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The blood-brain (BBB) and blood-nerve barriers ensure protection of the nervous system but pose a challenge for treatment of pain since it restricts passage of many therapeutic drugs. Although it is unknown which blood-neural barrier is more relevant, or whether permeabilities are the same for different barriers, we proposed that the inefficiency of thioglitazone type agonists for peroxisome proliferator-activated receptor gamma (PPARɣ) is due to their difficulty in passage through the BBB. We developed a new highly BBB penetrable PPARɣ agonist for the treatment of neuropathic pain, assuming BBB permeability is a rule of thumb to estimate the overall permeability of relevant blood-neural barriers. The peak ELB00824/ pioglitazone concentration (Cmax) in the brain was 5.4 versus 0.2 µM in blood at equivalent doses (10 mg/kg i.p.). The series of studies presented here indicate that ELB00824 may be the most potent PPARɣ agonist currently known for acute reduction of neuropathic pain in trigeminal nerve in rat and mouse models. Low dose PPARɣ agonist, ELB00824 (10 mg/kg), effectively decreased neuropathic hypersensitivity in mice and rats at both acute and chronic time points, a dose 100-fold lower than the effective dose (1000 mg/kg, i.p.) of pioglitazone. Comparisons of ELB00824 alone or in combination with gabapentin or carbamazepine are provided. While PPARɣ agonists used to treat Type 2 diabetes produce several adverse side effects, sub-chronic oral toxicity study provided promising results that ELB00824 does not produce any significant short-term toxicity. The study animals of either sex remained alive and healthy with no significant alteration of body weight long-term. Toxicity study results obtained were satisfactory, with no significant alterations in any serum biochemistry parameters.
Learn More >Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus with obscure underlying mechanisms. The adaptor protein APPL1 is critical in mediating the insulin sensitizing and insulin signaling. In neurons, APPL1 reportedly affects synaptic plasticity, while its role in the pathogenesis of PDN is masked. Our western blotting revealed significantly decreased APPL1 expression in the dorsal horn in streptozocin (STZ)-induced rats versus the control rats, coupled with concomitant mechanical and thermal hyperalgesia. Afterwards, the determination of exact localization of APPL1 in spinal cord by immunofluorescent staining assay revealed highly expressed APPL1 in the lamina of spinal dorsal horn in control rats, with the overexpression in neurons, microglia and underexpression in astrocytes. The APPL1 expression in laminae I and II was significantly downregulated in PDN rats. Additionally, APPL1 deficiency or overexpression contributed to the increase or decrease of Map and Bassoon, respectively. The localization and immunoactivity of APPL1 and mammalian target of rapamycin (mTOR) were determined in spinal dorsal horn in PDN rats and control rats by immunohistochemistry, suggesting pronounced decrease in APPL1 expression in the superficial layer of the spinal cord in PDN rats, with p-mTOR expression markedly augmented. APPL1 knockdown by infection with lentiviral vector facilitated the activation of mTOR and abrogated mechanical withdrawal threshold (MWT) values in PDN rats. Genetically overexpressed APPL1 significantly eliminated the activation of mTOR and resulted in the augmented MWT values and thermal withdrawal latency (TWL) values. Further, the APPL1 levels affect phosphorylation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), and Akt, the phosphorylation of AMPK and Akt as well as the small GTPase, Rab5 expression in PDN rats. Our results uncovered a novel mechanism by which APPL1 deficiency facilitates the mTOR activation, and thus exacerbates the hyperalgesia in STZ-induced diabetic rats, presumably via the regulation of Rab5/Akt and AMPK signaling pathway.
