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Opioid use disorder (OUD) is a mounting public health problem with substantial morbidity and mortality. Stress involvement in the course of OUD is generally accepted, but little is understood about the underlying neurobiological mechanisms in part due to a lack of laboratory-based models for chronic stress exposure. Post-traumatic stress disorder (PTSD) may be construed as a psychopathological prototype of chronic stress owing to the essential diagnostic criteria of experiencing and reliving a stressful event(s). Literature search on OUD and PTSD neurobiology was undertaken and the relevant data were integrated within four key areas: (1) OUD and PTSD comorbidity, (2) neurobiological overlap between OUD and PTSD; (3) chronic opioids- and stress-induced alterations of the reward-, stress- (i.e., "anti-reward") and related circuits and (4) mechanistically informed treatments of OUD and/or PTSD. Our findings suggest that even in the absence of prior opioid exposure PTSD patients may be susceptible for the development of OUD by the reason of similar (to those induced by opioids) reward alterations that may be targeted for therapeutic interventions.
Learn More >Pain experienced during neonatal intensive care management can influence neurodevelopmental outcome and the somatosensory and/or emotional components of pain response in later life. Alterations in biological factors (e.g. peripheral and central somatosensory function and modulation, brain structure and connectivity) and psychosocial factors (e.g. gender, coping style, mood, parental response) that influence pain have been identified in children and young adults born very preterm or extremely preterm. Earlier gestational age at birth and cumulative pain exposure from tissue-breaking procedures and/or neonatal surgery influence the degree of change. In neonatal rodents, repeated needle insertion or hindpaw incision identify developmentally-regulated and activity-dependent long term alterations in nociceptive processing, and the efficacy of novel or current analgesic interventions can be compared. As prior neonatal experience and sex may influence current pain experience or the risk of persistent pain, these factors should be considered within the biopsychosocial assessment and formulation of pain in later life.
Learn More >Dermatological manifestations are common in systemic diseases, such as chronic kidney disease. The present study investigated the clinical features and possible influencing factors of pruritus in patients with chronic renal failure (CRF). A total of 382 inpatients were enrolled from the Department of Nephrology at The Second Affiliated Hospital of Chongqing Medical University. A total of 138 subjects were hemodialysis patients, 41 were peritoneal dialysis patients, and 203 were chronic renal failure patients. The patients' clinical performance was observed, and the data was recorded for analysis. The prevalence of pruritus in hemodialysis patients was greater than that in peritoneal dialysis patients. A total of 187 patients were accompanied by xerodermia and 109 patients had pruritus at the same time. With effective and regular dialysis, pruritus could be alleviated in 40% of patients. The intensity of pruritus in the enrolled patients ranged from mild itching to irritability during day and night periods. Moreover, pruritus was intermittent or persistent, and/or limited to generalized. Following treatment, 35% of patients had poor results. A significant difference was noted in the levels of serum urea nitrogen, creatinine, serum phosphorus, calcium × phosphorus, and parathyroid hormone (PTH) between patients with pruritus and non-pruritus. Xerodermia is a common skin manifestation in patients with chronic renal failure and is associated with the occurrence of pruritus. Local cold and heat stimulation can relieve pruritus to some extent, and adequate hemodialysis can also relieve itching.
Learn More >Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded on previous findings related to the 3 SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a 3-way interaction on placebo hypoalgesia. Using 2 well-established placebo procedures (verbal suggestion and learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC = 0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.
Learn More >: Chronic pain conditions of malignant and non-malignant etiology afflict a large group of the population and pose a vast economic burden on society. Intrathecal drug therapy is a viable treatment option in such patients who have failed conservative medical measures and less invasive pain management procedures. However, the clinical growth of intrathecal therapyin managing intractable chronic pain conditions continues to face many challenges and is likely underutilized secondary to its high-complexity and lack of understanding. : This review will briefly discuss the history of intrathecal drug delivery systems (IDDS), cerebrospinal fluid (CSF) flow dynamics, types of IDDS, indications and patient profile suitable for this therapy, and risks and complications related to IDDS. We will also discuss challenges faced by physicians utilizing this therapy and the future changes that are needed for making this treatment modality more efficacious. : IDDS offer an effective therapy for pain control in patients suffering from chronic intractable pain conditions. These devices provide a safer alternative to oral opioid medications with reduced systemic side effects. Adherence to best practices and continued clinical and basic science research is important to ensure continuing success of this therapy.
