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European Journal of Pain (London,... Mar 2022Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia. Reduction in the activity of...
BACKGROUND
Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia. Reduction in the activity of primary afferent neurons has been shown to be sufficient in alleviating peripherally generated pain. The cell bodies of such trigeminal nociceptors are located in the trigeminal ganglia (TG) with central processes that terminate in the brainstem trigeminal nucleus caudalis (TNC). The TG is therefore a strategic locus where afferent input can be manipulated. We hypothesized that chemogenetic inhibition of TG would suppress TNC neuronal activity and attenuate pain behaviour in a rat model of painful traumatic trigeminal neuropathy (PTTN).
METHODS
Trigeminal neuropathic pain was induced in adult male Sprague-Dawley rats (n = 24) via chronic constriction injury to the infraorbital nerve (ION-CCI). Naïve and sham rats were used as controls (n = 20/group). Rats within each group received TG-directed microinjections of AAV virus containing either the inhibitory hM4Di-DREADD construct or EGFP.
RESULTS
In the ION-CCI group, systemic administration of the DREADD agonist clozapine N-oxide (CNO) reversed the hypersensitivity phenotype in animals expressing hM4Di but not EGFP. CNO-mediated activation of hM4Di DREADD in ION-CCI animals was also associated with reduced Fos expression in the TNC elicited by repeated mechanical stimulation of the dermatome ipsilateral to the injury. There was no effect of CNO on pain behaviour or TNC Fos expression in eGFP animals.
CONCLUSION
Our results indicate that DREADDs may offer an effective therapeutic approach for treatment of trigeminal neuropathic pain.
SIGNIFICANCE
Trigeminal neuropathic pain is highly resistant to therapy and we are in dire need of novel approaches. This study provides further evidence for the successful application of DREADDs as an effective tool for modulating central nervous system function. CNO mediated activation of hM4Di-DREADDs in the trigeminal ganglion (TG) attenuates nerve injury induced neuropathic pain by acting on hyperactive TG cells. It also establishes the TG as an effective target to manage pain in the face and head. Accessing the TG in clinical populations is a relatively simple and safe procedure, making this approach highly significant. Moreover, the methodology described here has applications in trigeminal neuropathic pain from traumatic other etiologies and in spinal neuropathic pain. Chronic pain syndromes are characterized by a progressive failure of brain centers to adequately inhibit pain and as these are identified, we may be able to target them for therapy. Therefore, our findings might have wide application in chronic pain syndromes.
Topics: Animals; Hyperalgesia; Male; Neuralgia; Neurons; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion; Trigeminal Neuralgia
PubMed: 34767278
DOI: 10.1002/ejp.1887 -
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 -
Cephalalgia : An International Journal... Mar 2019Migraine is two to three times more prevalent in women than in men, but the mechanisms involved in this gender disparity are still poorly understood. In this respect,... (Review)
Review
BACKGROUND
Migraine is two to three times more prevalent in women than in men, but the mechanisms involved in this gender disparity are still poorly understood. In this respect, calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology and, more recently, the functional interactions between ovarian steroid hormones, CGRP and the trigeminovascular system have been recognized and studied in more detail.
AIMS
To provide an overview of CGRP studies that have addressed gender differences utilizing animal and human migraine preclinical research models to highlight how the female trigeminovascular system responds differently in the presence of varying ovarian steroid hormones.
CONCLUSIONS
Gender differences are evident in migraine. Several studies indicate that fluctuations of ovarian steroid hormone (mainly estrogen) levels modulate CGRP in the trigeminovascular system during different reproductive milestones. Such interactions need to be considered when conducting future animal and human experiments, since these differences may contribute to the development of gender-specific therapies.
Topics: Animals; Calcitonin Gene-Related Peptide; Estrogens; Female; Gonadal Steroid Hormones; Humans; Male; Migraine Disorders; Receptors, Calcitonin Gene-Related Peptide; Sex Characteristics; Trigeminal Ganglion
PubMed: 29082826
DOI: 10.1177/0333102417739584 -
International Journal of Molecular... Jun 2021The ionotropic P2X receptor, P2X, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known...
