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A migraine is clinically characterized by repeated headache attacks that entail considerable disability. Many patients with migraines experience postdrome, the symptoms of which include tiredness and photophobia. Calcitonin gene-related peptide (GGRP) is critically implicated in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, sensitizes the trigeminovascular system. In our previous study, CSD caused hypomotility in the light zone and tendency for photophobia at 72 h, at which time trigeminal sensitization had disappeared. We proposed that this CSD-induced disease state would be useful for exploring therapeutic strategies for migraine postdrome. In the present study, we observed that the CGRP receptor antagonist, olcegepant, prevented the hypomotility in the light zone and ameliorated light tolerability at 72 h after CSD induction. Moreover, olcegepant treatment significantly elevated the threshold for facial heat pain at 72 h after CSD. Our results raise the possibility that CGRP blockade may be efficacious in improving hypoactivity in the light environment by enhancing light tolerability during migraine postdrome. Moreover, our data suggest that the CGRP pathway may lower the facial heat pain threshold even in the absence of overt trigeminal sensitization, which provides an important clue to the potential mechanism whereby CGRP blockade confers migraine prophylaxis.
Learn More >Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy individuals and migraine-like attacks in patients; however, it is not clear whether targeting this system could be therapeutically efficacious. To effectively target the PACAP system, an understanding of PACAP receptor distribution is required. Therefore, this study aimed to characterize commercially available antibodies and use these to detect PACAP-responsive receptors in the TG. Antibodies were initially validated in receptor transfected cell models and then used to explore receptor expression in rat and human TG. Antibodies were identified that could detect PACAP-responsive receptors, including the first antibody to differentiate between the PAC and PAC receptor splice variants. PAC, VPAC, and VPAC receptor-like immunoreactivity were observed in subpopulations of both neuronal and glial-like cells in the TG. In this study, PAC, VPAC, and VPAC receptors were detected in the TG, suggesting they are all potential targets to treat migraine. These antibodies may be useful tools to help elucidate PACAP-responsive receptor expression in tissues. However, most antibodies exhibited limitations, requiring the use of multiple methodologies and the careful inclusion of controls.
Learn More >Treatment with opioids not only inhibits nociceptive transmission but also elicits a rebound and persistent increase in primary afferent input to the spinal cord. Opioid-elicited long-term potentiation (LTP) from TRPV1-expressing primary afferents plays a major role in opioid-induced hyperalgesia and analgesic tolerance. Here, we determined whether opioid-elicited LTP involves vesicular glutamate transporter-2 (VGluT2) or vesicular GABA transporter (VGAT) neurons in the spinal dorsal horn of male and female mice and identified underlying signaling mechanisms. Spinal cord slice recordings revealed that µ-opioid receptor (MOR) stimulation with DAMGO initially inhibited dorsal root-evoked EPSCs in 87% VGluT2 neurons and subsequently induced LTP in 49% of these neurons. Repeated morphine treatment increased the prevalence of VGluT2 neurons displaying LTP with a short onset latency. In contrast, DAMGO inhibited EPSCs in 46% VGAT neurons but did not elicit LTP in any VGAT neurons even in morphine-treated mice. Spinal superficial laminae were densely innervated by MOR-containing nerve terminals and were occupied by mostly VGluT2 neurons and few VGAT neurons. Furthermore, conditional knockout in dorsal root ganglion neurons diminished DAMGO-elicited LTP in lamina II neurons and attenuated hyperalgesia and analgesic tolerance induced by repeated treatment with morphine. In addition, DAMGO-elicited LTP in VGluT2 neurons was abolished by protein kinase C inhibition, gabapentin, knockout, or disrupting the α2δ-1-NMDA receptor interaction with an α2δ-1 C terminus peptide. Thus, brief MOR stimulation distinctively potentiates nociceptive primary afferent input to excitatory dorsal horn neurons via α2δ-1-coupled presynaptic NMDA receptors, thereby causing hyperalgesia and reducing opioids' analgesic actions.Opioid drugs are potent analgesics for treating severe pain and are commonly used during general anesthesia. However, opioid use often induces pain hypersensitivity, rapid loss of analgesic efficacy, and dose escalation, which can cause dependence, addiction, and even overdose fatality. This study demonstrates for the first time that brief opioid exposure preferentially augments primary sensory input to genetically identified glutamatergic excitatory, but not GABAergic/glycinergic inhibitory, neurons in nociceptive dorsal horn circuits. This opioid-elicited synaptic plasticity is cell type-specific and mediated by protein kinase C- and α2δ-1-dependent activation of NMDA receptors at primary sensory nerve terminals. These findings elucidate how intraoperative use of opioids aggravates postoperative pain and increases opioid consumption and suggest new strategies to improve opioid analgesic efficacy.
Learn More >A biopsychosocial rehabilitation is recommended for chronic nonspecific low back pain (CNLBP); however, its effectiveness compared to the traditional supervised exercise therapy of CNLBP treatment is still unclear.
Learn More >This study probes into the function and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived exosomes loaded with miR-150-5p in mechanical allodynia.
