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The mu opioid receptor (MOR) modulates nociceptive pathways, reward processing, and mediates the strong analgesic and addictive properties of both medicinal as well as abused opioid drugs. MOR function has been extensively studied, and tools to manipulate or visualize the receptor protein are available. However, circuit mechanisms underlying MOR-mediated effects are less known, because genetic access to MOR-expressing neurons is lacking. Here we report the generation of a knock-in -Cre mouse line, which allows targeting and manipulating MOR opioid-responsive neurons. A cDNA encoding a T2A cleavable peptide and Cre-recombinase fused to enhanced green fluorescent protein (eGFP/Cre) was inserted downstream of the gene sequence. The resulting Cre line shows intact gene transcription. MOR and eGFP/Cre proteins are co-expressed in the same neurons, and localized in cytoplasmic and nuclear compartments, respectively. MOR signaling is unaltered, demonstrated by maintained DAMGO-induced G protein activation, MOR function is preserved as indicated by normal morphine-induced analgesia, hyperlocomotion and sensitization. The Cre-recombinase efficiently drives expression of Cre-dependent reporter genes, shown by local-virally-mediated expression in the medial habenula and brain wide fluorescence upon breeding with tdTomato reporter mice, the later showing a distribution patterns typical of MOR expression. Finally, we demonstrate that optogenetic activation of MOR neurons in the ventral tegmental area of -Cre mice evokes strong avoidance behavior, as anticipated from the literature. The -Cre line is therefore an excellent tool for both mapping and functional studies of MOR-positive neurons, and will be of broad interest for opioid, pain and addiction research. Here we develop an innovative tool to characterize circuit mechanisms underlying opioid actions, which may help the research communities to improve the knowledge on circuitry adaptation and response to opioid. The tool is particularly relevant in the context of the current opioid crisis. Medicinal and abused opioids act primarily on Mu Opioid Receptor (MOR) and we developed here a Cre mouse line to specifically target and manipulate MOR-expressing neurons. This resource is with huge potential for mapping, molecular characterization and functional studies of opioid-responsive neurons.
Learn More >To define the characteristics of post-traumatic headache with cluster headache phenotype (PTH-CH) and to compare these characteristics with primary CH.
Learn More >The Pain Catastrophizing Scale (PCS) is a widely used self-report tool to evaluate pain related catastrophizing. The PCS was developed using classical test theory and has been shown to be psychometrically sound among various populations. However, it's current three subscales are rarely used in clinical practice, offering potential for an abbreviated version that reduces administrative burden and can be used to estimate full scale scores, yet is not bound by the inclusion of items from each subscale. Hence, the aim of the current study was to develop a unidimensional abbreviated version of the PCS through findings from qualitative, classical test theory, and newer Rasch analysis.
Learn More >The goal of this study was to examine the associations among posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), sleep quality, pain interference, and quality of life in combat veterans.
Learn More >A growing body of literature shows that justice-related appraisals are significant determinants of pain-related outcomes and prolonged trajectories of recovery. We conducted a systematic review of the literature assessing the relationship between perceived injustice and pain-related outcomes in individuals with musculoskeletal pain.
Learn More >Chronic pain (CP) may increase the risk for major adverse cardiac and cerebrovascular events (MACCEs); however, this issue is still unclear in the Asian population. We conducted this study to delineate it.
Learn More >Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there is limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans.In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n=52) and pain-free comparison controls (n=30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. CSF samples were analyzed for ten proinflammatory mediators using Meso Scale Discovery platform.Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P=0.002), intercellular adhesion molecule (ICAM) 1 (P=0.007) and vascular cell adhesion molecule (VCAM) 1 (P=0.006). OA patients with central sensitization possibly indicated by arm pressure pain detection threshold (PPDT) <250 kPa showed significantly higher CSF levels of Fms related tyrosine kinase 1 (Flt-1) (P=0.044) and interferon gamma-induced protein 10 (IP-10) (P=0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation (PVC), Flt-1 was elevated (P=0.025), and in patients with punctate stimulus wind-up-ratio ≥2, CSF monocyte chemoattractant protein 1 (MCP-1) was higher (P=0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote site PPDT and PVC pain, and MCP-1 with temporal summation in the area of maximum pain.Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.
Learn More >The purpose of this study was to examine the changes in cold block of unmyelinated C-fibers in the tibial nerve by pre-conditioning with heating and to develop a safe method for thermal block of C-fiber conduction. In 7 cats under α-chloralose anesthesia, C-fiber evoked potentials elicited by electrical stimulation were recorded on the tibial nerve during block of axonal conduction induced by exposing a small segment (9 mm) of the nerve to cooling (from 35 °C to ≤5 °C) or heating (45 °C). Before heating partial, reproducible, and reversible cold block was first detected at a threshold cold block temperature of 15 °C and complete cold block occurred at a temperature of ≤5 °C. After heating the nerve at 45 °C for 5-35 minutes the threshold cold block temperature significantly (p<0.05) increased from 15° C to 25 °C and the complete cold block temperature significantly (p<0.05) increased from ≤5 °C to 15°C on average. The increased cold block temperatures persisted for the duration of the experiments (30-100 minutes) while the amplitude of the C-fiber evoked potential measured at 35 °C recovered significantly (p<0.05) to about 80% of control. This study discovered a novel thermal method to block mammalian C-fibers at an elevated temperature (15-25 °C), providing the opportunity to develop a thermal nerve block technology to suppress chronic pain of peripheral origin. The interaction between heating and cooling effects on C-fiber conduction indicates a possible interaction between different temperature sensitive channels known to be present in the mammalian C-fibers.
Learn More >Ketamine and Magnesium for Refractory Neuropathic Pain: A Randomized, Double-blind, Crossover Trial.
Ketamine is often used for the management of refractory chronic pain. There is, however, a paucity of trials exploring its analgesic effect several weeks after intravenous administration or in association with magnesium. The authors hypothesized that ketamine in neuropathic pain may provide pain relief and cognitive-emotional benefit versus placebo and that a combination with magnesium may have an additive effect for 5 weeks.
Learn More >: To examine rates and correlates of dual cannabis and prescription pain reliever (PPNR) use and misuse among U.S. individuals aged 50+ who reported past-year cannabis use.: Using the 2015-2018 National Survey of Drug Use and Health, we examined cannabis nonuse/use and PPNR nonuse/use/misuse among all 35,229 respondents, and then focused on 2,632 past-year cannabis users to examine the risk of PPNR use but no misuse and the risk of PPNR misuse, compared to PPNR nonuse.: More than one-half of older cannabis users used PPNR in the past year. Multinomial logistic regression results show that the risks of PPNR use/no misuse and PPNR misuse were higher among those who had more chronic medical conditions and a major depressive episode. The risk of PPNR use/no misuse was also associated with high frequency and medical cannabis use. The risk of PPNR misuse was also associated with younger cannabis initiation age and cannabis and other illicit drug use disorders.: Correlates of dual cannabis and PPNR use/misuse among older adults are poor physical and mental health problems and problematic cannabis use.: Older adults with cannabis and PPNR misuse need access to evidence-based treatment, including medication-assisted treatment when needed.
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