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Dorsal root ganglion stimulation (DRGS) is a neurostimulation therapy used to manage chronic pain that does not respond to conventional therapies. Unfortunately, not all patients receive sufficient pain relief from DRGS, leaving them with few other treatment options. Presently, our understanding of the mechanisms of action of DRGS is incomplete, preventing us from determining why some patients do not receive analgesia from the therapy. One hypothesis suggests that DRGS augments the filtering of action potentials (APs) at the T-junction of nociceptive C-neurons. To test this hypothesis, we utilized a computational modeling approach in which we developed a population of one thousand biophysically distinct C-neuron models which each produced electrophysiological characteristics (e.g., AP height, AP duration) reported in previous experimental studies. We used this population of model C-neurons to study how morphological and electrophysiological characteristics affected the propagation of APs through the T-junction. We found that trains of APs can propagate through the T-junction in the orthodromic direction at a higher frequency than in the antidromic direction due to the decrease in axonal diameter from the peripheral to spinal axon. Including slow outward conductances in the axonal compartments near the T-junction reduced following frequencies to ranges measured experimentally. We next used the population of C-neuron models to investigate how DRGS affected the orthodromic propagation of APs through the T-junction. Our data suggest that suprathreshold DRGS augmented the filtering of APs at the T-junction of some model C-neurons while increasing the activity of other model C-neurons. However, the stimulus pulse amplitudes required to induce activity in C-neurons (i.e., several mA) fell outside the range of stimulation pulse amplitudes used clinically (i.e., typically ≤1 mA). Furthermore, our data suggest that somatic GABA currents activated directly or indirectly by the DRGS pulse may produce diverse effects on orthodromic AP propagation in C-neurons. These data suggest DRGS may produce differential effects across a population of C-neurons and indicate that understanding how inherent biological variability affects a neuron's response to therapeutic electrical stimulation may be helpful in understanding its mechanisms of action.
Acupuncture is commonly used as a treatment for migraines. Animal studies have suggested that acupuncture can decrease neuropeptides, immune cells, and proinflammatory and excitatory neurotransmitters, which are associated with the pathogenesis of neuroinflammation. In addition, acupuncture participates in the development of peripheral and central sensitization through modulation of the release of neuronal-sensitization-related mediators (brain-derived neurotrophic factor, glutamate), endocannabinoid system, and serotonin system activation. Clinical studies have demonstrated that acupuncture may be a beneficial migraine treatment, particularly in decreasing pain intensity, duration, emotional comorbidity, and days of acute medication intake. However, specific clinical effectiveness has not been substantiated, and the mechanisms underlying its efficacy remain obscure. With the development of biomedical and neuroimaging techniques, the neural mechanism of acupuncture in migraine has gained increasing attention. Neuroimaging studies have indicated that acupuncture may alter the abnormal functional activity and connectivity of the descending pain modulatory system, default mode network, thalamus, frontal-parietal network, occipital-temporal network, and cerebellum. Acupuncture may reduce neuroinflammation, regulate peripheral and central sensitization, and normalize abnormal brain activity, thereby preventing pain signal transmission. To summarize the effects and neural mechanisms of acupuncture in migraine, we performed a systematic review of literature about migraine and acupuncture. We summarized the characteristics of current clinical studies, including the types of participants, study designs, and clinical outcomes. The published findings from basic neuroimaging studies support the hypothesis that acupuncture alters abnormal neuroplasticity and brain activity. The benefits of acupuncture require further investigation through basic and clinical studies.
