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Cannabis is often used to manage pain among persons who suffer from chronic pain. Yet, despite much literature suggesting cannabis use problems are associated with mental health problems, little work has examined mechanisms of this relationship among a chronic pain population. Chronic pain is also associated with emotion dysregulation. Individuals with chronic pain who experience cannabis use problems may have less capacity to regulate negative emotions, which could relate to greater anxiety, depression, and suicidal ideation. Thus, the current study explored whether emotion dysregulation explained, in part, the relation between cannabis use problems and anxiety, depression, and suicidal ideation among adults with chronic pain. Participants were 431 opioid-using adults with current moderate to severe chronic pain, 176 were current cannabis users, of which 30.20% reported cannabis use problems. Results indicated a significant indirect relationship between cannabis use problems and anxiety [95% CI (.03, .05)], depression [95% CI (.03, .06)], and suicidal ideation [95% CI (.01, .01)] via emotion dysregulation. Tests of specificity suggested potential for a bi-directional effect for suicidal ideation (.001). Initial findings suggest that emotion dysregulation may be an important mechanism in the relationship between cannabis use problems and mental health among adults with chronic pain.
Learn More >Opioid analgesics such as morphine have indispensable roles in analgesia. However, morphine use can elicit side effects such as respiratory depression and constipation. It has been reported that G protein-biased agonists as substitutes for classic opioid agonists can alleviate (or even eliminate) these side effects. The compounds PZM21 and TRV130 could be such alternatives. Nevertheless, there are controversies regarding the efficacy and G protein-biased ability of PZM21. To demonstrate a rationale for the reduced biasing agonism of PZM21 compared with that of TRV130 at the molecular level, we undertook a long-term molecular dynamics simulation of the μ-opioid receptor (MOR) upon the binding of three ligands: morphine, TRV130, and PZM21. We found that the delayed movement of the W293 (Ballesteros-Weinstein numbering) side chain was a factor determining the dose-dependent agonism of PZM21. Differences in conformational changes of W318, Y326, and Y336 in PZM21 and TRV130 explained the observed differences in bias between these ligands. The extent of water movements across the receptor channel was correlated with analgesic effects. Taken together, these data suggest that the observed differences in conformational changes of the studied MOR-ligand complexes point to the low-potency and lower bias effects of PZM21 compared with the other two ligands, and they lay the foundation for the development of G protein-biased agonists.
Learn More >Pain and depression are common in the population and co-morbid with each other. Both are predictive of one another and are also associated with cognitive function; people who are in greater pain and more depressed respectively perform less well on tests of cognitive function. It has been argued that pain might cause deterioration in cognitive function, whereas better cognitive function earlier in life might be a protective factor against the emergence of disease. When looking at the dynamic relationship between these in chronic diseases, studying samples that already have advanced disease progression often confounds this relationship.
Learn More >Despite being a life-restricting condition, chronic pain remains poorly treated. A better understanding of the underlying mechanisms of chronic pain and thence development of innovative targets is therefore essential. Recently we have started to elucidate the importance of the role of microRNAs (miRs) in preclinical chronic pain. miRs are small, non-coding RNAs that regulate genes including those involved in nociceptive signalling. MiRs can exert their effects both intracellularly and extracellularly, the latter of which requires that they are released either as naked species or packaged in exosomes. Here we discuss changes in miR expression that occur in the dorsal root ganglia in murine models of chronic pain. We consider the downstream targets of changes in miR expression, including voltage-gated ion channels, as well as discuss extracellular consequences such as changes in macrophage phenotype that constitute of means by which neuron-immune cell crosstalk occurs. Such miR-mediated intracellular communication could provide a novel target for the treatment of chronic pain, which would be most effective if tailored to the specific cause of pain. Indeed, we conclude by reviewing evidence for the involvement of miRs in clinical cases of chronic pain, supporting the notion that tailored, miR-targeted therapies could prove to be an effective new strategy for the treatment of chronic pain clinically.
