Background
Temporomandibular disorders (TMD) are diagnosed based on symptom presentation and, like other functional pain disorders, often lack definitive pathology. There is a strong association ...between elevated stress levels and the severity of TMD‐related pain, which suggests that alterations in autonomic tone may contribute to this pain condition.
Objectives
This narrative review examines the association between altered autonomic function and pain in TMD.
Methods
Relevant articles were identified by searching PubMed and through the reference list of those studies.
Results
TMD sufferers report an increased incidence of orthostatic hypotension. As in other chronic musculoskeletal pain conditions, TMD is associated with increased sympathetic tone, diminished baroreceptor reflex sensitivity and decreased parasympathetic tone. It remains to be determined whether ongoing pain drives these autonomic changes and/or is exacerbated by them. To examine whether increased sympathetic tone contributes to TMD‐related pain through β2 adrenergic receptor activation, clinical trials with the beta blocker propranolol have been undertaken. Although evidence from small studies suggested propranolol reduced TMD‐related pain, a larger clinical trial did not find a significant effect of propranolol treatment. This is consistent with human experimental pain studies that were unable to demonstrate an effect of β2 adrenergic receptor activation or inhibition on masticatory muscle pain. In preclinical models of temporomandibular joint arthritis, β2 adrenergic receptor activation appears to contribute to inflammation and nociception, whereas in masticatory muscle, α1 adrenergic receptor activation has been found to induce mechanical sensitisation. Some agents used to treat TMD, such as botulinum neurotoxin A, antidepressants and α2 adrenergic receptor agonists, may interact with the autonomic nervous system as part of their analgesic mechanism.
Conclusion
Even if dysautonomia turns out to be a consequence rather than a causative factor of painful TMD, the study of its role has opened up a greater understanding of the pathogenesis of this condition.
•Cannabidiol and cannabinol alone and in combination reversed masseter muscle sensitization in a behavioral model of temporomandibular disorders.•Both cannabinoids decreased the mechanical ...sensitivity of masseter muscle afferent fibers.•Though not as effective as delta-9-tetrahydrocannabinol, these compounds do not cause psychotropic effects.
This study investigated whether local intramuscular injection of non-psychoactive cannabinoids, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC) and their combinations can decrease nerve growth factor (NGF)-induced masticatory muscle sensitization in female rats.
In awake rats, changes in mechanical sensitivity induced by intramuscular injection of NGF and cannabinoids were measured by applying an electronic von Frey hair over the masseter muscle to measure the withdrawal response. The effect of CBD (5 mg/ml) and CBN (1 mg/ml) or their combinations CBD/CBN (1:1 mg/ml or 5:1 mg/ml) were assessed. To confirm a peripheral action, electrophysiological experiments were undertaken in anesthetized rats to examine whether intramuscular injections of CBD (5 mg/ml) and CBN (1 mg/ml) altered the mechanical threshold of masticatory muscle mechanoreceptors.
In behavioral experiments, CBD (5 mg/ml) or CBN (1 mg/ml) decreased NGF-induced mechanical sensitization. Combinations of CBD/CBN induced a longer-lasting reduction of mechanical sensitization than either compound alone. No significant change in mechanical withdrawal threshold was observed in the contralateral masseter muscles and no impairment of motor function was found with the inverted screen test after any of the treatments. Consistent with behavioral results, CBD (5 mg/ml), CBN (1 mg/ml) and the combination of CBD/CBN (1:1 mg/ml) increased the mechanical threshold of masseter muscle mechanoreceptors. However, combining CBD/CBN (5:1 mg/ml) at a higher ratio reduced the duration of this effect. This may indicate an inhibitory effect of higher concentrations of CBD on CBN.
These results suggest that peripheral application of these non-psychoactive cannabinoids may provide analgesic relief for chronic muscle pain disorders such as temporomandibular disorders and fibromyalgia without central side effects.
Background
Although the role of glutamate in migraine pathogenesis remains uncertain, there has been significant interest in the development of drug candidates that target glutamate receptors. ...Activation of trigeminovascular afferent fibers is now recognized as a crucial step to the onset of a migraine episode. New evidence suggests a dysfunction in peripheral glutamate regulation may play a role in this process.
Objective
To provide a narrative review of the role of peripheral glutamate dysfunction in migraine.
