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Multiple sclerosis is an autoimmune disease with a distinct female bias, as well as a high prevalence of neuropathic pain in both sexes. The dorsal root ganglia (DRG) contain the primary sensory neurons that give rise to pain, and damage to these neurons may lead to neuropathic pain. Here, we investigate the sex differences of the DRG transcriptome in a mouse model of MS.
Learn More >A prospective observational study.
Learn More >Protein phosphatase-1 (PP1) is ubiquitously distributed in the nervous system and catalyzes the dephosphorylation of numerous substrates. The specificity and efficacy of PP1-mediated dephosphorylation depend on scaffolding proteins that anchor PP1 to the close vicinity of substrates. Spinophilin is one of the scaffolding proteins which are able to direct PP1 into postsynaptic density and regulate the synaptic transmission and plasticity. Here we found that spinophilin was enriched in dorsal root ganglia (DRG) neurons and engaged in the modification of nociceptive signaling processing. Disturbing spinophilin/PP1 interaction in DRG neurons led to the enhanced sensitivity of mice to heat and mechanical stimuli. The transient receptor potential vanilloid 1 (TRPV1) was identified as an important target for spinophilin modification. Our data showed that spinophilin physically interacted with TRPV1 and facilitated PP1 dephosphorylation of TRPV1 at Ser502. Disruption of spinophilin/PP1 complex enhanced Ser502 phosphorylation and boosted TRPV1 expression on plasma membrane. Peripheral inflammation induced by formalin disturbed spinophilin/PP1 interaction, which removed PP1-mediated inhibition and caused a marked increase of TRPV1 phosphorylation. Viral expression of wild-type spinophilin in DRG neurons repressed TRPV1 phosphorylation and alleviated formalin-induced inflammatory pain. These data suggested that spinophilin/PP1 complex negatively controlled TRPV1 function in DRG neurons.
Learn More >In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo,49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.
Learn More >Recent resting-state fMRI studies associated extensive musical training with increased insula-based connectivity in large-scale networks involved in salience, emotion, and higher-order cognitive processes. Similar changes have also been found in chronic pain patients, suggesting that both types of experiences can have comparable effects on insula circuitries. Based on these observations, the current study asked the question whether, and if so in what way, different forms of experience-dependent neuroplasticity may interact. Here we assessed insula-based connectivity during fMRI resting-state between musicians and non-musicians both with and without chronic pain, and correlated the results with clinical pain duration and intensity. As expected, insula connectivity was increased in chronic pain non-musicians relative to healthy non-musicians (with cingulate cortex and supplementary motor area), yet no differences were found between chronic pain non-musicians and healthy musicians. In contrast, musicians with chronic pain showed decreased insula connectivity relative to both healthy musicians (with sensorimotor and memory regions) and chronic pain non-musicians (with the hippocampus, inferior temporal gyrus, and orbitofrontal cortex), as well as lower pain-related inferences with daily activities. Pain duration correlated positively with insula connectivity only in non-musicians, whereas pain intensity exhibited distinct relationships across groups. We conclude that although music-related sensorimotor training and chronic pain, taken in isolation, can lead to increased insula-based connectivity, their combination may lead to higher-order plasticity (metaplasticity) in chronic pain musicians, engaging brain mechanisms that can modulate the consequences of maladaptive experience-dependent neural reorganization (i.e., pain chronification).
Learn More >Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems. One of the most studied neurotransmitters related to pain disorders is serotonin. Estrogen can modify serotonin synthesis and metabolism, promoting a general increase in its tonic effects. Studies evaluating the relationship between serotonin and disorders such as irritable bowel syndrome, fibromyalgia, migraine, and other types of headache suggest a clear impact of this neurotransmitter, thereby increasing the interest in serotonin as a possible future therapeutic target. This literature review describes the importance of substances such as serotonin and ovarian hormones in pain perception and illustrates the relationship between those two, and their direct influence on the presentation of the aforementioned pain-related conditions. Additionally, we review the pathways and receptors implicated in each disorder. Finally, the objective was to stimulate future pharmacological research to experimentally evaluate the potential of serotonin modulators and ovarian hormones as therapeutic agents to regulate pain in specific subpopulations.
Learn More >Sickle cell disease (SCD) is a group of inherited disorders of haemoglobin (Hb) structure in a person who has inherited two mutant globin genes (one from each parent), at least one of which is always the sickle mutation. It is estimated that between 5% and 7% of the world's population are carriers of the mutant Hb gene, and SCD is the most commonly inherited blood disorder. SCD is characterized by distorted sickle-shaped red blood cells. Manifestations of the disease are attributed to either haemolysis (premature red cell destruction) or vaso-occlusion (obstruction of blood flow, the most common manifestation). Shortened lifespans are attributable to serious comorbidities associated with the disease, including renal failure, acute cholecystitis, pulmonary hypertension, aplastic crisis, pulmonary embolus, stroke, acute chest syndrome, and sepsis. Vaso-occlusion can lead to an acute, painful crisis (sickle cell crisis, vaso-occlusive crisis (VOC) or vaso-occlusive episode). Pain is most often reported in the joints, extremities, back or chest, but it can occur anywhere and can last for several days or weeks. The bone and muscle pain experienced during a sickle cell crisis is both acute and recurrent. Key pharmacological treatments for VOC include opioid analgesics, non-opioid analgesics, and combinations of drugs. Non-pharmacological approaches, such as relaxation, hypnosis, heat, ice and acupuncture, have been used in conjunction to rehydrating the patient and reduce the sickling process.
Learn More >It has long been thought that severe chronic pain conditions, such as Complex Regional Pain Syndrome (CRPS), are not only associated with, but even maintained by a reorganisation of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used functional MRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable to those of the healthy hand and controls. We found no differential relation between affected vs. unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.This study shows that the spatial map of the fingers in S1 is largely preserved in chronic CRPS. These findings challenge the treatment rationale for restoring somatotopic representations in CRPS patients.
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