Learn More >Depression, anxiety and somatization influence the recovery of people with musculoskeletal pain. A Delphi study was conducted to reach consensus on the most appropriate self-administered questionnaires to assess these psychosocial factors in people at risk of developing persistent musculoskeletal pain. A multidisciplinary panel of international experts was identified via PubReMiner. The experts (N=22) suggested 24 questionnaires in Round 1. In Round 2, experts rated the questionnaires on suitability, considering clinimetrics, content, feasibility, personal experiences and expertise. The highest ranked questionnaires were retained for Round 3, in which the experts made a final assessment of the suitability of the questionnaires. Sensitivity analyses were performed to assess the impact of (1) not all experts having participated in each round, and (2) experts having been involved in relevant questionnaire development. Consensus (i.e., ≥75% agreement) was reached for the following questionnaires. For depression: Patient Health Questionnaire-9, Beck Depression Inventory-II, Center for Epidemiological Studies-Depression Scale, and Depression Subscale of the Depression, Anxiety and Stress Scales. In the sensitivity analyses, consensus was also reached for the Depression Subscale of the Hospital Anxiety Depression Scale. For anxiety: Generalized Anxiety Disorder Scale-7, State and Trait Anxiety Inventory, and Pain Anxiety Symptoms Scale. For somatization: no recommendation could be made. Perspective This study generated a short-list of preferred questionnaires to assess depression, anxiety and somatization in people with musculoskeletal pain. Broad implementation of these questionnaires by clinicians and researchers will facilitate easier comparison and pooling of baseline and outcome data. Some of the recommended questionnaires still require validation in this population.
Learn More >Gerontological research reveals considerable interindividual variability in aging phenotypes, which has motivated research efforts to identify 'aging biomarkers.' Aging biomarkers are used to calculate biological age, which are better predictors of disease risk and residual lifespan when compared to chronological age alone. Emerging evidence using the epigenetic clock as an aging biomarker supports highly reliable individualized predictions about future health. The current study aimed to determine whether an epigenetic aging biomarker was associated with chronic pain in older adults (60-83 years old). A subset of participants (n=29) in the Neuromodulatory Examination of Pain and Mobility Across the Lifespan (NEPAL) study underwent a blood draw, demographic, psychological, cognitive and pain assessments. We estimated Horvath's epigenetic clock and calculated the difference between epigenetic age and chronological age that has been previously reported to predict overall mortality risk. Older individuals without chronic pain (n=9) had significantly "younger" epigenetic age compared to those with chronic pain (n=20, p<0.05). Older epigenetic age was associated with greater pain during daily activities (r=0.494, p=0.010) and anatomical pain sites (r=0.741, p<0.001), but not pain frequency/duration. An older epigenetic age was also associated with higher vibratory detection thresholds (r=0.490, p=0.021), heat pain thresholds (r=-0.478, p=0.028), and pressure pain thresholds at the trapezius (r=-0.571, p=0.006), but not thermal detection, pressure pain at the quadriceps or pain inhibition (p's>0.05). Epigenetic aging was associated with greater emotional stability (r=-0.461, p=0.027), conscientiousness (r=-0.549, p=0.007) and lower extraversion (r=0.414, p=0.049), but not depression or affect (p's>0.05). Epigenetic aging was also associated with lower episodic (r=-0.698, p=0.001) and working memory (r=-0.760, p<0.001). Our findings suggest that chronic pain is associated with accelerated epigenetic aging in healthy, community-dwelling older individuals and future studies with larger samples are needed to confirm our findings. An aging biomarker such as the epigenetic clock may help identify people with chronic pain at greater risk of functional decline and poorer health outcomes.
Learn More >Previous studies suggest that truncal regional anaesthesia (TRA), including techniques such as paravertebral block, may contribute significantly to analgesia after mastectomy. However, the severity and impact of postoperative pain varies markedly amongst individuals, making the identification of patients who would benefit most from TRA a potentially important step toward personalised perioperative care.
Learn More >Migraine affects over a billion people worldwide in any year and is the second most common cause of years lost due to disability. Not "just a headache", morbidity washes though society and carries a substantial economic and social cost. Understanding of migraine pathophysiology has progressed significantly. Animal models and functional neuroimaging have yielded significant insight into brain structures that mediate migraine symptoms. The role of small peptides as neurotransmitters within this network has been elucidated, allowing the generation of novel therapeutic approaches that have been validated by randomised placebo-controlled trials. Migraine is underdiagnosed and undertreated. Treatment of migraine should be proactive. An acute and, when indicated, preventive strategy should be formulated with the patient. Comorbid medication overuse must be supportively managed. Migraine-specific medications are making their way from bench to bedside. They promise an improved safety profile and ease of use in comparison to older, repurposed medications. Devices promise a non-drug alternative should patients prefer. The migraine understanding and treatment landscape is changing rapidly.
Learn More >Aim of this study was to detect the expression of miR-15a in rats following chronic constriction injury (CCI) and to investigate the regulatory functions of miR-15a during neuropathic pain (NP) development.
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