Browse by Audience
Fibromyalgia is defined by idiopathic, chronic, widespread musculoskeletal pain. In adults with fibromyalgia, meta-analysis of lower-leg skin biopsy demonstrated 45% pooled prevalence of abnormally low epidermal neurite density (END). END <5th centile of the normal distribution is the consensus diagnostic threshold for small-fiber neuropathy. However, the clinical significance of END findings in fibromyalgia is unknown. The prevalence of small fiber pathology has not yet been studied in juvenile fibromyalgia.
Learn More >Suicidality is common in patients with migraine. Here, we performed a systematic review and estimated the prevalence of suicidal ideation (SI) and suicide attempt (SA) in patients with migraine.
Learn More >Primary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that all somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor that is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that transcription factors induced early after peripheral nerve injury confer the cellular plasticity required for sensory neurons to transform into a regenerative state.
Learn More >Src family kinases (SFK) are a group of non-receptor tyrosine kinases which play a pivotal role in cellular responses and oncogenesis. Accumulating evidence suggest that SFK also act as a key component in signalling pathways of the central nervous system (CNS) in both physiological and pathological conditions. Despite the crucial role of SFK in signal transduction of the CNS, the relationship between SFK and molecules implicated in pain has been relatively unexplored. This article briefly reviews the recent advances uncovering the interplay of SFK with diverse membrane proteins and intracellular proteins in the CNS and the importance of SFK in the pathophysiology of migraine and neuropathic pain. Mechanisms underlying the role of SFK in these conditions and potential clinical applications of SFK inhibitors in neurological diseases are also summarised. We propose that SFK are the convergent point of signalling pathways in migraine and neuropathic pain and may constitute a promising therapeutic target for these diseases.
Learn More >Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.
Learn More >How is neuropathic pain regulated in peripheral sensory neurons? Importins are key regulators of nucleocytoplasmic transport. In this study, we found that importin α3 (also known as karyopherin subunit alpha 4) can control pain responsiveness in peripheral sensory neurons in mice. Importin α3 knockout or sensory neuron-specific knockdown in mice reduced responsiveness to diverse noxious stimuli and increased tolerance to neuropathic pain. Importin α3-bound c-Fos and importin α3-deficient neurons were impaired in c-Fos nuclear import. Knockdown or dominant-negative inhibition of c-Fos or c-Jun in sensory neurons reduced neuropathic pain. In silico screens identified drugs that mimic importin α3 deficiency. These drugs attenuated neuropathic pain and reduced c-Fos nuclear localization. Thus, perturbing c-Fos nuclear import by importin α3 in peripheral neurons can promote analgesia.
Learn More >Patients with back pain can show one or more features of spinal osteoarthritis (OA), such as morning stiffness, limited or painful range of motion (ROM), and lumbar disc degeneration (LDD). However, whether these features are prognostic of long-term back pain has not been investigated.
Learn More >Chronic pain induces a multitude of harmful effects; recently it has been suggested that chronic pain is also associated with premature aging, manifested in shortened telomere length (TL). However, evidence for this hypothesis is scarce and inconsistent. The aim was twofold: 1) Investigate whether chronic pain is associated with premature aging, and 2) Determine whether physical exercise (PE) moderates this association if it exists. Participants were 116 male subjects, with (n=67) and without chronic pain (n=49). Blood samples for TL analysis were collected and participants were interviewed and completed questionnaires. As a part of the cohort, we included people with physical disability; this variable was controlled in the analysis. The TL of individuals with chronic pain was significantly shorter than that of pain-free individuals. Regression analysis revealed a significant moderating effect of PE on chronic pain and TL, above and beyond the effects of disability, age, and weight. Whereas chronic pain was associated with shorter telomeres in participants who did not exercise, this association was non-significant among participants who did exercise. The results suggest that chronic pain is associated with premature ageing; however, PE may mitigate this association and may protect individuals against the harmful effects of chronic pain. PERSPECTIVE: The study suggest that it is important to monitor signs of premature ageing among chronic pain patients as they are at risk. However, chronic pain patients may benefit from regular physical exercise in this respect as it may moderate premature ageing.
Learn More >The concentration of the multifunctional protein clusterin is reduced in the plasma of subjects with degenerative scoliosis and carpal tunnel syndrome but elevated in the cerebrospinal fluid of neuropathic pain patients successfully treated with spinal cord stimulation. The present work tries to increase the knowledge of pain-associated changes of plasma and brain clusterin by using an animal model of neuropathy. We studied the effects of sciatic nerve ligation on mechanical allodynia (von Frey test), anxiety (elevated plus maze test), plasma clusterin (enzyme-linked immunosorbent assay) and clusterin expression in the nucleus accumbens and prefrontal cortex of adult male Wistar rats (western blot). The possible modulatory role of high fat dieting was also studied, bearing in mind that obesity has been also reported to influence nociception, clusterin levels and prefrontal cortex activation. Animals with nerve ligation showed mechanical allodynia, anxiety and a marked downregulation of clusterin in the mitochondrial fraction of the prefrontal cortex. Animals fed on high fat also exhibited a slight increase of the sensitivity to mechanical stimuli and anxiety; however, the diet did not potentiate the effects of nerve ligation. The results did not confirm a parallelism between neuropathy, obesity and alterations of plasma levels of clusterin, but strongly suggest that the protein could be involved in the functional reorganization of the prefrontal cortex which has been recently reported in chronic pain conditions.
Learn More >