Browse by Audience
Oxidative stress induced post-translational protein modifications are associated with the development of inflammatory hypersensitivities. At least 90% of cellular reactive oxygen species (ROS) are produced in the mitochondria, where the mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), is located. MnSOD's ability to reduce ROS is enhanced by the mitochondrial NAD-dependent deacetylase sirtuin (SIRT3). SIRT3 can reduce ROS levels by deacetylating MnSOD and enhancing its ability to neutralize ROS or by enhancing the transcription of MnSOD and other oxidative stress-responsive genes. SIRT3 can be post-translationally modified through carbonylation which results in loss of activity. The contribution of post-translational SIRT3 modifications in central sensitization is largely unexplored. Our results reveal that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with natural and synthetic antioxidants, prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD, and blocked the development of thermal hyperalgesia. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization.
Learn More >Neuropathic pain is a pathological condition induced by a lesion or disease affecting the somatosensory system, with symptoms like allodynia and hyperalgesia. It has a multifaceted pathogenesis as it implicates several molecular signaling pathways involving peripheral and central nervous systems. Affective and cognitive dysfunctions have been reported as comorbidities of neuropathic pain states, supporting the notion that pain and mood disorders share some common pathogenetic mechanisms. The understanding of these pathophysiological mechanisms requires the development of animal models mimicking, as far as possible, clinical neuropathic pain symptoms. Among them, the Spared Nerve Injury (SNI) model has been largely characterized in terms of behavioral and functional alterations. This model is associated with changes in neuronal firing activity at spinal and supraspinal levels, and induces late neuropsychiatric disorders (such as anxious-like and depressive-like behaviors, and cognitive impairments) comparable to an advanced phase of neuropathy. The goal of this review is to summarize current findings in preclinical research, employing the SNI model as a tool for identifying pathophysiological mechanisms of neuropathic pain and testing pharmacological agent.
Learn More >Alterations in the brain's μ-opioid receptor (MOR) system have been associated with several neuropsychiatric diseases. Also healthy individuals vary considerably in MOR availability. Multiple epidemiological factors have been proposed to influence MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. We compiled [C]carfentanil positron emission tomography scans from 204 individuals with no neurologic or psychiatric disorders, and estimated the effects of sex, age, body mass index (BMI) and smoking on [C]carfentanil binding potential using between-subject regression analysis. We also examined hemispheric differences in MOR availability. Older age was associated with increase in MOR availability in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders. Lateralized MOR system may reflect hemispheric work distribution in central emotion and pain processes.
Learn More >Pain is the most common symptom reported in clinical practice, meaning that it is associated with many pathologies as either the origin or a consequence of other illnesses. Furthermore, pain is a complex emotional and sensorial experience, as the correspondence between pain and body damage varies considerably. While these issues are widely acknowledged in clinical pain research, until recently they have not been extensively considered when exploring animal models, important tools for understanding pain pathophysiology. Interestingly, chronic pain is currently considered a risk factor to suffer psychiatric disorders, mainly stress-related disorders like anxiety and depression. Conversely, pain appears to be altered in many psychiatric disorders, such as depression, anxiety and schizophrenia. Thus, pain and psychiatric disorders have been linked in epidemiological and clinical terms, although the neurobiological mechanisms involved in this pathological bidirectional relationship remain unclear. Here we review the evidence obtained from animal models about the co-morbidity of pain and psychiatric disorders, placing special emphasis on the different dimensions of pain.
Learn More >Whereas impaired multisensory processing of bodily stimuli and distorted body representation are well-established in various chronic pain disorders, such research has focused on exteroceptive bodily cues and neglected bodily signals from the inside of the body (or interoceptive signals). Extending existing basic and clinical research, we investigated for the first time interoception and its neurophysiological correlates in patients with complex regional pain syndrome (CRPS). In three different experiments, including a total of 36 patients with CRPS and 42 aged-gender matched healthy controls, we measured interoceptive sensitivity (heart beat counting task, HBC) and neural responses to heartbeats (heartbeat evoked potentials, HEP). As hypothesized, we observed reduced sensitivity in perceiving interoceptive bodily stimuli, i.e. their heartbeat, in two independent samples of CRPS patients (studies 1 and 2). Moreover, the cortical processing of their heartbeat, i.e. the HEP, was reduced compared to controls (study 3) and reduced interoceptive sensitivity and HEPs were related to CRPS patients' motor impairment and pain duration. By providing consistent evidence for impaired processing of interoceptive bodily cues in CRPS, this study shows that the perceptual changes occurring in chronic pain include signals originating from the visceral organs, suggesting changes in the neural body representation, that includes next to exteroceptive, also interoceptive bodily signals. By showing that impaired interoceptive processing is associated with clinical symptoms, our findings also encourage the use of interoceptive-related information in future rehabilitation for chronic pain.
Learn More >Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally-restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain; and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
Learn More >Several studies have shown that oral sucrose reduces pain in newborns. However, sucrose has no efficacy in eliminating pain and long-term effects remain unclear. Breast milk may be useful as an alternative, safe sweet solution. Sensorial saturation (SS) is a multisensory analgesic non-pharmacological treatment, which includes touch and sounds as distractors. This study aimed to compare the analgesic effects of SS with sucrose (SSS), SS with breast milk (SSB), and oral sucrose alone (S24%) in neonates undergoing venipuncture.
Learn More >Stigma is associated with many health conditions, including chronic pain. Research on health-related stigma is limited by the lack of validated instruments that distinguish among various stigma-related constructs. We aimed to develop and validate such a measure for pediatric functional abdominal pain (FAP). Felt stigma (FS) was defined as comprising both perceived and internalized stigma. Stigma concealment (SC) was defined as efforts by stigmatized individuals to prevent others from learning of their condition.
Learn More >Previous case-control investigations of type I Chiari malformation (CMI) have reported cognitive deficits and microstructural white matter abnormalities, as measured by diffusion tensor imaging (DTI). CMI is also typically associated with pain, including occipital headache, but the relationship between pain symptoms and microstructure is not known.
Learn More >First-degree relatives (FDR) of patients with rheumatoid arthritis (RA) have a higher risk for the development of RA. In the stages prior to the development of arthritis, nonspecific musculoskeletal (MSK) manifestations may occur. The aim of the study is to describe the frequency of rheumatic regional pain syndromes (RRPS) in FDR of RA patients. A cross-sectional study was carried out from July 2016 to September 2018. Parents, offspring, and siblings of RA patients completed the Community Oriented Program in the Rheumatic Diseases (COPCORD) questionnaire. Rheumatoid factor (RF) IgG, IgM, and IgA; anticitrullinated peptide antibodies (ACPAs); C-reactive protein (CRP); and erythrocyte sedimentation rate (ESR) were determined. All subjects with a positive COPCORD (defined by the presence of musculoskeletal pain) were evaluated and classified. Three hundred thirty-five FDRs participated, 75.8% were female, mean age of 44.15 years; 138 (41.2%) were diagnosed with at least one RRPS; 72 (21.5%) had rotator cuff tendinitis, 51 (15.2%) pes anserine bursitis, and 39 (11.6) lateral epicondylitis; RA was diagnosed in 24 (7.16%) subjects, undifferentiated arthritis (UA) in 30 (8.9%) and inflammatory arthralgia (AI) in 104 (31%). We found anti-CCP positivity in 6.8%, RF IgA in 22.3%, RF IgM in 48.6%, and RF IgG in 8.9%. The presence of RRPS was higher in this RA-FDR group compared to general population. Clinical evaluation of this risk group should include screening for RRPS.
Learn More >