Method
A review of recent literature from neurobiological, pharmacological and genomic studies was conducted to support peripheral glutamate dysfunction as a potential element in migraine pathogenesis.
Results
Studies in rats suggest that elevated blood glutamate mechanically sensitizes trigeminal afferent fibers and stimulates the release of calcitonin-gene related peptide and other neuropeptides to promote and maintain neurogenic inflammation. These effects may be driven by upregulation of glutamate receptors, and modifications to reuptake and metabolic pathways of glutamate. Furthermore, genome wide association studies have found polymorphisms in glutamate receptor and transporter genes that are associated with migraine.
Conclusion
The role of peripheral glutamate signalling in the onset and maintenance of migraine is not completely elucidated and future studies are still needed to confirm its role in migraine pathogenesis.
Migraine is a common neurological disorder characterized by recurrent headache episodes that accompany sensory-motor disturbances, such as higher sensitivity to touch and light, extremity heaviness ...or weakness, and speech or language disabilities. Worldwide, migraine is one of the top 10 causes of disability and hence poses a huge economic burden to society. On average, migraine occurs in 12% of population but its occurrence is sexually dimorphic, as it is two to three times more prevalent in women than in men. This female to male ratio of migraine prevalence is age- and sex hormone-dependent. Advancements in understanding migraine pathogenesis have also revealed an association with both genetics and epigenetics. The severity of migraine, in terms of its attack duration, headache intensity, frequency, and occurrence of migraine-associated symptoms, has generally been reported to be greater in women. Sex differences in migraine disability and comorbidities, such as psychiatric disorders, have also been noted in some population-based studies. However, research on sex-related differences in response to migraine treatments is relatively scarce. Although a general observation is that women consume more medication than men for migraine treatment, strategies for the use of abortive and preventive medications for migraine are generally similar in both sexes. This narrative review summarizes available findings on sexually distinct responses to abortive and prophylactic pharmacotherapy of migraine. Basic experimental data and clinical findings will be presented, and potential mechanisms underlying sex-based responses will be discussed to highlight the importance and value of sex-based treatment in migraine research and practice.
•Higher GABA receptor expression by skin than masticatory muscle ganglion neurons.•GABA receptor agonists attenuate sensory transmission through the trigeminal ganglion.•Muscle afferent conduction ...velocity determines response to GABA receptor agonists.•There is a sex-related difference in sensory gating through the ganglion.
While the trigeminal ganglion is often considered a passive conduit of sensory transmission, neurons and satellite glial cells (SGCs) within it can release neurotransmitters and express neuroreceptors. Some trigeminal ganglion neurons contain the neurotransmitter γ-aminobutyric acid (GABA) and express GABA receptors. There is behavioral evidence that increased GABA levels in the trigeminal ganglion decreases nociception, while a loss of GABA receptors results in hyperalgesia, although the neural mechanisms for this remain to be investigated. In this study, the expression of GABA receptors by trigeminal ganglion neurons that innervate rat labial skin and masseter muscle was compared using immunohistochemistry. The effect of intraganglionic administration of GABA receptor agonists was investigated by single unit recording of trigeminal brainstem and ganglion neuron responses to stimulation of the labial skin and/or masseter muscle in anesthetized rats. The mean frequency of expression of GABAA and GABAB receptors by masseter and labial skin ganglion neurons was 62.5% and 92.7%, and 55.4% and 20.3%, respectively. The expression of both GABA receptors was significantly greater in skin ganglion neurons. Masticatory muscle evoked brainstem trigeminal neuron responses were significantly attenuated by intraganglionic injection of muscimol (GABAA) but not baclofen (GABAB). The mechanical sensitivity of slow and fast conducting masticatory muscle afferent fibers was decreased and increased, respectively, by intraganglionic injection of both muscimol and baclofen. Activation of GABAA receptors may exert a gating effect on sensory transmission through the trigeminal ganglion by decreasing putative nociceptive input and enhancing innocuous sensory input.
