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For several widely-used patient-reported outcome measures (PROMs) in chronic musculoskeletal pain (CMSP) rehabilitation, it is still not known whether they are responsive to change, and what the smallest detectable change (SDC) and minimal clinically important change (MCIC) are. Knowledge of these values can be used to accurately interpret change scores in research and clinical practice.
Learn More >The development of analgesic tolerance to opioids is an important limitation in the management of chronic pain. Spinal cord glial cell activation appears to play a pivotal role in the development and maintenance of opioid tolerance, indicating the presence of an opioid-induced neuronal-glial interaction; however, how opioids drive this cross-talk is still elusive. In search of treatments to attenuate morphine analgesic tolerance, our research focused on the role of Notch signaling pathway, one of the most important mechanisms of cell-to-cell interactions, in the spinal dorsal horn after morphine repeated exposure and whether Notch inhibition attenuates morphine analgesic tolerance. Double immunofluorescence experiments on spinal sections from morphine-tolerant mice showed a neuronal localization of Notch-1 receptor whereas the Notch ligand Jagged was localized on neighboring astrocytes. Morphine-induced μ opioid receptor (MOR) stimulation triggered Notch-1 signaling activation and this event was mediated by astrocyte JNK activation. Notch-1 activation selectively reduced the expression of histone deacetylase (HDAC)-1, resulting in an overphosphorylation of PKC and ERK, kinases involved in MOR phosphorylation and internalization after repeated morphine exposure. Notch-1 signaling inhibition, through intrathecal administration of the γ-secretase inhibitor, DAPT, counteracted PKC and ERK overphosphorylation, MOR internalization, and analgesic tolerance. Conversely, the HDAC-1 inhibitor, LG325, further aggravated MOR internalization, PKC overphosphorylation, and analgesic tolerance.Our findings implicate the MOR-triggered Notch-1 signaling in promoting MOR internalization and morphine analgesic tolerance by epigenetic regulation mechanisms. These data suggest that Notch-1 inhibitors could represent an innovative therapeutic perspective for the management of opioid tolerance in chronic pain therapy.
Learn More >Despite its prevalence and high disease burden, the pathophysiological mechanisms underlying chronic migraine (CM) are not well understood. As CM is a complex disorder associated with a range of sensory, cognitive, and affective comorbidities, examining structural network disruption may provide additional insights into CM symptomology beyond studies of focal brain regions. Here, we compared structural interconnections in patients with CM (n = 52) and healthy controls (HC) (n = 48) using MRI measures of cortical thickness and subcortical volume combined with graph theoretical network analyses. The analysis focused on both local (nodal) and global measures of topology to examine network integration, efficiency, centrality, and segregation. Our results indicated that patients with CM had altered global network properties that were characterized as less integrated and efficient (lower global and local efficiency) and more highly segregated (higher transitivity). Patients also demonstrated aberrant local network topology that was less integrated (higher path length), less central (lower closeness centrality), less efficient (lower local efficiency) and less segregated (lower clustering). These network differences not only were most prominent in the limbic and insular cortices but also occurred in frontal, temporal, and brainstem regions, and occurred in the absence of group differences in focal brain regions. Taken together, examining structural correlations between brain areas may be a more sensitive means to detect altered brain structure and understand CM symptomology at the network level. These findings contribute to an increased understanding of structural connectivity in CM and provide a novel approach to potentially track and predict the progression of migraine disorders.This study is registered on ClinicalTrials.gov (Identifier: NCT03304886).
Learn More >Triple-negative breast cancer (TNBC) is very aggressive with high metastatic and mortality rates and unfortunately, except for chemotherapy, there are few therapeutic options. The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) regulates numerous processes important for cancer progression, metastasis, and neuropathic pain. The pro-drug FTY720 (fingolimod, Gilenya) used to treat multiple sclerosis is phosphorylated in the body to a S1P mimic that binds to S1PRs, except S1PR2, and also acts as a functional antagonist of S1PR1. This review highlights current findings showing that FTY720 has multiple anti-cancer activities and simultaneously prevents formation and actions of S1P. Moreover, in mouse breast cancer models, treatment with FTY720 reduces tumor growth, metastasis, and enhances sensitivity of advanced and hormonal refractory breast cancer and TNBC to conventional therapies. We discuss recent studies demonstrating that neuropathic pain induced by the chemotherapeutic bortezomib is also greatly reduced by administration of clinically relevant doses of FTY720, likely by targeting S1PR1 on astrocytes. FTY720 also shows promising anticancer potential in pre-clinical studies and is FDA approved, thus we suggest in this review that further studies are needed to pave the way for fast-tracking approval of FTY720/fingolimod for enhancing chemotherapy effectiveness and reduction of painful neuropathies.
