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Intervertebral disc degeneration (IDD) causes a variety of signs and symptoms, such as low back pain (LBP), intervertebral disc herniation, and spinal stenosis, which contribute to high social and economic costs. IDD results from many factors, including genetic factors, aging, mechanical injury, malnutrition, and so on. The pathological changes of IDD are mainly composed of the senescence and apoptosis of nucleus pulposus cells (NPCs), the progressive degeneration of extracellular matrix (ECM), the fibrosis of annulus fibrosus (AF), and the inflammatory response. At present, IDD can be treated by conservative treatment and surgical treatment based on patients' symptoms. However, all of these can only release the pain but cannot reverse IDD and reconstruct the mechanical function of the spine. The latest research is moving towards the field of biotherapy. Mesenchymal stem cells (MSCs) are regard as the potential therapy of IDD because of their ability to self-renew and differentiate into a variety of tissues. Moreover, the non-coding RNAs (ncRNAs) are found to regulate many vital processes in IDD. There have been many successes in the in vitro and animal studies of using biotherapy to treat IDD, but how to transform the experimental data to real therapy which can apply to humans is still a challenge. This article mainly reviews the treatment strategies and research progress of IDD and indicates that there are many problems that need to be solved if the new biotherapy is to be applied to clinical treatment of IDD. This will provide reference and guidance for clinical treatment and research direction of IDD.
Learn More >Morphine abuse is a devastating disorder that affects millions of people worldwide, and literature evidence indicates a relationship between opioid abuse and the circadian clock.
Learn More >The potential for the development of opioid-induced hyperalgesia (OIH) provokes debate about whether long-term treatment with opioids is advisable and effective. If OIH develops during acute administration, will continuation of opioids actually make the pain worse? Hence, it is not surprising that OIH is part of the rationale used to promote deprescribing opioids in patients with chronic pain. But is there evidence that OIH is a clinically relevant phenomenon? This Commentary examines the evidence for OIH in randomized clinical trials in both the acute and chronic settings. Of critical importance in such an assessment is a trial design capable of differentiating OIH, tolerance, withdrawal-mediated pain sensitivity and worsening of the disease. However, studies published to date that purport to give evidence of OIH via experimentally induced pain all lack the rigour needed to differentiate these phenomena. Patient-reported measures of pain and analgesic consumption in these trials are not consistent with the presence of clinically significant OIH. At present, there is insufficient evidence from well-designed clinical trials that OIH is a clinically relevant phenomenon. Hence, while there are other reasons to avoid long-term use of opioids, the potential for the development of hyperalgesia during chronic opioid treatment is not a sound rationale for deprescribing these drugs in patients with chronic pain.
Learn More >Isoflurane (ISO) has been widely used in clinical anesthesia, and exposure to ISO leads to cognitive dysfunction. Our paper aimed to investigate the effect of miR-128-3p on cognitive impairment, inflammation, and oxidative stress elicited by ISO anesthesia in Sprague-Dawley (SD) rats. The SD rats were treated with ISO to mimic the ISO-injured situation, and the concentration of miR-128-3p was quantified utilizing real-time PCR. The miR-128-3p's impacts in ISO-engendered rat models on the respects of inflammatory condition and oxidative activities were measured by the commercial kits. The Morris water maze test was adopted to measure the neuro-function regarding miR-128-3p. Additionally, the target was tested by the alternation of luciferase activity. The irritation of ISO suppressed miR-128-3p expression in rats, which was enhanced by the injection of miR-128-3p agomir. The adverse roles of ISO on inflammation, oxidative stress, and cognitive disorders were partially abrogated by an increment of miR-128-3p. A miR-128-3p's interconnection with specificity protein 1 (SP1) was pinpointed, and aggrandized mRNA levels of SP1 were found under ISO state. MiR-128 acted as a regulator in ISO damage in the respects of cognition, inflammation, and oxidative stress. The SP1's link of miR-128-3p was showcased.
Learn More >Changing attitudes about marijuana have led to an increase in use of medicinal marijuana, especially for painful chronic conditions. Patients ask rheumatologists for guidance on this topic. This review provides up-to-date information on the safety and efficacy of medicinal cannabis for rheumatic disease pain.
Learn More >The kappa opioid receptor has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu opioid receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally-mediated side effects have limited their clinical translation. Here, we modify an active endogenous dynorphin peptide to improve drug-likeness and develop safer KOPr agonists for clinical use.