Abstract Mast cells are immune cells minimally present in normal tendon tissue. The increased abundance of mast cells in tendinopathy biopsies and at the sites of tendon injury suggests an unexplored ...role of this cell population in overuse tendon injuries. Mast cells are particularly present in tendon biopsies from patients with more chronic symptom duration and a history of intensive mechanical loading. This study, therefore, examined the cross talk between mast cells and human tendon cells in either static or mechanically active conditions in order to explore the potential mechanistic roles of mast cells in overuse tendon injuries. A coculture of isolated human tenocytes and mast cells (HMC-1) combined with Flexcell Tension System for cyclic stretching of tenocytes was used. Additionally, human tenocytes were exposed to agonists and antagonists of substance P (SP) receptors. Mast cell degranulation was assessed by measuring β-hexosaminidase activity. Transwell and cell adhesion assays were used to evaluate mast cell migration and binding to tendon extracellular matrix components (collagen and fibronectin), respectively. Gene expressions were analyzed using real time qRT-PCR. Our results indicate that mechanical stimulation of human tenocytes leads to release of SP which, in turn, activates mast cells through the Mas-related G-protein-coupled receptor X2 (MRGPRX2). The degranulation and migration of mast cells in response to MRGPRX2 activation subsequently cause human tenocytes to increase their expression of inflammatory factors, matrix proteins and matrix metalloproteinase enzymes. These observations may be important in understanding the mechanisms by which tendons become tendinopathic in response to repetitive mechanical stimulation.
Abstract
Monosodium glutamate induces behaviors thought to reflect headache and nausea in rats. We explored the effects of the
N
-methyl-
d
-aspartate receptor antagonist ...(2R)-amino-5-phosphonovaleric acid, the inotropic glutamate receptor antagonist kynurenic acid, and the CGRP receptor antagonist olcegepant, on monosodium glutamate-induced increases in nocifensive, headache-like and nausea behaviours. Effects of these antagonists on motor function were examined with a rotarod. The effect of the dopamine receptor antagonist metoclopramide and the serotonin 3 receptor antagonist ondansetron on nausea behaviour was also assessed. (2R)-amino-5-phosphonovaleric acid, and to a lesser extent, kynurenic acid and olcegepant, reduced nocifensive and headache-like behaviours evoked by monosodium glutamate. No alteration in motor function by (2R)-amino-5-phosphonovaleric acid, kynurenic acid or olcegepant was observed. No sex-related differences in the effectiveness of these agents were identified. Nausea behaviour was significantly more pronounced in male than in female rats. Olcegepant, ondansetron and metoclopramide ameliorated this nausea behaviour in male rats. Ondansetron and metoclopramide also reduced headache-like behaviour in male rats. These findings suggest that peripheral
N
-methyl-
d
-aspartate receptor activation underlies monosodium glutamate-induced headache-like behaviour but does not mediate the nausea behaviour in rats.
•This article overviews polarimetric observations, their history and expected developments, and resulting aerosol products.•The paper was conceived during the workshop APOLO-2017 held in Hefei, ...China, in October 2017.
Polarimetry is one of the most promising types of remote sensing for improved characterization of atmospheric aerosol. Indeed, aerosol particles constitute a highly variable atmospheric component characterized by a large number of parameters describing particle sizes, morphologies (including shape and internal structure), absorption and scattering properties, amounts, horizontal and vertical distribution, etc. Reliable monitoring of all these parameters is very challenging, and therefore the aerosol effects on climate and environment are considered to be among the most uncertain factors in climate and environmental research. In this regard, observations that provide both the angular distribution of the scattered atmospheric radiation as well as its polarization state at multiple wavelengths covering the UV–SWIR spectral range carry substantial implicit information on the atmospheric composition. Therefore, high expectations in improving aerosol characterization are associated with detailed passive photopolarimetric observations.
The critical need to use space-borne polarimetry for global accurate monitoring of detailed aerosol properties was first articulated in the late 1980s and early 1990s. By now, several orbital instruments have already provided polarization observations from space, and a number of advanced missions are scheduled for launch in the coming years by international and national space agencies. The first and most extensive record of polarimetric imagery was provided by POLDER-I, POLDER-II, and POLDER/PARASOL multi-angle multi-spectral polarization sensors. Polarimetric observations with the POLDER-like design intended for collecting extensive multi-angular multi-spectral measurements will be provided by several instruments, such as the MAI/TG-2, CAPI/TanSat, and DPC/GF-5 sensors recently launched by the Chinese Space Agency. Instruments such as the 3MI/MetOp-SG, MAIA, SpexOne and HARP2 on PACE, POSP, SMAC, PCF, DPC–Lidar, ScanPol and MSIP/Aerosol-UA, MAP/Copernicus CO2 Monitoring, etc. are planned to be launched by different space agencies in the coming decade. The concepts of these future instruments, their technical designs, and the accompanying algorithm development have been tested intensively and analyzed using diverse airborne prototypes. Certain polarimetric capabilities have also been implemented in such satellite sensors as GOME-2/MetOp and SGLI/GCOM-C.
