic. In this review, we address the role of the trigeminal ganglion in TN and underlying molecules and neuropeptides implicated in trigeminal pain pathways in processing pathological orofacial pain. We also reviewed different modulation approaches in TG for TN management. Furthermore, we discuss the prospect of targeting trigeminal ganglion to manage such intractable pain.
Topics: Humans; Trigeminal Ganglion; Quality of Life; Trigeminal Neuralgia; Neuralgia; Facial Pain
PubMed: 36424545
DOI: 10.1186/s10194-022-01512-x -
Cephalalgia : An International Journal... Nov 2019The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its... (Review)
Review
INTRODUCTION
The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its cellular components. Being mainly responsible for the sensory innervation of the anterior regions of the head, it is a major target for headache research. One intriguing question is if the trigeminal ganglion is merely a transition site for sensory information from the periphery to the central nervous system, or if intracellular modulatory mechanisms and intercellular signaling are capable of controlling sensory information relevant for the pathophysiology of headaches.
METHODS
An online search based on PubMed was made using the keyword "trigeminal ganglion" in combination with "anatomy", "headache", "migraine", "neuropeptides", "receptors" and "signaling". From the relevant literature, further references were selected in view of their relevance for headache mechanisms. The essential information was organized based on location and cell types of the trigeminal ganglion, neuropeptides, receptors for signaling molecules, signaling mechanisms, and their possible relevance for headache generation.
RESULTS
The trigeminal ganglion consists of clusters of sensory neurons and their peripheral and central axon processes, which are arranged according to the three trigeminal partitions V1-V3. The neurons are surrounded by satellite glial cells, the axons by Schwann cells. In addition, macrophage-like cells can be found in the trigeminal ganglion. Neurons express various neuropeptides, among which calcitonin gene-related peptide is the most prominent in terms of its prevalence and its role in primary headaches. The classical calcitonin gene-related peptide receptors are expressed in non-calcitonin gene-related peptide neurons and satellite glial cells, although the possibility of a second calcitonin gene-related peptide receptor in calcitonin gene-related peptide neurons remains to be investigated. A variety of other signal molecules like adenosine triphosphate, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion cells and may act at receptors on adjacent neurons or satellite glial cells.
CONCLUSIONS
The trigeminal ganglion may act as an integrative organ. The morphological and functional arrangement of trigeminal ganglion cells suggests that intercellular and possibly also autocrine signaling mechanisms interact with intracellular mechanisms, including gene expression, to modulate sensory information. Receptors and neurotrophic factors delivered to the periphery or the trigeminal brainstem can contribute to peripheral and central sensitization, as in the case of primary headaches. The trigeminal ganglion as a target of drug action outside the blood-brain barrier should therefore be taken into account.
Topics: Adenosine Triphosphate; Afferent Pathways; Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Cytokines; Headache; Humans; Intercellular Signaling Peptides and Proteins; Migraine Disorders; Nerve Growth Factors; Neuropeptides; Nitric Oxide; Nociception; Rats; Receptors, Calcitonin Gene-Related Peptide; Receptors, Neuropeptide; Sensory Receptor Cells; Signal Transduction; Trigeminal Ganglion
PubMed: 29989427
DOI: 10.1177/0333102418786261 -
Advances in Biological Regulation May 2016Somatosensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are responsible for detecting thermal and tactile stimuli. They are also the primary... (Review)
Review
Somatosensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are responsible for detecting thermal and tactile stimuli. They are also the primary neurons mediating pain and itch. A large number of cell surface receptors in these neurons couple to phospholipase C (PLC) enzymes leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and the generation of downstream signaling molecules. These neurons also express many different ion channels, several of which are regulated by phosphoinositides. This review will summarize the knowledge on phosphoinositide signaling in DRG neurons, with special focus on effects on sensory and other ion channels.