Rheumatic diseases, such as osteoarthritis and rheumatoid arthritis, affect over 750 million people worldwide and contribute to approximately 40% of chronic pain cases. Inflammation and tissue damage contribute to pain in rheumatic diseases, but pain often persists even when inflammation/damage is resolved. Mechanisms that cause this persistent pain are still unclear. Mitochondria are essential for a myriad of cellular processes and regulate neuronal functions. Mitochondrial dysfunction has been implicated in multiple neurological disorders, but its role in sensory processing and pain in rheumatic diseases is relatively unexplored. This review provides a comprehensive understanding of how mitochondrial dysfunction connects inflammation and damage-associated pathways to neuronal sensitization and persistent pain. To provide an overall framework on how mitochondria control pain, we explored recent evidence in inflammatory and neuropathic pain conditions. Mitochondria have intrinsic quality control mechanisms to prevent functional deficits and cellular damage. We will discuss the link between neuronal activity, mitochondrial dysfunction and chronic pain. Lastly, pharmacological strategies aimed at reestablishing mitochondrial functions or boosting mitochondrial dynamics as therapeutic interventions for chronic pain are discussed. The evidence presented in this review shows that mitochondria dysfunction may play a role in rheumatic pain. The dysfunction is not restricted to neuronal cells in the peripheral and central nervous system, but also includes blood cells and cells at the joint level that may affect pain pathways indirectly. Pre-clinical and clinical data suggest that modulation of mitochondrial functions can be used to attenuate or eliminate pain, which could be beneficial for multiple rheumatic diseases.
Endometriosis is a disease defined by the presence of endometrial tissue in extrauterine locations. This chronic condition is frequently associated with pain and emotional disorders and has been related with altered immune function. However, the specific involvement of immune cells in pain and behavioral symptoms of endometriosis has not been yet elucidated. Here, we implement a mouse model of non-surgical endometriosis in which immunocompetent mice develop abdomino-pelvic hypersensitivity, cognitive deficits, anxiety and depressive-like behaviors. This behavioral phenotype correlates with expression of inflammatory markers in the brain, including the immune cell marker CD4. Depletion of CD4 + cells decreases the anxiety-like behavior of mice subjected to the endometriosis model, whereas abdomino-pelvic hypersensitivity, depressive-like behavior and cognitive deficits remain unaltered. The present data reveal the involvement of the immune response characterized by CD4 + white blood cells in the anxiety-like behavior induced by endometriosis in mice. This model, which recapitulates the symptoms of human endometriosis, may be a useful tool to study the immune mechanisms involved in pain and behavioral alterations associated to endometriosis.
Chronic pain is a significant and costly problem all over the world that negatively impacts the quality of life of sufferers. There are clear discrepancies between the prevalence of chronic pain in society and the low priority assigned to educating future physicians about the complexities of pain. This condition also occurs in other undergraduate health science students, although research in this area has not been studied as much as in medical schools. Based on the International Association for the Study of Pain (IASP) Pain Curriculum Outline, a systematic search of the available literature, and the authors' own experiences, we highlight some relevant tips to educate health science trainees in the management of patients with chronic pain. These tips highlight current international recommendations for a comprehensive approach to this prevalent problem in society, which should be learnt during the university training of health professionals.
Discrimination of cues predicting non-nociceptive/nociceptive stimuli is essential for predicting whether a non-painful or painful stimulus will be administered and for eliciting placebo/nocebo (pain reduction/pain enhancement) effects. Dysfunction of the neural system involved in placebo effects has been implicated in the pathology of chronic pain, while female sex is one of the important risk factors for development of chronic pain in young adults. The dorsolateral prefrontal cortex (dl-PFC) is suggested to be involved in placebo effects and is sensitive to sex and age. In this study, to examine the neural mechanisms by which sex and age alter placebo and nocebo effects, we analyzed cerebral hemodynamic activities in the dl-PFC in different sex and age groups during a differential conditioning task. During the training session, two different sounds were followed by low- and high-intensity electrical shocks. In the following recording session, electrical shocks, the intensity of which was mismatched to the sounds, were occasionally administered to elicit placebo and nocebo effects. In young female participants, both placebo effects and hemodynamic responses to the conditioned sounds in the right dl-PFC were significantly lower than those in elderly female participants, while there were no age differences in male participants. The hemodynamic responses to the sound paired with the safe stimulus in the right dl-PFC were significantly correlated with placebo effects, except in the young female group. These results suggest that blunted placebo effects in the young female participants are ascribed to blunted responses to the sound associated with the safe stimulus in the right dl-PFC, and that sex- and age-related factors may alter the responsiveness of the right dl-PFC to associative cues predicting a safe stimulus.