A number of aerosol retrieval products have been developed based on the available measurements and successfully used for different scientific applications. However, the completeness and accuracy of aerosol data operationally derived from polarimetry do not yet appear to have reached the accuracy levels implied by theoretical sensitivity studies that analyzed the potential information content of satellite polarimetry. As a result, the dataset provided by MODIS is still most frequently used by the scientific community, yet this sensor has neither polarimetric nor multi-angular capabilities. Admittedly polarimetric multi-angular observations are highly complex and have extra sensitivities to aerosol particle morphology, vertical variability of aerosol properties, polarization of surface reflectance, etc. As such, they necessitate state-of-the-art forward modeling based on first-principles physics which remains rare, and conventional retrieval approaches based on look-up tables turn out to be unsuitable to fully exploit the information implicit in the measurements. Several new-generation retrieval approaches have recently been proposed to address these challenges. These methods use improved forward modeling of atmospheric (polarized) radiances and implement a search in the continuous space of solutions using rigorous statistically optimized inversions. Such techniques provide more accurate retrievals of the main aerosol parameters such as aerosol optical thickness and yield additional parameters such as aerosol absorption. However, the operational implementation of advanced retrieval approaches generally requires a significant extra effort, and the forward-modeling part of such retrievals still needs to be substantially improved.
Ground-based passive polarimetric measurements have also been evolving over the past decade. Although polarimetry helps improve aerosol characterization, especially of the fine aerosol mode, the operators of major observational networks such as AERONET remain reluctant to include polarimetric measurements as part of routine retrievals owing to their high complexity and notable increase in effort required to acquire and interpret polarization data.
In addition to remote-sensing observations, polarimetric characteristics of aerosol scattering have been measured in situ as well as in the laboratory using polar nephelometers. Such measurements constitute direct observations of single scattering with no contributions from multiple scattering effects and therefore provide unique data for the validation of aerosol optical models and retrieval concepts.
This article overviews the above-mentioned polarimetric observations, their history and expected developments, and the state of resulting aerosol products. It also discusses the main achievements and challenges in the exploitation of polarimetry for the improved characterization of atmospheric aerosols.
Temporomandibular Disorder (TMD) patients report amplification of pain in the masticatory muscles after psychological trauma or stressful conditions. The mechanisms underlying this phenomenon are yet ...to be elucidated. This study combined immunohistochemistry with single cell in vivo electrophysiology recordings of masticatory muscle afferent fibers to investigate the role of α1-adrenergic receptors in muscle nociception. It was found that a subset of trigeminal afferent fibers which innervate the masseter and temporal muscles expressed α1a, α1b and α1d receptors, including a smaller number of putative nociceptors which co-expressed TrpV1 receptors. Local injection of the selective α1 adrenergic receptor agonist phenylephrine into masticatory muscle decreased and increased the mechanical activation threshold of slow and fast conducting afferent fibers, respectively. This effect was reversed by co-administration of the α1 selective antagonist terazosin. To rule out the possibility that local ischemia was responsible for the observed effect of phenylephrine on masticatory muscle afferent fibers, additional experiments were conducted where blood flow to the masticatory muscle was reduced by common carotid artery occlusion. This investigation found that muscle blood flow occlusion increased the mechanical activation threshold of the majority of masticatory muscle afferent fibers unrelated to conduction velocity. These findings suggest that under conditions of increased sympathetic tone, such as those related to stress, noradrenaline may sensitize masticatory muscle nociceptors to increase pain and desensitize muscle proprioceptors to alter muscle tone, through activation of α1 receptors.
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•Masticatory muscle afferent fibers express α1 receptors.•α1 receptor activation sensitizes masticatory muscle nociceptors.•α1 receptor activation desensitizes masticatory muscle proprioceptors.•Acute masticatory muscle blood flow occlusion does not sensitize nociceptors.
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