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Although the mechanisms responsible for migraine initiation remain unknown, recent evidence shows that brain function is different immediately preceding a migraine. This is consistent with the idea that altered brain function, particularly in brainstem sites, may either trigger a migraine or facilitate a peripheral trigger that activates the brain, resulting in pain. The aim of this longitudinal study is therefore to expand on the above findings, and to determine if brainstem function oscillates over a migraine cycle in individual subjects. We performed resting state functional magnetic resonance imaging in three migraineurs and five controls each weekday for four weeks. We found that although resting activity variability was similar in controls and interictal migraineurs, brainstem variability increased dramatically during the 24-hour period preceding a migraine. This increase occurred in brainstem areas in which orofacial afferents terminate: the spinal trigeminal nucleus and dorsal pons. These increases were characterized by increased power at infra-slow frequencies, principally between 0.03 and 0.06 Hz. Furthermore, these power increases were associated with increased regional homogeneity, a measure of local signal coherence. The results show within-individual alterations in brain activity immediately preceding migraine onset and support the hypothesis that altered regional brainstem function before a migraine attack is involved in underlying migraine neurobiology.
Learn More >Naturally occurring spine osteoarthritis is clinically associated with the manifestation of chronic inflammatory muscle (myofascial) disease. The purpose of this study was to investigate the causal association between experimentally induced spine osteoarthritis and neurogenic inflammatory responses within neurosegmentally linked myotomes. Wistar Kyoto rats were randomly assigned to spine facet compression surgery (L4-L6) or sham surgery. Animals exposed to facet compression surgery demonstrated radiographic signs of facet-osteoarthritis (L4-L6 spinal levels) and sensory changes (allodynia, thermal hyperalgesia) at 7, 14 and 21 days post-intervention, consistent with the induction of central sensitization; no radiologic or sensory changes were observed after sham surgery. Increased levels of proinflammatory biomarkers including substance P (SP), calcitonin gene related peptide (CGRP), protease-activated receptor-2 (PAR2) and calcium/calmodulin dependent protein kinase II (CaMKII) were observed post-surgery within neurosegmentally-linked rectus femoris (L2-L5) muscle when compared to the non-segmentally linked biceps brachii (C4-C7) muscle; no differences were observed between muscles in the sham surgery group. These findings offer novel insight into the potential role of spine osteoarthritis and neurogenic inflammatory mechanisms in the pathophysiology of chronic inflammatory muscle (myofascial) disease.
Learn More >Using neurokinin 1 receptor (NK1R) internalization to measure of substance P release in rat spinal cord slices, we found that it was induced by the adenylyl cyclase (AC) activator forskolin, by the protein kinase A (PKA) activators 6-Bnz-cAMP and 8-Br-cAMP, and by the activator of exchange protein activated by cAMP (Epac) 8-pCPT-2-O-Me-cAMP (CPTOMe-cAMP). Conversely, AC and PKA inhibitors decreased substance P release induced by electrical stimulation of the dorsal root. Therefore, the cAMP signaling pathway mediates substance P release in the dorsal horn. The effects of forskolin and 6-Bnz-cAMP were not additive with NMDA-induced substance P release and were decreased by the NMDA receptor blocker MK-801. In cultured dorsal horn neurons, forskolin increased NMDA-induced Ca entry and the phosphorylation of the NR1 and NR2B subunits of the NMDA receptor. Therefore, cAMP-induced substance P release is mediated by the activating phosphorylation by PKA of NMDA receptors. Voltage-gated Ca channels, but not by TRPV1 or TRPA1, also contributed to cAMP-induced substance P release. Activation of PKA was required for the effects of forskolin and the three cAMP analogs. Epac2 contributed to the effects of forskolin and CPTOMe-cAMP, signaling through a Raf – mitogen-activated protein kinase pathway to activate Ca channels. Epac1 inhibitors induced NK1R internalization independently of substance P release. In rats with latent sensitization to pain, the effect of 6-Bnz-cAMP was unchanged, whereas the effect of forskolin was decreased due to the loss of the stimulatory effect of Epac2. Hence, substance P release induced by cAMP decreases during pain hypersensitivity.
Learn More >The presence or absence of clearly defined symptoms and underlying pathophysiology may be a crucial variable related to variability in wellbeing and stigmatization in individuals with chronic pain (ICPs). In the context of pain, absence of clearly defined symptoms and pathophysiology deviates from the widely endorsed biomedical model and as such, may lead to stigmatization, which in turn could be related to ICPs' wellbeing.
Learn More >Pain catastrophizing and pain acceptance are psychological factors that have been shown to be associated with pain-related outcomes and predict multidisciplinary pain treatment outcomes. However, they are rarely examined in the same study. This study aimed to: (a) assess the independent roles of pain catastrophizing and pain acceptance as predictors of pain intensity, pain interference, and depression; and (b) evaluate the potential moderating role of pain acceptance on the association between pain catastrophizing and both pain and function.
