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The Journal of Manual & Manipulative... Feb 2022Tensioning techniqueswere the first neurodynamic techniques used therapeutically in the management of people with neuropathies. This article aims to provide a balanced...
Tensioning techniqueswere the first neurodynamic techniques used therapeutically in the management of people with neuropathies. This article aims to provide a balanced evidence-informed view on the effects of optimal tensile loading on peripheral nerves and the use of tensioning techniques. Whilst the early use of neurodynamics was centered within a mechanical paradigm, research into the working mechanisms of tensioning techniques revealed neuroimmune, neurophysiological, and neurochemical effects. and research confirms that tensile loading is required for mechanical adaptation of healthy and healing neurons and nerves. Moreover, elimination of tensile load can have detrimental effects on the nervous system. Beneficial effects of tensile loading and tensioning techniques, contributing to restored homeostasis at the entrapment site, dorsal root ganglia and spinal cord, include neuronal cell differentiation, neurite outgrowth and orientation, increased endogenous opioid receptors, reduced fibrosis and intraneural scar formation, improved nerve regeneration and remyelination, increased muscle power and locomotion, less mechanical and thermal hyperalgesia and allodynia, and improved conditioned pain modulation. However, animal and cellular models also show that 'excessive' tensile forces have negative effects on the nervous system. Although robust and designed to withstand mechanical load, the nervous system is equally a delicate system. Mechanical loads that can be easily handled by a healthy nervous system, may be sufficient to aggravate clinical symptoms in patients. This paper aims to contribute to a more balanced view regarding the use of neurodynamics and more specifically tensioning techniques.
Topics: Animals; Ganglia, Spinal; Humans; Hyperalgesia; Neurons; Peripheral Nervous System Diseases; Spinal Cord
PubMed: 34781843
DOI: 10.1080/10669817.2021.2001736 -
International Journal of Molecular... Nov 2020Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two... (Review)
Review
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD's mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD's action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD's pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD's action and future perspectives for research.
Topics: Analgesics; Cannabidiol; Cannabinoids; Dronabinol; Humans; Hyperalgesia; Neuralgia; Pain Management
PubMed: 33238607
DOI: 10.3390/ijms21228870 -
Nature Jun 2022Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured...
Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.
Topics: Animals; Chronic Pain; Hyperalgesia; Mechanoreceptors; Mice; Neuralgia; Nociceptors; Skin
PubMed: 35614217
DOI: 10.1038/s41586-022-04777-z -
Cancer Immunology Research Dec 2022Oxaliplatin is an antineoplastic agent frequently used in the treatment of gastrointestinal tumors. However, it causes dose-limiting sensorimotor neuropathy, referred to...
Oxaliplatin is an antineoplastic agent frequently used in the treatment of gastrointestinal tumors. However, it causes dose-limiting sensorimotor neuropathy, referred to as oxaliplatin-induced peripheral neuropathy (OIPN), for which there is no effective treatment. Here, we report that the elevation of neutrophil extracellular traps (NET) is a pathologic change common to both cancer patients treated with oxaliplatin and a murine model of OIPN. Mechanistically, we found that NETs trigger NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and the subsequent release of IL18 by macrophages, resulting in mechanical hyperalgesia. In NLRP3-deficient mice, the mechanical hyperalgesia characteristic of OIPN in our model was reduced. In addition, in the murine model, treatment with the IL18 decoy receptor IL18BP prevented the development of OIPN. We further showed that eicosapentaenoic acid (EPA) reduced NET formation by suppressing the LPS-TLR4-JNK pathway and thereby abolished NLRP3 inflammasome activation and the subsequent secretion of IL18, which markedly prevented oxaliplatin-induced mechanical hyperalgesia in mice. These results identify a role for NET-triggered NLRP3 activation and IL18 release in the development of OIPN and suggest that utilizing IL18BP and EPA could be effective treatments for OIPN.
Topics: Animals; Mice; Disease Models, Animal; Extracellular Traps; Hyperalgesia; Inflammasomes; Interleukin-18; NLR Family, Pyrin Domain-Containing 3 Protein; Oxaliplatin; Peripheral Nervous System Diseases
PubMed: 36255412
DOI: 10.1158/2326-6066.CIR-22-0197 -
Journal of Neuroinflammation Jan 2020Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we...
BACKGROUND
Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs.
METHODS
Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis.
RESULTS
BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1β, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1β in the SDH of our CYP-induced cystitis model.