Toothache (TA) is a common and severe pain, but its effects on the brain are somewhat unclear. In this study, functional magnetic resonance imaging (fMRI) was used to compare regional homogeneity (ReHo) between TA patients and a normal control group and to explore the brain activity changes during TA, establishing the theoretical basis for the mechanism of neuropathic pain. In total, 20 TA patients and 20 healthy controls (HCs) were recruited and underwent assessment of pain, and then resting-state fMRI (rs-fMRI). The ReHo method was used to analyze the original whole-brain images. Pearson's correlation analysis was used to assess the relationship between mean ReHo values in each brain region and clinical symptoms, and the receiver operating characteristic (ROC) curve was used to conduct correlation analysis on the brain regions studied. The ReHo values of the right lingual gyrus (RLG), right superior occipital gyrus (RSOG), left middle occipital gyrus (LMOG) and right postcentral gyrus (RPG) in the TA group were significantly higher than in HCs. The mean ReHo values in the RLG were positively correlated with the anxiety score (AS) ( = 0.723, < 0.001), depression score (DS) ( = 0.850, < 0.001) and visual analogue score (VAS) ( = 0.837, < 0.001). The mean ReHo values of RSOG were also positively correlated with AS ( = 0.687, = 0.001), DS ( = 0.661, = 0.002) and VAS ( = 0.712, < 0.001). The areas under the ROC curve of specific brain area ReHo values were as follows: RLG, 0.975; RSOG, 0.959; LMOG, 0.975; RPG, 1.000. Various degrees of brain activity changes reflected by ReHo values in different areas of the brain indicate the impact of TA on brain function. These findings may reveal related neural mechanisms underlying TA.
Joint pain and arthralgia can be manifestations of COVID-19, and studies evaluating long COVID symptoms identified the persistence of these disorders. Moreover, some case reports highlighted the development of new inflammatory arthritis in patients with COVID-19, suggesting a possible relation. Viral infections and rheumatic diseases share a documented relationship; they have been associated with genetic and environmental risk factors responsible for some of them. There is crosstalk between viruses and the immune system during the development of several rheumatic diseases. Moreover, infections may participate in the pathogenesis of autoimmune rheumatic diseases and contribute to patient mortality. Therefore, it is crucial to provide a clearer insight into the interaction between viral infections and rheumatic diseases. Here, we provide a mini-review of the current literature with the aim of shedding light on the relationship between COVID-19 and rheumatic or musculoskeletal diseases, which is still unclear. Specifically, we examined several aspects: risk for the rheumatic population of acquiring the virus or developing severe symptoms, similarities of COVID-19 and arthritis, the possible rheumatic consequence of COVID-19, of rheumatic drugs and vaccines, and COVID-19 prevention in rheumatic patients through vaccination.
Chronic pain is a common, profoundly disabling and complex condition whose effects on identity may explain the distress experienced by those affected by it. This paper concerns a study exploring how the relationship with pain and sense of self evolved following participation in a pain management program (PMP). Participants were interviewed at three timepoints: before attending a PMP, 1 month after the PMP and 6 months after the PMP. To facilitate a deep experiential description of pain and its effects, interviews were guided by participant-generated drawings of pain and Self. Interviews and drawings were analyzed longitudinally using interpretative phenomenological analysis. The evolving experience of participants was outlined through different trajectory types. Here we describe the upward and positive trajectory of three female participants who were able to regain control over their lives. From a state of psychological stress where pain was represented as an aggressive and oppressive presence, participants' drawings, their narratives and indeed their lives, changed for the best. Pain stopped being the main feature, they were able to integrate it into their lives, make important changes and find a new balance. The results demonstrate the idiosyncratic nature of chronic pain and offer a nuanced account of its links to the lifeworld of those living with it.
Duloxetine has been reported to significantly relieve the pain of persistent idiopathic dentoalveolar pain (PIDP); however, the number of studies available is scarce and no study has identified the predictors of response of duloxetine for the treatment of PIDP.