Topics: Animals; Calcium; Ganglia, Spinal; Gene Expression Regulation; Humans; Ion Channels; Isoenzymes; Neurons; Pain Perception; Phosphatidylinositol 4,5-Diphosphate; Sensory Thresholds; Signal Transduction; Touch Perception; Trigeminal Ganglion; Type C Phospholipases
PubMed: 26724974
DOI: 10.1016/j.jbior.2015.11.012 -
Neuroscience Jan 2018A fundamental question in the investigation of any sensory system is what physical signals drive its sensory neurons during natural behavior. Surprisingly, in the... (Review)
Review
A fundamental question in the investigation of any sensory system is what physical signals drive its sensory neurons during natural behavior. Surprisingly, in the whisker system, it is only recently that answers to this question have emerged. Here, we review the key developments, focussing mainly on the first stage of the ascending pathway - the primary whisker afferents (PWAs). We first consider a biomechanical framework, which describes the fundamental mechanical forces acting on the whiskers during active sensation. We then discuss technical progress that has allowed such mechanical variables to be estimated in awake, behaving animals. We discuss past electrophysiological evidence concerning how PWAs function and reinterpret it within the biomechanical framework. Finally, we consider recent studies of PWAs in awake, behaving animals and compare the results to related studies of the cortex. We argue that understanding 'what the whiskers tell the brain' sheds valuable light on the computational functions of downstream neural circuits, in particular, the barrel cortex.
Topics: Afferent Pathways; Animals; Biomechanical Phenomena; Somatosensory Cortex; Touch Perception; Trigeminal Ganglion; Vibrissae
PubMed: 28843998
DOI: 10.1016/j.neuroscience.2017.08.005 -
Current Biology : CB Feb 2022Sensory nerves are information bottlenecks giving rise to distinct sensory worlds across animal species. Here, we investigate trigeminal ganglion and sensory nerves of...
Sensory nerves are information bottlenecks giving rise to distinct sensory worlds across animal species. Here, we investigate trigeminal ganglion and sensory nerves of elephants. The elephant trigeminal ganglion is very large. Its maxillary branch, which gives rise to the infraorbital nerve innervating the trunk, has a larger diameter than the animal's spinal cord, i.e., trunk innervation is more substantive than connections of the brain to the rest of the body. Hundreds of satellite cells surround each trigeminal neuron, an indication of exceptional glial support to these large projection neurons. Fiber counts of Asian elephant infraorbital nerves of averaged 4,00,000 axons. The infraorbital nerve consists of axons that are ∼10 μm thick and it has a large diameter of 17 mm, roughly 3 times as thick as the optic and 6 times as thick as the vestibulocochlear nerve. In most mammals (including tactile specialists) optic nerve fibers greatly outnumber infraorbital nerve fibers, but in elephants the infraorbital nerve fiber count is only slightly lower than the optic nerve fiber count. Trunk innervation (nerves and ganglia) weighs ∼1.5 kg in elephant cows. Our findings characterize the elephant trigeminal ganglion as one of the largest known primary sensory structures and point to a high degree of tactile specialization in elephants.
Topics: Afferent Pathways; Animals; Axons; Cattle; Elephants; Female; Neurons; Trigeminal Ganglion
PubMed: 35063122
DOI: 10.1016/j.cub.2021.12.051 -
Journal of Neural Transmission (Vienna,... Apr 2020The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons... (Review)
Review
The trigeminal ganglion with its three trigeminal nerve tracts consists mainly of clusters of sensory neurons with their peripheral and central processes. Most neurons are surrounded by satellite glial cells and the axons are wrapped by myelinating and non-myelinating Schwann cells. Trigeminal neurons express various neuropeptides, most notably, calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP). Two types of CGRP receptors are expressed in neurons and satellite glia. A variety of other signal molecules like ATP, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion neurons and signal to neighboring neurons or satellite glial cells, which can signal back to neurons with same or other mediators. This potential cross-talk of signals involves intracellular mechanisms, including gene expression, that can modulate mediators of sensory information, such as neuropeptides, receptors, and neurotrophic factors. From the ganglia cell bodies, which are outside the blood-brain barrier, the mediators are further distributed to peripheral sites and/or to the spinal trigeminal nucleus in the brainstem, where they can affect neural transmission. A major question is how the sensory neurons in the trigeminal ganglion differ from those in the dorsal root ganglion. Despite their functional overlap, there are distinct differences in their ontogeny, gene expression, signaling pathways, and responses to anti-migraine drugs. Consequently, drugs that modulate cross-talk in the trigeminal ganglion can modulate both peripheral and central sensitization, which may potentially be distinct from sensitization mediated in the dorsal root ganglion.
