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Diabetes mellitus and its consequences continue to put a significant demand on medical resources across the world. Diabetic neuropathic pain (DNP) is a frequent diabetes mellitus chronic microvascular outcome. Allodynia, hyperalgesia, and aberrant or lack of nerve fibre sensation are all symptoms of DNP. These clinical characteristics will lead to worse quality of life, sleep disruption, depression, and increased mortality. Although the availability of numerous medications that alleviate the symptoms of DNP, the lack of long-term efficacy and unfavourable side effects highlight the urgent need for novel treatment strategies. This review paper systematically analysed the preclinical research on the treatment of DNP using plant phytochemicals that contain only tannins. A total of 10 original articles involved in and experiments addressing the promising benefits of phytochemical tannins on DNP were examined between 2008 and 2021. The information given implies that these phytochemicals may have relevant pharmacological effects on DNP symptoms through their antihyperalgesic, anti-inflammatory, and antioxidant properties; however, because of the limited sample size and limitations of the studies conducted so far, we were unable to make definitive conclusions. Before tannins may be employed as therapeutic agents for DNP, more study is needed to establish the specific molecular mechanism for all of these activities along the pain pathway and examine the side effects of tannins in the treatment of DNP.
Learn More >Neuropathic pain (NP) is one of the most common types of clinical pain. The common causes of this syndrome include injury to the central or peripheral nervous systems and pathological changes. NP is characterized by spontaneous pain, hyperalgesia, abnormal pain, and paresthesia. Because of its diverse etiology, the pathogenesis of NP has not been fully elucidated and has become one of the most challenging problems in clinical medicine. This kind of pain is extremely resistant to conventional treatment and is accompanied by serious complications. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), contribute to diverse biological processes by regulating the expression of various mRNAs involved in pain-related pathways, at the posttranscriptional level. Abnormal regulation of ncRNAs is closely related to the occurrence and development of NP. In this review, we summarize the current state of understanding of the roles of different ncRNAs in the development of NP. Understanding these mechanisms can help develop novel therapeutic strategies to prevent or treat chronic pain.
Learn More >Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician's perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.
Learn More >Peripheral edema (i.e., lower limb swelling) can cause pain, weakness, and limited range of motion. However, few studies have examined its prevalence in the U.S. or its association with demographics, comorbidities, activity, or mobility. This study used data from the Health and Retirement Study, a nationally representative longitudinal survey of U.S. adults (age 51+/ N = 19,988 for 2016), to evaluate time trends and correlates of peripheral edema using weighted descriptive statistics and logistic regressions, respectively. Peripheral edema was assessed with the question "Have you had… // Persistent swelling in your feet or ankles?" The weighted prevalence of edema among older U.S. adults was 19% to 20% between 2000 and 2016. Peripheral edema was associated with older age, female sex, non-white race, low wealth, obesity, diabetes, hypertension, pain, low activity levels, and mobility limitations (odds ratios ranging from 1.2-5.6; p-values ≤0.001). This study provides the first estimates of national prevalence and correlates of peripheral edema among older Americans. Peripheral edema is common and strongly associated with comorbidities, pain, low activity levels, and mobility limitations, and disproportionately affects poorer and minority groups. Peripheral edema should be a focus of future research in order to develop novel and cost-effective interventions.
Learn More >Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population aged 65 and over. Additionally, non-motor symptoms such as pain and gastrointestinal dysregulation are also common in PD. These impairments might stem from a dysregulation within the gut-brain axis that alters immunity and the inflammatory state and subsequently drives neurodegeneration. There is increasing evidence linking gut dysbiosis to the severity of PD's motor symptoms as well as to somatosensory hypersensitivities. Altogether, these interdependent features highlight the urgency of reviewing the links between the onset of PD's non-motor symptoms and gut immunity and whether such interplays drive the progression of PD. This review will shed light on maladaptive neuro-immune crosstalk in the context of gut dysbiosis and will posit that such deleterious interplays lead to PD-induced pain hypersensitivity.
Learn More >Vestibular migraine (VM) is the most common neurological cause of vertigo in adults. Previous neuroimaging studies have reported structural alterations in areas associated with pain and vestibular processing. However, it is unclear whether altered resting-state functional connectivity (FC) exists in brain regions with structural abnormalities in patients with VM.
