Practical approaches to improving translatability and reproducibility in preclinical pain research

Soliman, Nadia; Denk, Franziska

doi:10.1016/j.bbi.2023.09.023

Cited by 2 publications

(2 citation statements)

References 49 publications

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“…An unsigned co-expression network was built using the top 25% of expressed genes (20 counts in at least 50% of samples) ranked by observed variance, and modules were identified using the dynamic tree cut algorithm. 8 We assigned biological functions to these modules by looking at over-represented GO biological process terms. We then used the module eigengene, i.e.…”

Section: Rna Sequencingmentioning

confidence: 99%

“…5,6 These inadequacies of treatments stem in part from a lack of understanding of the pathophysiology of peripheral neuropathic pain and the limited translation of findings from preclinical models to humans. 7,8 Calls to use human tissues to understand disease pathology are thus growing. 9,10 However, access to human peripheral nerve tissues, however, remains a major challenge, especially in the context of neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

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The Molecular Signature of Neuropathic Pain in a Human Model System

Sandy-Hindmarch,

Chang,

Scheuren

et al. 2024

Preprint

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Peripheral neuropathic pain remains challenging to treat, partly due to our limited understanding of the molecular mechanisms at play in humans. In this multicentre cohort study, we describe the local molecular signature of neuropathic pain at the lesion site, using peripheral nerves of patients with Morton’s neuroma as a human model system of neuropathic pain.Plantar tibial nerves were collected from 22 patients with Morton’s neuroma (18 female, median age 60.0 [IQR 16.0] years) and control nerves from 11 participants (4 females, 58.0 [21.0] years) without a nerve injury. Pre-surgery, we collected data on pain severity, duration and nature (e.g., neuropathic pain inventory, NPSI).RNA bulk sequencing of peripheral nerves identified 3349 genes to be differentially expressed between Morton’s neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses (WGCNA) revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed that the densities of macrophages as well as B-cells were higher in Morton’s neuroma than control samples. The findings for T-cells were inconclusive. Modules associated with defence response, neurogenesis and muscle system development correlated with paroxysmal and evoked pain in people with Morton’s neuroma. Macrophage cell populations identified by deconvolution analysis as well as single differentially expressed genes (MARCO, CD163, STAB1;indicating the presence of a specific M(GC) subset of macrophages) correlated with paroxysmal pain.Immunofluorescent analyses confirmed the presence of demyelination, higher densities of intraneural T-cells and CD163+MARCO+macrophage subsets in Morton’s neuroma compared to control nerves. Histological CD68+macrophage density correlated with burning pain. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+subset implicated.

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Section: Rna Sequencingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Molecular Signature of Neuropathic Pain in a Human Model System

Sandy-Hindmarch,

Chang,

Scheuren

et al. 2024

Preprint

Self Cite

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Making sense of feelings

Key,

Brown

2024

Neuroscience of Consciousness

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Internal feeling states such as pain, hunger, and thirst are widely assumed to be drivers of behaviours essential for homeostasis and animal survival. Call this the ‘causal assumption’. It is becoming increasingly apparent that the causal assumption is incompatible with the standard view of motor action in neuroscience. While there is a well-known explanatory gap between neural activity and feelings, there is also a disjuncture in the reverse direction—what role, if any, do feelings play in animals if not to cause behaviour? To deny that feelings cause behaviours might thus seem to presage epiphenomenalism—the idea that subjective experiences, including feelings, are inert, emergent and, on some views, non-physical properties of brain processes. Since epiphenomenalism is antagonistic to fundamental commitments of evolutionary biology, the view developed here challenges the standard view about the function of feelings without denying that feelings have a function. Instead, we introduce the ‘sense making sense’ hypothesis—the idea that the function of subjective experience is not to cause behaviour, but to explain, in a restricted but still useful sense of ‘explanation’. A plausible framework is derived that integrates commonly accepted neural computations to blend motor control, feelings, and explanatory processes to make sense of the way feelings are integrated into our sense of how and why we do and what we do.

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Practical approaches to improving translatability and reproducibility in preclinical pain research

Cited by 2 publications

References 49 publications

The Molecular Signature of Neuropathic Pain in a Human Model System

The Molecular Signature of Neuropathic Pain in a Human Model System

Making sense of feelings

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