CONCLUSIONS
In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1β, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.
Topics: Animals; Astrocytes; Brain-Derived Neurotrophic Factor; Cyclophosphamide; Cystitis; Female; Hyperalgesia; Immunosuppressive Agents; Inflammation; Microglia; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord Dorsal Horn
PubMed: 31931832
DOI: 10.1186/s12974-020-1704-0 -
Redox Biology Jun 2023Bone cancer pain (BCP) impairs patients' quality of life. However, the underlying mechanisms are still unclear. This study investigated the role of spinal interneuron...
Bone cancer pain (BCP) impairs patients' quality of life. However, the underlying mechanisms are still unclear. This study investigated the role of spinal interneuron death using a pharmacological inhibitor of ferroptosis in a mouse model of BCP. Lewis lung carcinoma cells were inoculated into the femur, resulting in hyperalgesia and spontaneous pain. Biochemical analysis revealed that spinal levels of reactive oxygen species and malondialdehyde were increased, while those of superoxide dismutase were decreased. Histological analysis showed the loss of spinal GAD65+ interneurons and provided ultrastructural evidence of mitochondrial shrinkage. Pharmacologic inhibition of ferroptosis using ferrostatin-1 (FER-1, 10 mg/kg, intraperitoneal for 20 consecutive days) attenuated ferroptosis-associated iron accumulation and lipid peroxidation and alleviated BCP. Furthermore, FER-1 inhibited the pain-associated activation of ERK1/2 and COX-2 expression and prevented the loss of GABAergic interneurons. Moreover, FER-1 improved analgesia by the COX-2 inhibitor Parecoxib. Taken together, this study shows that pharmacological inhibition of ferroptosis-like cell death of spinal interneurons alleviates BCP in mice. The results suggest that ferroptosis is a potential therapeutic target in patients suffering on BCP and possibly other types of pain.
Topics: Mice; Animals; Hyperalgesia; Cancer Pain; Ferroptosis; Quality of Life; Pain; Bone Neoplasms; Cell Death
PubMed: 37084690
DOI: 10.1016/j.redox.2023.102700 -
Brain : a Journal of Neurology Feb 2023Chemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced...
Chemotherapy-induced peripheral neuropathy is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of chemotherapy-induced peripheral neuropathy characterized by mechanical and cold hypersensitivity. Current therapies for chemotherapy-induced peripheral neuropathy are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of chemotherapy-induced peripheral neuropathy and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. Sigma-1 receptor antagonist, a highly selective antagonist of Sigma-1 receptor, has shown effectiveness in a phase II clinical trial for oxaliplatin chemotherapy-induced peripheral neuropathy. However, the mechanisms involved in the beneficial effects of Sigma-1 receptor antagonist are little understood. We combined biochemical and biophysical (i.e. intermolecular Förster resonance energy transfer) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including Sigma-1 receptor antagonist, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, Sigma-1 receptor antagonists reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a Sigma-1 receptor antagonists prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of chemotherapy-induced peripheral neuropathy and could inform the development of novel therapeutics for neuropathic pain.
Topics: Mice; Humans; Animals; Oxaliplatin; TRPA1 Cation Channel; Antineoplastic Agents; Transient Receptor Potential Channels; Neuralgia; Hyperalgesia; Sigma-1 Receptor
PubMed: 35871491
DOI: 10.1093/brain/awac273 -
The Journal of Clinical Investigation Jun 2023Neuropathic pain remains poorly managed by current therapies, highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models,...
Neuropathic pain remains poorly managed by current therapies, highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote a proinflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of upregulation of chemokine CCL2 after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGF-β-related pathway activation and acquired an M2-like antinociceptive phenotype. Indeed, neuropathic allodynia was attenuated after conditional knockout of miR-21 and restored by TGF-βR inhibitor (SB431542) administration. Since TGF-βR2 and TGF-β1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a proinflammatory phenotype via suppression of such an antiinflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at an M2-like state and attenuate neuropathic pain.
Topics: Humans; Hyperalgesia; Transforming Growth Factor beta; Macrophages; Neuralgia; Sensory Receptor Cells; MicroRNAs; Ganglia, Spinal
PubMed: 37071481
DOI: 10.1172/JCI164472 -
EBioMedicine Apr 2023Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of chemotherapy and remains a huge clinical challenge. Here, we explore the role...