Learn More >Our aim was to assess gender differences in variables associated with the emotional and physical burdens of tension-type headache (TTH). Participants with TTH diagnosed according to the ICHD-III were recruited from three university-based hospitals (in Spain, Italy, Denmark) between January 2015 and June 2017. The physical/emotional headache burden was assessed with the Headache Disability Inventory (HDI-P/HDI-E, respectively). Headache features were collected with a four-week diary. Sleep quality was assessed with Pittsburgh Sleep Quality Index. The Hospital Anxiety and Depression Scale evaluated anxiety and depressive symptom levels. Trait and state anxiety levels were evaluated with the State-Trait Anxiety Inventory. Two hundred and twelve (28% men) participants (aged 41-48 years old) participated. Multiple regression models revealed that sleep quality explained 36.7% of the variance of HDI-E and 31.1% of the variance of HDI-P in men, whereas headache intensity, depressive levels, and younger age explained 37.5% of the variance of HDI-E and 32.8% of the variance of HDI-P in women (all < .001). This study observed gender differences in variables associated with headache burden in TTH. Management of men with TTH should focus on interventions targeting sleep quality, whereas the management of women with TTH should combine psychological approaches and interventions targeting pain mechanisms.
Learn More >The aged population has a higher probability of developing chronic pain from acute insults because of age-associated low-grade inflammation. Several emerging studies have shown a crucial role of cap-dependent translation in the development of chronic pain in young adult animals; however, its role in the aged has never been reported. Acute and chronic inflammatory responses, including pain, are altered over age, and understanding how cap-dependent translation can represent an important and druggable pathway is imperative for understanding its therapeutic potential. Here we have tested how an inflammatory stimulus, complete Freund's adjuvant (CFA), affects spontaneous and evoked pain, as well as inflammation in young versus aged mice that lack functional cap-dependent translation machinery (eukaryotic translation initiation factor 4E (eIF4E)) compared with age-matched wild-type (WT) mice. Interestingly, we found that CFA-induced acute pain and inflammation are modulated by eIF4E phosphorylation in aged but not young animals. Aged transgenic animals showed attenuated paw temperature and inflammation, as well as a mitigation in the onset and quicker resolution in mechanical and thermal hypersensitivity. We found that levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α are elevated in dorsal root ganglia in aged WT and eIF4E transgenic groups, despite faster resolution of acute inflammation and pain in the aged eIF4E transgenic animals. We propose that these cytokines are important in mediating the observed behavioral responses in the young and represent an alternate pathway in the development of age-associated inflammation and behavioral consequences. These findings demonstrate that eIF4E phosphorylation can be a key target for treating inflammatory pain in the aged.
Learn More >Burst and high-frequency spinal cord stimulation (SCS), in contrast to low-frequency stimulation (LFS, < 200 Hz), reduce neuropathic pain without the side effect of paresthesia, yet it is unknown whether these methods' mechanisms of action (MoA) overlap. We used empirically based computational models of fiber threshold accommodation to examine the three MoA.
Learn More >In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.
Learn More >While opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse.
Learn More >Physical exercise has been shown to alter sensory functions, such as sensory detection or perceived pain. However, most contributing studies rely on the assessment of single thresholds, and a systematic testing of the sensory system is missing. This randomised, controlled cross-over study aims to determine the sensory phenotype of healthy young participants and to assess if sub-maximal endurance exercise can impact it. We investigated the effects of a single bout of sub-maximal running exercise (30 min at 80% heart rate reserve) compared to a resting control in 20 healthy participants. The sensory profile was assessed applying quantitative sensory testing (QST) according to the protocol of the German Research Network on Neuropathic Pain. QST comprises a broad spectrum of thermal and mechanical detection and pain thresholds. It was applied to the forehead of study participants prior and immediately after the intervention. Time between cross-over sessions was one week. Sub-maximal endurance exercise did not significantly alter thermal or mechanical sensory function (time × group analysis) in terms of detection and pain thresholds. The sensory phenotypes did not indicate any clinically meaningful deviation of sensory function. The alteration of sensory thresholds needs to be carefully interpreted, and only systematic testing allows an improved understanding of mechanism. In this context, sub-maximal endurance exercise is not followed by a change of thermal and mechanical sensory function at the forehead in healthy volunteers.
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