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This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.
Learn More >Migraine is the leading cause of years lived with disability in people under 50 and its burden is increased by calcitonin gene-related peptide (CGRP)-driven chronicity. Newly approved small molecules that antagonize the CGRP receptor, gepants, have advanced from the hepatotoxic first-generation telcagepant to third-generation intranasal zavegepant; during this process of drug development, rimegepant, ubrogepant and atogepant, which are orally administered, have been launched and approved for clinical use with no warning for hepatotoxicity. Real-world, long-term postmarketing data about the efficacy and safety of gepants are awaited. The aim of the present drug evaluation study was to provide an overview of the novel, third-generation intranasal Zavegepant, encompassing its development and future perspectives.
Learn More >In osteoarthritis (OA) clinical trials, a placebo is often used as control. Therefore, a thorough understanding of the placebo response is important for guiding drug development in OA.
Learn More >Earlier findings suggest that social stress such as abusive supervision may promote pain. In the present study we examine the possible moderating role of genetic variability in the gene in this process.
Learn More >In this work we strived to determine whether endocannabinoid system activity could account for the differences in acute inflammatory pain sensitivity in mouse lines selected for high (HA) and low (LA) swim-stress-induced analgesia (SSIA). Mice received intraplantar injections of 5% formalin and the intensity of nocifensive behaviours was scored. To assess the contribution of the endocannabinoid system, mice were intraperitoneally (i.p.) injected with rimonabant (0.3-3 mg/kg) prior to formalin. Minocycline (45 and 100 mg/kg, i.p.) was administered to investigate microglial activation. The possible involvement of the endogenous opioid system was investigated with naloxone (1 mg/kg, i.p.). Cannabinoid receptor types 1 and 2 (, ) and opioid receptor subtype (, , ) mRNA levels were quantified by qPCR in the structures of the central nociceptive circuit. Levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled with the mass spectrometry method (LC-MS/MS). In the interphase, higher pain thresholds in the HA mice correlated with increased spinal anandamide and 2-AG release and higher transcription. Downregulation of and mRNA was noted in HA and LA mice, respectively, however no differences in naloxone sensitivity were observed in either line. As opposed to the LA mice, inflammatory pain sensitivity in the HA mice in the tonic phase was attributed to enhanced microglial activation, as evidenced by enhanced and mRNA levels. To conclude, Cnr1 inhibitory signaling is one mechanism responsible for decreased pain sensitivity in HA mice in the interphase, while increased microglial activation corresponds to decreased pain thresholds in the tonic inflammatory phase.
Learn More >Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (i.e., "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically-based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (i.e., targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of pre-specified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: (1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, (2) designing clinical trials that can identify treatment-by-phenotype interactions, and (3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: : Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.
Learn More >Current treatments for chronic pain are unsatisfactory, therefore, new therapeutics are urgently needed. Our previous study indicated that K channel openers have analgesic effects, but the underlying mechanism has not been elucidated. We speculated that K channel openers might increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Postoperative pain was induced by plantar incision to establish a chronic pain model. Growth arrest-specific 6 (Gas6) and Axl mice were used for signaling studies. The microglia cell line BV-2 was cultured for the in vitro experiments. The K channel opener significantly attenuated incision-induced mechanical allodynia in mice associated with the upregulated expression of SOCS3. Opening K channels induced the expression of SOCS3 in the Gas6/Axl signaling pathway in microglia, inhibited incision-induced mechanical allodynia by activating the Gas6/Axl-SOCS3 signaling pathway, and induced inflammatory tolerance to relieve neuroinflammation and postoperative pain. We demonstrated that opening of the K channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relievef chronic pain. We explored a new target for anti-inflammatory and analgesic effects by regulating the innate immune system and provided a theoretical basis for clinical preemptive analgesia.
Learn More >The ketamine metabolite (2R,6R)-hydroxynorketamine, or (2R,6R)-HNK, was recently reported to evoke antinociception in response to a noxious thermal stimulus in healthy mice and reverse mechanical hypersensitivity in a murine model of neuropathic pain. This study reports the behavioral effects of (2R,6R)-HNK in male and female C57BL/6J mice exposed to a localized inflammatory pain condition and the broad pharmacological mechanism underlying this effect. Hind paw intraplantar injection of λ-carrageenan (CARR) caused inflammation and mechanical hypersensitivity in mice within 2 hours, lasting at least 48 hours. Intraperitoneal administration of (2R,6R)-HNK (10-30 mg/kg i.p.) 2 hours following CARR injection significantly reversed mechanical hypersensitivity within 1 hour in male and female mice, and the effect persisted for 24 hours following a single dose. The magnitude and timing of the analgesic effect of (2R,6R)-HNK were comparable to the non-steroidal anti-inflammatory drug carprofen. The reversal of hypersensitivity by (2R,6R)-HNK was blocked at 4 and 24 hours after administration by pretreatment with the AMPA receptor antagonist NBQX and was not accompanied by changes in locomotor activity. These findings reinforce the growing evidence supporting (2R,6R)-HNK as a novel analgesic in multiple preclinical pain models and further support an AMPAR-dependent mechanism of action. SIGNIFICANCE: The ketamine metabolite (2R,6R)-HNK reversed mechanical hypersensitivity associated with localized inflammation with onset less than one hour and duration greater than 24 hours in an effect comparable to the NSAID carprofen. Reversal of mechanical hypersensitivity by (2R,6R)-HNK is AMPAR-dependent.
Learn More >Pelvic pain has cognitive, behavioral, sexual, and emotional consequences. Nurses involved in pelvic floor rehabilitation clinics have contacts with patients reporting chronic pain and should know the most appropriate service for patient referral, to submit the problem to professionals capable of correctly assessing and managing the condition. Furthermore, in some countries nurses can use conservative methods to treat the painful symptoms inside a multidisciplinary team such as breathing retraining, biofeedback, and noninvasive neuromodulation. This paper aims to provide an overview of the literature regarding the role of rehabilitation nurses in dealing with patients suffering from chronic urogenital pelvic pain or urogenital painful syndromes, inside a multidisciplinary team.
Learn More >To evaluate the effect of an anti-inflammatory compared to a low-calorie diet on the physical and mental health of patients with knee OA.
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