Learn More >Increased vigilance in settings of potential threats or in states of vulnerability related to pain is important for survival. Pain disrupts sleep and conversely, sleep disruption enhances pain, but the underlying mechanisms remain unknown. Chronic pain engages brain stress circuits and increases secretion of dynorphin, an endogenous ligand of the kappa opioid receptor (KOR). We therefore hypothesized that hypothalamic dynorphin/KOR signaling may be a previously unknown mechanism that is recruited in pathological conditions requiring increased vigilance. We investigated the role of KOR in wakefulness, non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in freely moving naïve mice and in mice with neuropathic pain induced by partial sciatic nerve ligation (PSNL) using EEG/EMG recordings. Systemic continuous administration of U69,593, a KOR agonist, over 5 days through an osmotic minipump decreased the amount of NREM and REM sleep and increased sleep fragmentation in naive mice throughout the light-dark sleep cycle. We used KORcre mice to selectively express a Gi-coupled designer receptor activated by designer drugs (Gi-DREADD) in KORcre neurons of the hypothalamic paraventricular nucleus (PVN), a key node of the hypothalamic-pituitary-adrenal (HPA) stress response. Sustained activation of Gi-DREADD with clozapine-N-oxide (CNO) delivered in drinking water over 4 days disrupted sleep in these mice in a similar way as systemic U69,593. Mice with chronic neuropathic pain also showed disrupted NREM and total sleep that was normalized by systemic administration of two structurally different KOR antagonists, norbinaltorphimine (nor-BNI) and NMRA-140, currently in phase II clinical development, or by CRISPR/Cas9 editing of PVN KOR, consistent with endogenous KOR activation disrupting sleep in chronic pain. Unexpectedly, REM sleep was diminished by either systemic KOR antagonist or by CRISPR/Cas9 editing of PVN KOR in sham-operated mice. Our findings reveal previously unknown physiological and pathophysiological roles of dynorphin/KOR in eliciting arousal. Physiologically, dynorphin/KOR signaling affects transitions between sleep stages that promote REM sleep. Furthermore, while KOR antagonists do not promote somnolence in the absence of pain, they normalized disrupted sleep in chronic pain, revealing a pathophysiological role of KOR signaling that is selectively recruited to promote vigilance, increasing chances of survival. Notably, while this mechanism is likely beneficial in the short-term, disruption of the homeostatic need for sleep over longer periods may become maladaptive resulting in sustained pain chronicity. A novel approach for treatment of chronic pain may thus result from normalization of chronic pain-related sleep disruption by KOR antagonism.
Learn More >The discovery of the prominent action of Calcitonin Gene Related Peptide -CGRP- on trigeminal afferents and meningeal vessels, opened a new era in migraine treatment. However, how the block of nociceptive afferents could act on central mechanisms of migraine is still not clear. In this pilot study we aimed to test the effect of 3 months Galcanezumab (CGA) therapy on occipital visual reactivity in migraine patients, using the Steady State Visual Evoked Potentials-SSVEPs and Functional Near Infrared Spectroscopy -fNIRS.
Learn More >Pain is the most common nonmotor symptom of Parkinson's disease (PD) and is often undertreated. Deep brain stimulation (DBS) effectively mitigates the motor symptoms of this multisystem neurodegenerative disease; however, its therapeutic effect on nonmotor symptoms, especially pain, remains inconclusive. While there is a critical need to help this large PD patient population, guidelines for managing this significant disease burden are absent. Herein, the authors systematically reviewed the literature and conducted a meta-analysis to study the influence of traditional (subthalamic nucleus [STN] and globus pallidus internus [GPi]) DBS on chronic pain in patients with PD.
Learn More >Pleasant touch provides emotional and psychological support that helps mitigate social isolation and stress. However, the underlying mechanisms remain poorly understood. Using a pleasant touch-conditioned place preference (PT-CPP) test, we show that genetic ablation of spinal excitatory interneurons expressing prokineticin receptor 2 (PROKR2), or its ligand PROK2 in sensory neurons, abolishes PT-CPP without impairing pain and itch behaviors in mice. Mutant mice display profound impairments in stress response and prosocial behaviors. Moreover, PROKR2 neurons respond most vigorously to gentle stroking and encode reward value. Collectively, we identify PROK2 as a long-sought neuropeptide that encodes and transmits pleasant touch to spinal PROKR2 neurons. These findings may have important implications for elucidating mechanisms by which pleasant touch deprivation contributes to social avoidance behavior and mental disorders.
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