BACKGROUND
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of chemotherapy and remains a huge clinical challenge. Here, we explore the role of microcirculation hypoxia induced by neutrophil extracellular traps (NETs) in the development of CIPN and look for potential treatment.
METHODS
The expression of NETs in plasma and dorsal root ganglion (DRG) are examined by ELISA, IHC, IF and Western blotting. IVIS Spectrum imaging and Laser Doppler Flow Metry are applied to explore the microcirculation hypoxia induced by NETs in the development of CIPN. Stroke Homing peptide (SHp)-guided deoxyribonuclease 1 (DNase1) is used to degrade NETs.
FINDINGS
The level of NETs in patients received chemotherapy increases significantly. And NETs accumulate in the DRG and limbs in CIPN mice. It leads to disturbed microcirculation and ischemic status in limbs and sciatic nerves treated with oxaliplatin (L-OHP). Furthermore, targeting NETs with DNase1 significantly reduces the chemotherapy-induced mechanical hyperalgesia. The pharmacological or genetic inhibition on myeloperoxidase (MPO) or peptidyl arginine deiminase-4 (PAD4) dramatically improves microcirculation disturbance caused by L-OHP and prevents the development of CIPN in mice.
INTERPRETATION
In addition to uncovering the role of NETs as a key element in the development of CIPN, our finding provides a potential therapeutic strategy that targeted degradation of NETs by SHp-guided DNase1 could be an effective treatment for CIPN.
FUNDING
This study was funded by the National Natural Science Foundation of China81870870, 81971047, 81773798, 82271252; Natural Science Foundation of Jiangsu ProvinceBK20191253; Major Project of "Science and Technology Innovation Fund" of Nanjing Medical University2017NJMUCX004; Key R&D Program (Social Development) Project of Jiangsu ProvinceBE2019732; Nanjing Special Fund for Health Science and Technology DevelopmentYKK19170.
Topics: Mice; Animals; Extracellular Traps; Peripheral Nervous System Diseases; Oxaliplatin; Hyperalgesia; Antineoplastic Agents
PubMed: 36870200
DOI: 10.1016/j.ebiom.2023.104499 -
Journal of Neuroinflammation Jun 2022Gut microbiota has been found involved in neuronal functions and neurological disorders. Whether and how gut microbiota impacts chronic somatic pain disorders remain...
BACKGROUND
Gut microbiota has been found involved in neuronal functions and neurological disorders. Whether and how gut microbiota impacts chronic somatic pain disorders remain elusive.
METHODS
Neuropathic pain was produced by different forms of injury or diseases, the chronic constriction injury (CCI) of the sciatic nerves, oxaliplatin (OXA) chemotherapy, and streptozocin (STZ)-induced diabetes in mice. Continuous feeding of antibiotics (ABX) cocktail was used to cause major depletion of the gut microbiota. Fecal microbiota, biochemical changes in the spinal cord and dorsal root ganglion (DRG), and the behaviorally expressed painful syndromes were assessed.
RESULTS
Under condition of gut microbiota depletion, CCI, OXA, or STZ treatment-induced thermal hyperalgesia or mechanical allodynia were prevented or completely suppressed. Gut microbiota depletion also prevented CCI or STZ treatment-induced glial cell activation in the spinal cord and inhibited cytokine production in DRG in OXA model. Interestingly, STZ treatment failed to induce the diabetic high blood glucose and painful hypersensitivity in animals with the gut microbiota depletion. ABX feeding starting simultaneously with CCI, OXA, or STZ treatment resulted in instant analgesia in all the animals. ABX feeding starting after establishment of the neuropathic pain in CCI- and STZ-, but not OXA-treated animals produced significant alleviation of the thermal hyeralgesia or mechanical allodynia. Transplantation of fecal bacteria from SPF mice to ABX-treated mice partially restored the gut microbiota and fully rescued the behaviorally expressed neuropathic pain, of which, Akkermansia, Bacteroides, and Desulfovibrionaceae phylus may play a key role.
CONCLUSION
This study demonstrates distinct roles of gut microbiota in the pathogenesis of chronic painful conditions with nerve injury, chemotherapy and diabetic neuropathy and supports the clinical significance of fecal bacteria transplantation.
Topics: Animals; Anti-Bacterial Agents; Chronic Pain; Diabetes Mellitus; Gastrointestinal Microbiome; Hyperalgesia; Mice; Neuralgia; Rats; Rats, Sprague-Dawley
PubMed: 35764988
DOI: 10.1186/s12974-022-02523-w