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Procedures to relieve pain are performed frequently but there are concerns about patient selection, appropriate image-guidance, frequency, and training for physicians. Patients, healthcare providers, policymakers, and licensing bodies seek evidence-based recommendations to use these interventions judiciously. In this review we appraised the methodological quality of recent clinical practice guidelines (CPGs) for interventional pain procedures.
Learn More >To characterize self-reported use of acute prescription medication for migraine in a sample representing the US population.
Learn More >The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta-analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied.
Learn More >Pain is a necessary sensation that prevents further tissue damage, but can be debilitating and detrimental in daily life under chronic conditions. Neuronal activity strongly regulates the maturation of the somatosensory system, and aberrant sensory input caused by injury or inflammation during critical periods of early postnatal development can have prolonged, detrimental effects on pain processing. This review will outline the maturation of neuronal circuits responsible for the transmission of nociceptive signals and the generation of pain sensation-involving peripheral sensory neurons, the spinal cord dorsal horn, and brain-in addition to the influences of the neuroimmune system on somatosensation. This summary will also highlight the unique effects of neonatal tissue injury on the maturation of these systems and subsequent consequences for adult somatosensation. Ultimately, this review emphasizes the need to account for age as an independent variable in basic and clinical pain research, and importantly, to consider the distinct qualities of the pediatric population when designing novel strategies for pain management.
Learn More >The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking healthcare and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and non-inflamed appendix was collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of CGRP positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel, and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrates that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly.
Learn More >Effects of emotion suppression on physical health might be contingent on culture. Existing research on emotion regulation has mainly included western participants. Herewith the question arises, whether this gained expertise is transferable to an Asian culture.
Learn More >Stasis dermatitis (SD) is a common disease in the elderly population, with pruritus being one of the bothersome symptoms. However, there are few therapeutic modalities available for SD-associated itch because little is known about its pathophysiological mechanism. Therefore, we sought to investigate the mediators of itch in SD using an immunofluorescence study on patient lesions focusing on IL-31. Ex vivo stimulation studies using murine peritoneal macrophages were also used to elucidate the pathological mechanisms of IL-31 generation. In SD lesions, dermal infiltrating IL-31(+) cells were increased in number compared to healthy controls, and the majority of IL-31(+) cells were CD68(+) macrophages. The presence of itch in SD was significantly associated with the amount of CD68(+)/IL-31(+) macrophages and CD68(+)/CD163(+) M2 macrophages. The number of CD68(+)/IL-31(+) macrophages was correlated with the number of dermal CCR4(+) Th2 cells, IL-17(+) cells, basophils, substance P(+) cells, and dermal deposition of periostin and hemosiderin. Furthermore, murine peritoneal macrophages expressed an M2 marker arginase-1 and generated IL-31 when stimulated with a combination of substance P, periostin, and red blood cell lysate (representing hemosiderin). IL-31 from macrophages may play a role in itch in SD.
Learn More >Analgesic tolerance and hyperalgesia hinder the long-term utility of opioids. We examined whether spinal high mobility group box 1 (HMGB1) is involved in morphine tolerance and its underlying mechanisms by using a model of repeated intrathecal (i.t.) injections of morphine. The results showed that chronic i.t. morphine exposure led to increased expression of HMGB1, Toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) and their mRNAs in the dorsal horn. Morphine challenge also promoted HMGB1 expression and release in cultured spinal neurons, but these effects were inhibited by TAK-242, naloxone (antagonists of TLR4), and TLR4 siRNA. Intrathecal coadministration of morphine with TAK-242 or PDTC (inhibitor of NF-κB activation) also reduced HMGB1 expression in the spinal cord. Repeated i.t. coinjections of morphine with glycyrrhizin (GL, an HMGB1 inhibitor) or HMGB1 siRNA prevented reduction of the maximal possible analgesic effect (MPAE) of morphine and alleviated morphine withdrawal-induced hyperalgesia. The established morphine tolerance and hyperalgesia were partially reversed when i.t. injections of GL or HMGB1 antibody started at day 7 of morphine injection. Repeated i.t. injections of morphine with HMGB1 siRNA inhibited the activation of NF-κB, but not that of JNK and p38. A single i.t. injection of HMGB1 in naïve rats caused pain-related hypersensitivity and reduction in MPAE. Moreover, phosphorylated NF-κB p65, TNF-α, and IL-1β levels in the dorsal horn were upregulated following this treatment, but this upregulation was prevented by coinjection with TAK-242. Together, these results suggest that morphine-mediated upregulation of spinal HMGB1 contributes to analgesic tolerance and hyperalgesia via activation of TLR4/NF-κB signaling, and the HMGB1 inhibitor might be a promising adjuvant to morphine in the treatment of intractable pain in the clinic.
Learn More >One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity.
Learn More >Cluster headache (CH) shows a more severe clinical picture than migraine (Mig). We tested whether brain changes can explain such difference. Multimodal MRI was acquired in attack-free patients with CH (n = 12), Mig (n = 13) and in normal controls (NC, n = 13). We used FSL for MRI data analysis and nonparametric permutation testing for voxelwise analyses (p < 0.01, corrected). CH showed lower grey matter (GM) volume, compared to Mig and NC, in frontal cortex regions (inferior frontal gyrus and frontal pole [FP], respectively) and, only compared to Mig, in lateral occipital cortex (LOC). Functional connectivity (FC) of CH was higher than Mig and NC within working memory and executive control networks and, only compared to Mig, between cerebellar and auditory language comprehension networks. In the attack-free state, the CH brain seems to be characterized by: (i) GM volume decrease, compared to both Mig and NC, in pain modulation regions (FP) and, only with respect to Mig, in a region of visual processing modulation during pain and working memory (LOC); (ii) increased FC at short range compared to both Mig and NC and at long range only with respect to Mig, in key cognitive networks, likely due to maladaptation towards more severe pain experience.
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