Neurogenic inflammation as a novel treatment target for chronic pain syndromes

Seidel, Matthias; Hügle, Thomas; Morlion, Barton; Koltzenburg, M; Chapman, Victoria; MaassenVanDenBrink, Antoinette; Lane, Nancy E.; Perrot, Serge; Zieglgänsberger, W.

doi:10.1016/j.expneurol.2022.114108

Cited by 21 publications

(24 citation statements)

References 133 publications

(145 reference statements)

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“…These findings are similar to those found for diabetic peripheral neuropathy wherein significantly reduced Tuj-1 levels and nerve fibers were reported in those with the most pain [ 12 , 13 ]. CGRP expression being reduced in some patient samples was similar to findings in painful diabetic neuropathy as well [ 22 ]. Importantly, findings such as reduced nerve fiber density were independent of BMI, supporting our data that it is not merely an “expansion” of the tissue in lipedema causing reduced Tuj-1 cell density [ 23 ].…”

Section: Discussionsupporting

confidence: 76%

“…A recent genetic study identifying a mutation in Akr1c1 in a family with lipedema speculated that the analgesic activity of allopregnanolone may play a role in lipedema-associated pain [ 21 ]. In this study, we identified the expression of two key neuropeptides (CGRP and NGF) that have been previously associated with nociceptive pain pathways or neurogenic inflammation are significantly altered in the skin of lipedema patients–lower in early stages and raised in Stage 3 participants, compared to controls [ 22 ]. We also show significantly decreased neuron body/subcutaneous neuronal precursor density (neuron-specific class III β-tubulin Tuj-1) in lipedema abdominal skin.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, findings such as reduced nerve fiber density were independent of BMI, supporting our data that it is not merely an “expansion” of the tissue in lipedema causing reduced Tuj-1 cell density [ 23 ]. Neurogenic inflammation is often mediated by an acute sensitization of sensory neurons in response to released neuropeptides, such as NGF, and impacts vasculature remodeling, immune cell extravasation, and tissue inflammation [ 22 , 24 ]. Chronic sensitization of peripheral nerve endings hypersensitizes the neurons resulting in autologous neurotransmitter release (CGRP and Substance p ) contributing to neurogenic inflammation [ 25 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

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Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema

Chakraborty

Crescenzi

Usman

et al. 2022

IJMS

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Lipedema is a disease with abnormally increased adipose tissue deposition and distribution. Pain sensations have been described in the clinical evaluation of lipedema, but its etiology remains poorly understood. We hypothesized that pain sensitivity measurements and ex vivo quantitation of neuronal cell body distribution in the skin would be lipedema stage-dependent, and could, thus, serve to objectively characterize neuropathic pain in lipedema. The pain was assessed by questionnaire and peripheral cutaneous mechanical sensitization (von-Frey) in lipedema (n = 27) and control (n = 23) consenting female volunteers. Dermal biopsies from (n = 11) Stages 1–3 lipedema and control (n = 10) participants were characterized for neuronal cell body and nociceptive neuropeptide calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) distribution. Stage 2 or 3 lipedema participants responded positively to von Frey sensitization in the calf and thigh, and Stage 3 participants also responded in the arm. Lipedema abdominal skin displayed reduced Tuj-1+ neuronal cell body density, compared to healthy controls, while CGRP and NGF was significantly elevated in Stage 3 lipedema tissues. Together, dermal neuronal cell body loss is consistent with hyper-sensitization in patients with lipedema. Further study of neuropathic pain in lipedema may elucidate underlying disease mechanisms and inform lipedema clinical management and treatment impact.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema

Chakraborty

Crescenzi

Usman

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…Neuro-immune signaling may occur when innate immune cells produce algogenic factors that act on the pain pathway [ 5 ]. Indeed, during OA progression, the nociceptors innervating joints can be sensitized by locally generated mediators, such as inflammatory cytokines and chemokines, nerve growth factor (NGF) [ 6 ], and disease-associated molecular patterns (DAMPs) [ 7 , 8 ] ( Figure 1 ).…”

Section: Neuro-immune Mechanisms Underlying Oamentioning

confidence: 99%

Targeting Neuroinflammation in Osteoarthritis with Intra-Articular Adelmidrol

et al. 2022

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Neuroinflammation is an emerging therapeutic target in chronic degenerative and autoimmune diseases, such as osteoarthritis (OA) and rheumatoid arthritis. Mast cells (MCs) play a key role in the homeostasis of joints and the activation of MCs induces the release of a huge number of mediators, which fuel the fire of neuroinflammation. Particularly, synovial MCs release substances which accelerate the degradation of the extra-cellular matrix causing morphological joint changes and cartilage damage and inducing the proliferation of synovial fibroblasts, angiogenesis, and the sprouting of sensory nerve fibers, which mediate chronic pain. Palmitoylethanolamide (PEA) is a well-known MCs modulator, but in osteoarthritic joints, its levels are significantly reduced. Adelmidrol, a synthetic derivate of azelaic acid belonging to the ALIAmides family, is a PEA enhancer. Preclinical and clinical investigations showed that the intra-articular administration of Adelmidrol significantly reduced MC infiltration, pro-inflammatory cytokine release, and cartilage degeneration. The combination of 1% high molecular weight hyaluronic acid and 2% Adelmidrol has been effectively used for knee osteoarthritis and, a significant improvement in analgesia and functionality has been recorded.

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“…Chronic pain, affecting one fifth of the world’s population [ 1 , 2 ], is often caused by neuropathic states and inflammatory conditions of various etiology [ 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Development of a Silicone-Based Polymer Matrix as a Suitable Transdermal Therapeutic System for Diallyl Disulfide

et al. 2022

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There is an unmet need for novel therapeutic tools relieving chronic pain. Hydrogen sulfide (H2S) is highly involved in pain processes; however, the development of ideal matrices for sulfide donor compounds remains a great pharmaceutical challenge. We aimed to establish a suitable transdermal therapeutic system (TTS) using the H2S donor diallyl disulfide (DADS) as a model compound. After the preparation of DADS, its solubility was investigated in different liquid excipients (propylene glycol, polyethylene glycol, silicone oil) and its membrane diffusivity was assessed in silicone matrices of different compositions. Drug-releasing properties of DADS-containing patches with different silicone oil contents were determined with Franz and flow-through cells. We found a correlation between the liquid excipient content of the patch and the diffusion rate of DADS. DADS showed the best solubility in dimethyl silicone oil, and the diffusion constant was proportional to the amount of oil above the 3 m/m% threshold value. The 8-day-old patch showed a significantly lower, but better-regulated, drug release over time than the 4-day-old one. In conclusion, the silicone-based polymer matrix developed in this study is suitable for stable storage and optimal release of DADS, providing a good basis for a TTS applied in chronic pain.

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Neurogenic inflammation as a novel treatment target for chronic pain syndromes

Cited by 21 publications

References 133 publications

Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema

Indications of Peripheral Pain, Dermal Hypersensitivity, and Neurogenic Inflammation in Patients with Lipedema

Targeting Neuroinflammation in Osteoarthritis with Intra-Articular Adelmidrol

Development of a Silicone-Based Polymer Matrix as a Suitable Transdermal Therapeutic System for Diallyl Disulfide

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