Learn More >Clinical studies have shown that schizophrenia is accompanied by hypoalgesia. Accordingly, we have previously reported that a chronic schizophrenia-related rat substrain (Wisket) showed decreased acute heat pain sensitivity. The aim of the present study was to determine the mechanical pain sensitivity and the effects of opioid ligands in a chronic osteoarthritic pain model generated using Wisket rats. Our previous molecular biological studies indicated that the impairment in opioid and cannabinoid receptor functions observed in these animals did not explain their altered pain sensitivity. Therefore, we aimed to investigate another endogenous antinociceptive system, i.e., the oxytocinergic system (which is also implicated in schizophrenia) via the determination the brain-region specific oxytocin receptor mRNA expression in Wisket rats. Osteoarthritis was induced in male adult control Wistar rats without any interventions and in Wisket rats after juvenile social isolation and ketamine treatment. The degree of allodynia and the effects of systemic morphine or intrathecal endomorphin-1 administration were determined. Furthermore, the expression of the oxytocin receptor mRNA was assessed in different brain structures (prefrontal cortex, striatum, diencephalon, brainstem, and olfactory bulb). A lower degree of allodynia was observed in the Wisket group compared with control animals 1 and 2 weeks after the induction of osteoarthritis, which was accompanied by a comparable degree of edema. Systemically or intrathecally applied opioids caused similar time-response curves in both groups, with apparently shorter effects in Wisket animals. The expression of the oxytocin receptor mRNA was lower in most of the brain regions (with the exception of the diencephalon) investigated in Wisket rats vs. the control animals. In summary, both acute and chronic hypoalgesia (as nonspecific symptoms in patients with schizophrenia) can be simulated in Wisket animals as endophenotypes despite the impairment of the endogenous antinociceptive systems evaluated. Thus, this model might be an appropriate tool for further investigation of the molecular basis of altered pain perception in schizophrenia.
Learn More >Starting in the late 1990s, the pharmaceutical industry sought to increase prescribing of opioids for chronic non-cancer pain. Influencing the content of clinical practice guidelines may have been one strategy industry employed. In this study we assessed potential risk of bias from financial conflicts of interest with the pharmaceutical industry in guidelines for opioid prescribing for chronic non-cancer pain published between 2007 and 2013, the peak of opioid prescribing.
Learn More >Administration of chemicals (pruritogens) into the skin evokes itch based on signal transduction mechanisms that generate action potentials mainly in mechanically sensitive and sensitive primary afferent C-fibers (pruriceptors). These signals from peripheral neurons are processed in spinal and supra-spinal centers of the central nervous system and finally generate the sensation of itch. Compared to chemical stimulation, electrical activation of pruriceptors would allow for better temporal control and thereby a more direct functional assessment of their activation. Here, we review the electrical stimulation paradigms which were used to evoke itch in humans in the past. We further evaluate recent attempts to explore electrically induced itch in atopic dermatitis patients. Possible mechanisms underlying successful pruritus generation in chronic itch patients by transdermal slowly depolarizing electrical stimulation are discussed.
Learn More >To examine the association between the number of chronic nighttime insomnia symptoms and the risk of chronic widespread pain (CWP) and pain-related disability.
Learn More >Despite the widespread study of how injured nerves contribute to chronic pain, there are still major gaps in our understanding of pain mechanisms. This is particularly true of pain resulting from nerve injury, or neuropathic pain, wherein tactile or thermal stimuli cause painful responses that are particularly difficult to treat with existing therapies. Curiously, this stimulus-driven pain relies upon intact, uninjured sensory neurons that transmit the signals that are ultimately sensed as painful. Studies that interrogate uninjured neurons in search of cell-specific mechanisms have shown that nerve injury alters intact, uninjured neurons resulting in an activity that drives stimulus-evoked pain. This review of neuropathic pain mechanisms summarizes cell-type-specific pathology of uninjured sensory neurons and the sensory ganglia that house their cell bodies. Uninjured neurons have demonstrated a wide range of molecular and neurophysiologic changes, many of which are distinct from those detected in injured neurons. These intriguing findings include expression of pain-associated molecules, neurophysiological changes that underlie increased excitability, and evidence that intercellular signaling within sensory ganglia alters uninjured neurons. In addition to well-supported findings, this review also discusses potential mechanisms that remain poorly understood in the context of nerve injury. This review highlights key questions that will advance our understanding of the plasticity of sensory neuron subpopulations and clarify the role of uninjured neurons in developing anti-pain therapies.
Learn More >Expectation affects pain experience in humans. Numerous studies have reported that pre-stimulus activity in the anterior insular cortex (aIC), together with prefrontal and limbic regions, integrated pain intensity and expectations. However, it is unclear whether the resting-state functional connectivity (rs-FC) between the aIC and other brain regions affects chronic pain. The purpose of this study was to examine the rs-FC between the aIC and the whole brain regions in female patients with severe knee osteoarthritis (OA).
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