Learn More >Mounting evidence from animal models of inflammatory and neuropathic pain suggests that inflammation regulates the resolution of pain by producing specialized pro-resolving mediators (SPMs), such as resolvin D1 (RvD1). However, it remains unclear how SPMs are induced in the central nervous system and whether these mechanisms can be reconciled with outcomes of neuromodulation therapies for pain, such as spinal cord stimulation. Here, we show that in a male rat model of neuropathic pain produced by spared nerve injury (SNI), 1 kHz spinal cord stimulation (1 kHz SCS) alone was sufficient to reduce mechanical allodynia and increase RvD1 in the cerebrospinal fluid (CSF). SNI resulted in robust and persistent mechanical allodynia and cold allodynia. Spinal cord electrode implantation was conducted at the T11-T13 vertebral level 1 week after SNI. The spinal locations of the implanted electrodes were validated by X-Ray radiography. 1 kHz SCS was applied for 6 h at 0.1 ms pulse-width, and this stimulation alone was sufficient to effectively reduce nerve injury-induced mechanical allodynia during stimulation without affecting SNI-induced cold allodynia. SCS alone significantly reduced interleukin-1β levels in both serum and CSF samples. Strikingly, SCS significantly increased RvD1 levels in the CSF but not serum. Finally, intrathecal injection of RvD1 (100 and 500 ng, i.t.) 4 weeks after nerve injury reduced SNI-induced mechanical allodynia in a dose-dependent manner. Our findings suggest that 1 kHz SCS may alleviate neuropathic pain via reduction of IL-1β and via production and/or release of RvD1 to control SNI-induced neuroinflammation.
Learn More >Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved.
Learn More >Trigeminal sensory neurons of transgenic knock-in (KI) mice expressing the R192Q missense mutation in the α1A subunit of neuronal voltage-gated Ca 2.1 Ca channels, which leads to familial hemiplegic migraine type 1 (FHM1) in patients, exhibit a hyperexcitability phenotype. Here, we show that the expression of Na 1.7 channels, linked to pain states, is upregulated in KI primary cultures of trigeminal ganglia (TG), as shown by increased expression of its α1 subunit. In the majority of TG neurons, Na 1.7 channels are co-expressed with ATP-gated P2X3 receptors (P2X3R), which are important nociceptive sensors. Reversing the trigeminal phenotype with selective Ca 2.1 channel inhibitor ω-agatoxin IVA inhibited Na 1.7 overexpression. Functionally, KI neurons revealed a TTX-sensitive inward current of larger amplitude that was partially inhibited by selective Na 1.7 blocker Tp1a. Under current-clamp condition, Tp1a raised the spike threshold of both wild-type (WT) and KI neurons with decreased firing rate in KI cells. Na 1.7 activator OD1 accelerated firing in WT and KI neurons, a phenomenon blocked by Tp1a. Enhanced expression and function of Na 1.7 channels in KI TG neurons resulted in higher excitability and facilitated nociceptive signaling. Co-expression of Na 1.7 channels and P2X3Rs in TGs may explain how hypersensitivity to local stimuli can be relevant to migraine.
Learn More >The most common cause of chronic musculoskeletal pain is chronic myofascial pain syndrome (MPS). MPS often presents with increased muscle stiffness, and the myofascial trigger point (MTrP). Imaging modalities have been used to identify the MTrP, but their role in the detection and diagnosis of MPS remains unclear. The purpose of this review was to identify evidence in literature for the use of imaging in the role of classifying and explaining the physiology of MTrPs. Since few imaging techniques have been performed on MTrPs, we explored the imaging techniques that can effectively image complex skeletal muscle microstructure, and how they could be used. As part of a scoping review, we conducted a systematic search from three medical databases (CINAHL, EMBASE and MEDLINE) from year to year to analyze past MTrP imaging, as well as analyzing imaging techniques performed on the microstructure of muscle. Previously, ultrasound has been used to differentiate active, latent MTrPs, but these studies do not adequately address their underlying anatomical structure. MRI remains the standard method of imaging skeletal muscle. The existing MRI literature suggests that the DTI technique can quantify muscle injury, strain, and structure. However, theoretically, HARDI and DKI techniques seem to provide more information for complex structural areas, although these modalities have a disadvantage of longer scan times and have not been widely used on skeletal muscle. Our review suggests that DTI is the most effective imaging modality that has been used to define the microstructure of muscle and hence, could be optimal to image the MTrP. HARDI and DKI are techniques with theoretical potential for analysis of muscle, which may provide more detailed information representative of finer muscle structural features. Future research utilizing MRI techniques to image muscle are necessary to provide a more robust means of imaging skeletal muscle and the MTrP.
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