Learn More >Mechanical allodynia is a cardinal feature of pathological pain. Recent work has demonstrated the necessity of A[graphic1] low-threshold mechanoreceptors (Aβ-LTMRs) for mechanical allodynia-like behaviors in mice, but it remains unclear whether these neurons are sufficient to produce pain under pathological conditions. Thus, we generated a transgenic mouse in which channelrhodopsin-2 (ChR2) is conditionally expressed in Vesicular Glutamate Transporter 1 (Vglut1) sensory neurons (Vglut1-ChR2), which is a heterogeneous population of large-sized sensory neurons with features consistent with (A[graphic3]-LTMRs). In naive male Vglut1-ChR2 mice, transdermal hindpaw photostimulation evoked withdrawal behaviors in an intensity- and frequency-dependent manner, which were abolished by local anesthetic and also selective A-fiber blockade. Surprisingly, male Vglut1-ChR2 mice did not show significant differences in light-evoked behaviors or real-time aversion after nerve injury, despite marked hypersensitivity to punctate mechanical stimuli. Thus, we conclude that optogenetic activation of cutaneous Vglut1-ChR2 neurons alone is not sufficient to produce pain-like behaviors in neuropathic mice. Mechanical allodynia, wherein innocuous touch is perceived as pain, is a common feature of pathological pain. To test the contribution of low-threshold mechanoreceptors to nerve injury-induced mechanical allodynia, we generated and characterized a new transgenic mouse (Vglut1-ChR2) to optogenetically activate cutaneous Vglut1-positive LTMRs. Using this mouse, we found that light-evoked behaviors were unchanged by nerve injury, which suggests that activation of Vglut1-positive LTMRs alone is not sufficient to produce pain. The Vglut1-ChR2 mouse will be broadly useful for the study of touch, pain and itch.
Learn More >The cold and menthol sensitive Transient Receptor Potential Melastatin 8 (TRPM8) channel is important for both physiological temperature detection and cold allodynia. Activation of G-protein coupled receptors (GPCRs) by pro-inflammatory mediators inhibits these channels. It was proposed that this inhibition proceeds via direct binding of G to the channel. TRPM8 requires the plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P or PIP] for activity. It was claimed however that a decrease in cellular levels of this lipid upon receptor activation does not contribute to channel inhibition. Here we show that supplementing the whole cell patch pipette with PI(4,5)P reduced inhibition of TRPM8 by activation of G-coupled receptors in mouse dorsal root ganglion (DRG) neurons isolated from both sexes. Stimulating the same receptors activated Phospholipase C (PLC) and decreased plasma membrane PI(4,5)P levels in these neurons. PI(4,5)P also reduced inhibition of TRPM8 by activation of heterologously expressed G-coupled muscarinic M1 receptors. Co-expression of a constitutively active G protein that does not couple to PLC inhibited TRPM8 activity, and in cells expressing this protein decreasing PI(4,5)P levels using a voltage sensitive 5'-phosphatase induced a stronger inhibition of TRPM8 activity than in control cells. Our data indicate that upon GPCR activation, G binding reduces the apparent affinity of TRPM8 for PI(4,5)P and thus sensitizes the channel to inhibition induced by decreasing PI(4,5)P levels.Increased sensitivity to heat in inflammation is partially mediated by inhibition of the cold- and menthol sensitive TRPM8 ion channels. Most inflammatory mediators act via GPCR-s that activate the Phospholipase C pathway leading to the hydrolysis of PI(4,5)P How receptor activation by inflammatory mediators leads to TRPM8 inhibition is not well understood. Here we propose that direct binding of G both reduces TRPM8 activity, and sensitizes the channel to inhibition by decreased levels of its cofactor PI(4,5)P Our data demonstrate the convergence of two downstream effectors of receptor activation G and PI(4,5)P hydrolysis in regulation of TRPM8.
Learn More >Pruritus is a common extrahepatic symptom in various liver disorders, in particularly those with cholestatic features. This review summarizes epidemiology, pathophysiology, evidence-based therapeutic recommendations and currently investigated drugs for pruritus in hepatobiliary disorders.
Learn More >To evaluate changes from baseline in patient-reported outcomes for measures of functioning and disability among patients with migraine treated with galcanezumab or placebo.
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