The ionotropic P2X receptor, P2X, is believed to regulate and/or generate nociceptive pain, and pain in several neuropathological diseases. Although there is a known relationship between P2X receptor activity and pain sensing, its detailed functional properties in trigeminal ganglion (TG) neurons remains unclear. We examined the electrophysiological and pharmacological characteristics of the P2X receptor and its functional coupling with other P2X receptors and pannexin-1 (PANX1) channels in primary cultured rat TG neurons, using whole-cell patch-clamp recordings. Application of ATP and Bz-ATP induced long-lasting biphasic inward currents that were more sensitive to extracellular Bz-ATP than ATP, indicating that the current was carried by P2X receptors. While the biphasic current densities of the first and second components were increased by Bz-ATP in a concentration dependent manner; current duration was only affected in the second component. These currents were significantly inhibited by P2X receptor antagonists, while only the second component was inhibited by P2X and receptor antagonists, PANX1 channel inhibitors, and extracellular ATPase. Taken together, our data suggests that autocrine or paracrine signaling via the P2X-PANX1-P2X receptor/channel complex may play important roles in several pain sensing pathways via long-lasting neuronal activity driven by extracellular high-concentration ATP following tissue damage in the orofacial area.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Connexins; Gene Expression Regulation; Humans; Nerve Tissue Proteins; Neurons; Patch-Clamp Techniques; Primary Cell Culture; Purinergic P2X Receptor Antagonists; Rats; Receptors, Purinergic P2X7; Trigeminal Ganglion
PubMed: 34205953
DOI: 10.3390/ijms22115978 -
Clinical and Experimental Immunology Jan 2022Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have... (Review)
Review
Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have emphasized the role of neuroinflammation following the activation of the trigeminal pathway at several peripheral and central sites including dural vessels, the trigeminal ganglion, and the trigeminal nucleus caudalis. The evidence of an induction of inflammatory events in migraine pathophysiological mechanisms has prompted researchers to investigate the human leukocyte antigen (HLA) phenotypes as well as cytokine genetic polymorphisms in order to verify their potential relationship with migraine risk and severity. Furthermore, the role of neuroinflammation in migraine seems to be supported by evidence of an increase in pro-inflammatory cytokines, both ictally and interictally, together with the prevalence of Th1 lymphocytes and a reduction in regulatory lymphocyte subsets in peripheral blood of migraineurs. Cytokine profiles of cluster headache (CH) patients and those of tension-type headache patients further suggest an immunological dysregulation in the pathophysiology of these primary headaches, although evidence is weaker than for migraine. The present review summarizes available findings to date from genetic and biomarker studies that have explored the role of inflammation in primary headaches.
Topics: Cytokines; Headache; Humans; Inflammation; Migraine Disorders; Trigeminal Ganglion
PubMed: 35020858
DOI: 10.1093/cei/uxab025 -
F1000Research 2022Arising at distinct positions in the head, the cranial ganglia are crucial for integrating various sensory inputs. The largest of these ganglia is the trigeminal...
Arising at distinct positions in the head, the cranial ganglia are crucial for integrating various sensory inputs. The largest of these ganglia is the trigeminal ganglion, which relays pain, touch and temperature information through its three primary nerve branches to the central nervous system. The trigeminal ganglion and its nerves are composed of derivatives of two critical embryonic cell types, neural crest cells and placode cells, that migrate from different anatomical locations, coalesce together, and differentiate to form trigeminal sensory neurons and supporting glia. While the dual cellular origin of the trigeminal ganglion has been known for over 60 years, molecules expressed by neural crest cells and placode cells that regulate initial ganglion assembly remain obscure. Prior studies revealed the importance of cell surface cadherin proteins during early trigeminal gangliogenesis, with Cadherin-7 and neural cadherin (N-cadherin) expressed in neural crest cells and placode cells, respectively. Although cadherins typically interact in a homophilic ( , like) fashion, the presence of different cadherins expressed in neural crest cells and placode cells raises the question as to whether heterophilic cadherin interactions may also be occurring. Given this, the aim of the study was to understand whether Cadherin-7 and N-cadherin were interacting during initial trigeminal ganglion formation. To assess potential interactions between Cadherin-7 and N-cadherin, we used biochemistry and innovative imaging assays conducted and , including in the forming chick trigeminal ganglion. Our data revealed a physical interaction between Cadherin-7 and N-cadherin. These studies identify a new molecular basis by which neural crest cells and placode cells can aggregate to build the trigeminal ganglion during embryogenesis.
Topics: Animals; Cadherins; Neural Crest; Neurons; Trigeminal Ganglion; Chick Embryo
PubMed: 36128560
DOI: 10.12688/f1000research.122686.2 -
Folia Morphologica 2020In this study, we explored the specific microanatomical properties of the trigeminal ganglion (TG) blood supply and its close neurovascular relationships with the...
BACKGROUND
In this study, we explored the specific microanatomical properties of the trigeminal ganglion (TG) blood supply and its close neurovascular relationships with the surrounding vessels. Possible clinical implications have been discussed.
MATERIALS AND METHODS
The internal carotid and maxillary arteries of 25 adult and 4 foetal heads were injected with a 10% mixture of India ink and gelatin, and their TGs subsequently underwent microdissection, observation and morphometry under a stereoscopic microscope.
