Pain
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Nerve growth factor (NGF)-R100E is a mutated form of human recombinant NGF that reduces the binding of NGF to its p75NTR receptor while retaining its affinity toward the TrkA receptor. Here, we used human wild type NGF and NGF-R100E knock-in mice to investigate the effects of this NGF mutation on inflammation-induced pain-related behaviors and bone loss. The hNGF-R100E mutation did not alter the nerve fiber density in the sciatic nerve, ankle joint synovium, and skin of naïve mice. ⋯ In conclusion, our study reveals that the hNGF-R100E mutation renders mice insensitive to inflammation-induced impact on joint loading and gait while preserving the development of the peripheral nociceptive neurons and sensitivity to punctate stimulation of the skin. Notably, the mutation uncovers a sex-dependent relationship between NGF and inflammation-induced bone loss. These findings offer valuable insights into NGF as a target for pain management and the interplay between NGF and bone architecture.
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Multicenter Study
What is associated with painful polyneuropathy? A cross-sectional analysis of symptoms and signs in patients with painful and painless polyneuropathy.
It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. ⋯ Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies.
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Pain-related motor adaptations may be enacted predictively at the mere threat of pain, before pain occurrence. Yet, in humans, the neurophysiological mechanisms underlying motor adaptations in anticipation of pain remain poorly understood. We tracked the evolution of changes in corticospinal excitability (CSE) as healthy adults learned to anticipate the occurrence of lateralized, muscle-specific pain to the upper limb. ⋯ Finally, stronger corticospinal inhibition correlated with greater trait anxiety. These results advance the mechanistic understanding of pain processes showing that pain-related motor adaptations are enacted at the mere threat of pain, as sets of anticipatory, topographically organized motor changes that are associated with the expected pain and are shaped by individual anxiety levels. Including such anticipatory motor changes into models of pain may lead to new treatments for pain-related disorders.
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The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). ⋯ However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment.
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The urocortin 1 (UCN1)-expressing centrally projecting Edinger-Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine triggers. Our study investigated EWcp's potential involvement in migraine. Using RNAscope in situ hybridization and immunostaining, we examined the expression of calcitonin gene-related peptide (CGRP) receptor components in both mouse and human EWcp and dorsal raphe nucleus (DRN). ⋯ Targeted ablation of EWcp/UCN1 neurons induced hyperalgesia. A positive functional connectivity between EW and STN as well as DRN has been identified by functional magnetic resonance imaging. The presented data strongly suggest the regulatory role of EWcp/UCN1 neurons in migraine through the STN and DRN with high translational value.