Learn More >Pruritus is one of the most distressing symptoms in cholestatic patients. Plasma autotaxin (ATX) activity correlates with the severity of pruritus in cholestatic patients, but the pathophysiology is unclear. To study pruritus in mice, we measured scratch activity in cholestatic Atp8b1 mutant mice, a model for Progressive Familial Intrahepatic Cholestasis type 1, and wild type mice (WT) with alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. To induce cholestasis, Atp8b1 mutant mice received a diet containing 0.1% cholic acid (CA) and WT mice were treated with ANIT. In these mice ATX was also overexpressed by transduction with AAV-ATX. Scratch activity was measured using an unbiased, electronic assay. Marked cholestasis was accomplished in both Atp8b1 mutant mice on a CA-supplemented diet and in ANIT-treatment in WT mice, but scratch activity was decreased rather than increased while plasma ATX activity was increased. Plasma ATX activity was further increased up to fivefold with AAV-ATX, but this did not induce scratch activity. In contrast to several reports two cholestatic mouse models did not display increased scratch activity as a measure of itch perception. Increasing plasma ATX activity by overexpression also did not lead to increased scratch activity in mice. This questions whether mice are suitable to study cholestatic itch.
Learn More >People with Parkinson's disease (PD) may live for multiple decades after diagnosis. Ensuring that effective healthcare provision is received across the range of symptoms experienced is vital to the individual's wellbeing and quality of life. As well as the hallmark motor symptoms, PD patients may also suffer from non-motor symptoms including persistent pain. This type of pain (lasting more than 3 months) is inconsistently described and poorly understood, resulting in limited treatment options. Evidence-based pain remedies are coming to the fore but therapeutic strategies that offer an improved analgesic profile remain an unmet clinical need. Since the ability to establish a link between the neurodegenerative changes that underlie PD and those that underlie maladaptive pain processing leading to persistent pain could illuminate mechanisms or risk factors of disease initiation, progression and maintenance, we evaluated the latest research literature seeking to identify causal factors underlying persistent pain in PD through experimental quantification. The majority of previous studies aimed to identify neurobiological alterations that could provide a biomarker for pain/pain phenotype, in PD cohorts. However heterogeneity of patient cohorts, result outcomes and methodology between human psychophysics studies overwhelmingly leads to inconclusive and equivocal evidence. Here we discuss refinement of pain-PD paradigms in order that future studies may enhance confidence in the validity of observed effect sizes while also aiding comparability through standardisation. Encouragingly, as the field moves towards cross-study comparison of data in order to more reliably reveal mechanisms underlying dysfunctional pain processing, the potential for better-targeted treatment and management is high.
Learn More >Monoclonal antibodies targeting CGRP or its receptor (anti-CGRP mAbs) are proven to be effective treatments in migraine prevention. Real-world evidence studies assessing their efficacy are scarce.
Learn More >Chronic postsurgical pain (CPSP) is a common complication after surgery; however, the underlying mechanisms of CPSP are poorly understood. As one of the most important inflammatory pathways, the Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway plays an important role in chronic pain. However, the precise role of the TLR4/NF-κB signaling pathway in CPSP remains unclear. In the present study, we established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR) and verified the effects and mechanisms of central and peripheral TLR4 and NF-κB on hyperalgesia in SMIR rats. The results showed that TLR4 expression was increased in both the spinal dorsal horn and dorsal root ganglia (DRGs) of SMIR rats. However, the TLR4 expression pattern in the spinal cord was different from that in DRGs. In the spinal cord, TLR4 was expressed in both neurons and microglia, whereas it was expressed in neurons but not in satellite glial cells in DRGs. Further results demonstrate that the central and peripheral TLR4/NF-κB signaling pathway is involved in the SMIR-induced CPSP by different mechanisms. In the peripheral nervous system, we revealed that the TLR4/NF-κB signaling pathway induced upregulation of voltage-gated sodium channel 1.7 (Nav1.7) in DRGs, triggering peripheral hyperalgesia in SMIR-induced CPSP. In the central nervous system, the TLR4/NF-κB signaling pathway participated in SMIR-induced CPSP by activating microglia in the spinal cord. Ultimately, our findings demonstrated that activation of the peripheral and central TLR4/NF-κB signaling pathway involved in the development of SMIR-induced CPSP.
Learn More >Despite application of multimodal pain management strategies, patients undergoing spinal fusion surgery frequently report severe postoperative pain. Methadone and ketamine, which are N-methyl-d-aspartate receptor antagonists, have been documented to facilitate postoperative pain control. This study therefore tested the primary hypothesis that patients recovering from spinal fusion surgery who are given ketamine and methadone use less hydromorphone on the first postoperative day than those give methadone alone.
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