RESULTS
The number of trigeminal arteries varied between 3 and 5 (mean 3.34), originating from 2 or 3 of the following sources: the inferolateral trunk (ILT) (100%), the meningohypophyseal trunk (MHT) (100%), and from the middle meningeal artery (MMA) (92%). In total, the mean diameter of the trigeminal branches was 0.222 mm. The trigeminal branch of the ILT supplied medial and middle parts of the TG, the branch of the MHT supplied the medial part of the TG, and the branch of the MMA supplied the lateral part of the TG. Additional arteries for the TG emerged from the dural vascular plexus and the vascular network of the plexal segment of the trigeminal nerve. Uniform and specific intraganglionicdense capillary network was observed for each sensory trigeminal neuron.
CONCLUSIONS
The reported features of the TG vasculature could be implied in a safer setting for surgical approach to the skull base, in relation to the surrounding structures. The morphometric data on TG vasculature provide anatomical basis for better understanding the complex TG blood supply from the internal and external carotid arteries.
Topics: Aged; Cadaver; Female; Fetus; Humans; Male; Microdissection; Middle Aged; Trigeminal Ganglion
PubMed: 31282551
DOI: 10.5603/FM.a2019.0062 -
Neuroscience Bulletin Apr 2021Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently...
Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.
Topics: Animals; Hyperalgesia; Mice; Neuralgia; Toll-Like Receptor 8; Trigeminal Ganglion; Trigeminal Neuralgia
PubMed: 33355900
DOI: 10.1007/s12264-020-00621-4 -
Communications Biology Apr 2022The functional imaging within the trigeminal ganglion (TG) is highly challenging due to its small size and deep localization. This study combined a methodological...
The functional imaging within the trigeminal ganglion (TG) is highly challenging due to its small size and deep localization. This study combined a methodological framework able to dive into the rat trigeminal nociceptive system by jointly providing 1) imaging of the TG blood vasculature at microscopic resolution, and 2) the measurement of hemodynamic responses evoked by orofacial stimulations in anesthetized rats. Despite the small number of sensory neurons within the TG, functional ultrasound imaging was able to image and quantify a strong and highly localized hemodynamic response in the ipsilateral TG, evoked not only by mechanical or chemical stimulations of corneal nociceptive fibers, but also by cutaneous mechanical stimulations of the ophthalmic and maxillary orofacial regions using a von Frey hair. The in vivo quantitative imaging of the TG's vasculature using ultrasound localization microscopy combined with in toto labelling reveals particular features of the vascularization of the area containing the sensory neurons, that are likely the origin of this strong vaso-trigeminal response. This innovative imaging approach opens the path for future studies on the mechanisms underlying changes in trigeminal local blood flow and evoked hemodynamic responses, key mechanisms for the understanding and treatment of debilitating trigeminal pain conditions.
Topics: Animals; Face; Microscopy; Rats; Rats, Sprague-Dawley; Trigeminal Ganglion; Ultrasonography
PubMed: 35393515
DOI: 10.1038/s42003-022-03273-4 -
The Bulletin of Tokyo Dental College Sep 2022Trigeminal neuralgia occurs in the orofacial region, characteristically causing pain that feels like a transient electric shock. Some histopathological studies have...
Trigeminal neuralgia occurs in the orofacial region, characteristically causing pain that feels like a transient electric shock. Some histopathological studies have reported that trigeminal neuralgia is caused by mechanical compression of the demyelinated trigeminal nerve; the pathophysiological mechanism behind this phenomenon remains to be clarified, however. Cell-cell interactions have also been reported to be involved in the development and modulation of some types of neuropathic pain. The purpose of this study was to investigate the potential contribution of cell-cell interactions to trigeminal neuralgia by measuring intracellular free Ca concentrations ([Ca]) in primary cultured trigeminal ganglion (TG) cells. Direct mechanical stimulation of TG cells induced an increase in [Ca] in both neuronal and non-neuronal cells, such as glial cells. Moreover, this increase was stimulus intensity-dependent and non-desensitizing. Direct mechanical stimulation increased [Ca] in neighboring cells as well, and this increase was inhibited by application of carbamazepine. These results indicate that direct mechanical stimulation affects Ca signaling. Trigeminal ganglion cells establish intercellular networks between themselves, suggesting that this is involved in the development and generation of trigeminal neuralgia.
Topics: Cell Communication; Cells, Cultured; Humans; Trigeminal Ganglion; Trigeminal Neuralgia
PubMed: 35965080
DOI: 10.2209/tdcpublication.2021-0034