Topics: Animals; Ganglia, Spinal; Humans; Neurons, Afferent; Neuropeptides; Nociception; Signal Transduction; Trigeminal Ganglion
PubMed: 32088764
DOI: 10.1007/s00702-020-02161-7 -
Neuroscience Bulletin Jan 2021Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive, abnormal trigeminal and central nervous system activity is likely to... (Review)
Review
Migraine is a common and debilitating headache disorder. Although its pathogenesis remains elusive, abnormal trigeminal and central nervous system activity is likely to play an important role. Transient receptor potential (TRP) channels, which transduce noxious stimuli into pain signals, are expressed in trigeminal ganglion neurons and brain regions closely associated with the pathophysiology of migraine. In the trigeminal ganglion, TRP channels co-localize with calcitonin gene-related peptide, a neuropeptide crucially implicated in migraine pathophysiology. Many preclinical and clinical data support the roles of TRP channels in migraine. In particular, activation of TRP cation channel V1 has been shown to regulate calcitonin gene-related peptide release from trigeminal nerves. Intriguingly, several effective anti-migraine therapies, including botulinum neurotoxin type A, affect the functions of TRP cation channels. Here, we discuss currently available data regarding the roles of major TRP cation channels in the pathophysiology of migraine and the therapeutic applicability thereof.
Topics: Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neurons; Transient Receptor Potential Channels; Trigeminal Ganglion
PubMed: 32870468
DOI: 10.1007/s12264-020-00569-5 -
Journal of Dental Research Aug 2022Chronic temporomandibular joint disorders (TMDs) present with pain in the temporomandibular joint (TMJ) and muscles of mastication. Risk factors for TMD include...
Chronic temporomandibular joint disorders (TMDs) present with pain in the temporomandibular joint (TMJ) and muscles of mastication. Risk factors for TMD include localized joint/muscle inflammation and estrogen status. This study determined whether mild tissue inflammation and estrogen status influenced the responses of trigeminal ganglion neurons to jaw palpation or jaw movement, 2 key diagnostic features of clinical TMD, in adult rats. Neuronal activity was recorded from male rats, ovariectomized (OvX) female rats, and OvX female rats injected with 17β-estradiol 24 h prior to testing (OvXE). Neurons were tested for responses to deep press over the TMJ region and jaw movement in 3 directions (open, protrusion, lateral) 10 d after intra-TMJ injection of a low dose of complete Freund's adjuvant (CFA) or vehicle (sham). Deep press evoked similar responses in all treatment groups. The response magnitude to jaw opening and protrusion was significantly greater for neurons recorded from OvXE CFA-treated rats than from OvX CFA-treated or OvXE sham rats. The responses to lateral movement of the jaw were similar across all treatment groups. Most neurons (70% to 90%) displayed a static response pattern to jaw movement independent of direction. Estradiol treatment also increased the proportion of neurons that were excited by jaw movement in >1 direction as compared with untreated OvX females or males. These results suggest that mild localized inflammation in the TMJ region during periods of elevated estrogen were sufficient to increase the peripheral driving force for jaw movement-evoked hyperalgesia.
Topics: Animals; Estradiol; Estrogens; Female; Freund's Adjuvant; Humans; Inflammation; Male; Ovariectomy; Rats; Rats, Sprague-Dawley; Temporomandibular Joint; Trigeminal Ganglion
PubMed: 35259995
DOI: 10.1177/00220345221077951 -
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