Learn More >Laparoscopic TAPP/TEP approaches are well-established options for the cure of inguinal hernias. As in the open approach, mesh fixation and poor-quality biologic response represent controversial questions and are a source of concerns. Furthermore, hernia defect patency represents another problem which seems not well acknowledged among surgeons. These problems are considered the cause of frequent intra and postoperative complications. To overcome these concerns, recently a different concept of cure has emerged. Based on a newly developed dynamic responsive 3D scaffold named ProFlor, a permanent hernia defect obliteration has been finalized. Following its inherent centrifugal expansion due to its dynamic responsivity, this hernia device is positioned fixation free within the defect and induces a probiotic biological response allowing for the re-establishment of the degenerated inguinal barrier. A laparoscopic approach with the 3D scaffold has been tested on 71 patients to demonstrate its effectiveness in reducing intra and postoperative complications. The operated patients presented with bilateral and/or recurrent inguinal hernia. Overall, 122 hernia defects were obliterated with 119 dynamic responsive scaffolds. The procedures were carried out from January 2018 to January 2022 with a defined protocol and detailed procedural steps. The laparoscopic technique with the 3D hernia scaffold allowed for fixation free placement, permanent defect obliteration and dynamically induced regenerative effects. The technique proved effective in reducing intra and postoperative complications. In particular, early postoperative pain and discomfort significantly decreased. No chronic pain and no recurrences were reported during follow up. The results achieved with the described laparoscopic technique seem to embody an innovative concept for inguinal hernia repair. Fixation free, dynamic responsive, permanent defect obliteration, histologically proven regenerative effects are the distinctive features of this 3D scaffold. It seems to embody a more physiological and pathogenetically coherent concept of cure, thus improving treatment results of this widespread disease.
Learn More >The primary aim of this pilot study was to test the feasibility and acceptability of a prototype of a novel digital system enabling somatosensory training at home by means of a gamified mobile application in patients with chronic pain. The secondary aims were to test the effect size of the intervention on clinical outcomes to power a subsequent randomized controlled trial. We conducted a pilot randomized controlled trial in patients with fibromyalgia. This was an 8-week crossover study, which included a 4-week somatosensory training phase (daily use with the novel digital system) and a 4-week control phase (no use of this new system) in a random order. Feasibility was tested by objectively measuring the adherence and retention rates. Acceptability and changes in pain and disability were measured through data from subjective questionnaires. Thirty-five patients completed the study. The satisfaction questionnaire indicated high training enjoyment, ease of use for daily training and interest to continue to use the intervention after the study. The adherence (93%) and retention (94%) rates were high. The effect sizes were moderate for pain intensity (0.57). The novel gamified technology for remotely delivered somatosensory training is feasible in a group of patients with fibromyalgia, and results in high engagement, satisfaction, and adherence. A subsequent clinical trial with the final version of the technology platform, including a longer training with more sensory training tasks and a bigger sample size is necessary.
Learn More >Physical activity, particularly walking, is commonly used for the treatment of diseases such as low back pain. In this study, the effects of walking wearing the new ToneFit Reha training belt (TFR) were compared to both Nordic walking and regular walking. The TFR is intended to intensify the effects of walking through the integration of two adjustable resistance handles.Ten patients with low back pain performed regular walking, Nordic walking and walking with the TFR in a movement laboratory. The kinematics of the trunk, upper extremities and lower extremities were measured, and the activity of the trunk and upper extremity muscles recorded. Data were analysed by repeated-measures ANOVA and paired t-test.Kinematics indicated that walking with the TFR introduces instability that was mitigated by a delayed peak trunk rotation (peak at 63.3% gait cycle, vs. 52.8% in walking (p=0.001) and 51.0% in NW (p=0.007)). Upper extremity kinematics (constrained elbow flexion, high peak shoulder abduction) showed movement patterns that need to be considered when training over a longer period. Increased muscle activity was observed especially for upper extremity muscles, when training with TFR. Overall, walking with the TFR was found to be a suitable therapy for use in a rehabilitation setting.
Learn More >Good clinical outcomes in orthopaedics are largely dictated by the biomedical model, despite mounting evidence of the role of psychosocial factors. Understanding orthopaedic providers' conceptualizations of good clinical outcomes and what facilitates and hinders them may highlight critical barriers and opportunities for training providers on biopsychosocial models of care and integrating them into practice.
Learn More >Molecular identification of bulbospinal ON neurons by GPER which drives pain and morphine tolerance.
The rostral ventromedial medulla (RVM) exerts bi-directional descending modulation of pain, attributable to the activity of electrophysiologically-identified pro-nociceptive ON and anti-nociceptive OFF neurons. Here we report that GABAergic ON neurons specifically express G protein-coupled estrogen receptor (GPER). GPER+ neurons exhibited characteristic ON-like responses upon peripheral nociceptive stimulation. Optogenetic activation of GPER+ neurons facilitated, whilst their ablation abrogated pain. Furthermore, activation of GPER caused depolarization of ON cells, potentiated pain and ameliorated morphine analgesia through desensitizing μ-type opioid receptor (MOR)-mediated activation of potassium currents. In contrast, genetic ablation or pharmacological blockade of GPER attenuated pain, enhanced morphine analgesia and delayed the development of morphine tolerance in diverse preclinical pain models. Our data strongly support GPER as a marker for GABAergic ON cells and also illuminate the mechanisms underlying hormonal regulation of pain and analgesia, highlighting GPER as a promising target for the treatment of pain and opioid tolerance.
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