Following peripheral axon injury, dysregulation of non-coding microRNAs (miRs) occurs in dorsal root ganglia (DRG) sensory neurons. Here we show that DRG neuron cell bodies release extracellular vesicles, including exosomes containing miRs, upon activity. We demonstrate miR-21-5p is released the exosomal fraction cultured following capsaicin activation TRPV1 receptors. Pure neuron-derived by are readily phagocytosed macrophages which an increase expression promotes a pro-inflammatory...

In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection cleaved SNAP-25 (cl-SNAP-25), protein SNARE complex targeted by neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate mechanism action on nociceptive pathways at peripheral and/or central level. After administration BoNT/A, we analyzed expression cl-SNAP-25, hindpaw's nerve endings spinal cord, together with behavioral...

Axonal degeneration in peripheral nerves after injury is accompanied by myelin degradation initiated Schwann cells (SCs). These activate autophagy, a ubiquitous cytoprotective process essential for and recycling of cellular constituents. Concomitantly to nerve insult axonal degeneration, neuropathic pain (NeP) arises. The role SC autophagy the mechanisms underlying NeP still unknown. In this study, we examined during early phase Wallerian induction chronification using murine model lesion...

In experimental and clinical pain studies, the sex of subjects was rarely taken into account, even if nociceptive inputs appear to be processed modulated by partially distinct neural mechanisms in each sex. this study we analysed, male female mice, behavioural neuronal responses developing, maintaining, recovering from neuropathic pain. Experiments were carried out adult CD1 mice using Chronic Constriction Injury (CCI) as model. We investigated temporal trend mechanical threshold together...

Abstract Sex differences play a role in pain sensitivity, efficacy of analgesic drugs and prevalence neuropathic pain, even if the underlying mechanisms are far from being understood. We demonstrate that male female mice react differently to structural functional changes induced by sciatic nerve ligature, used as model pain. Male show gradual decrease allodynia complete recovery while, females, gliosis still present four months after neuropathy induction. Administration 17β-estradiol is able...

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic in rats mice. Brain enzymatic activity FAAH endogenous levels its substrates, anandamide (AEA; <i>N</i>-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), <i>N</i>-palmitoylethanolamine (PEA), were measured control ST4070-treated ST4070 (10, 30, 100 mg/kg) orally...

There is a growing interest on the role of autophagy in diabetes pathophysiology, where development neuropathy one most frequent comorbidities. We have previously demonstrated that neuropathic pain after nerve damage exacerbated autophagy-defective heterozygous Ambra1 mice. Here, we show existence prediabetic state mice, characterized by hyperglycemia, intolerance to glucose and insulin resistance. Thus, further investigate hypothesis prediabetes may account for exacerbation allodynia...

D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with temporal-dependent concentration based on postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist NMDA receptors (NMDARs). Accordingly, high levels knockout mice for Ddo gene ( −/− ) or treated increase NMDAR-dependent processes. We have here evaluated effect long-term plastic changes along nociceptive pathway occurring chronic and acute pain condition. that show increased...

In Brief Severe pain is a common and debilitating complication of metastatic bone cancer. Current analgesics provide insufficient relief often lead to significant adverse effects. models cancer-induced pain, pathological sprouting sensory fibers at the tumor-bone interface occurs concomitantly with reactive astrocytosis in dorsal horn spinal cord. We observed that calcitonin gene-related peptide (CGRP)-fiber was associated an increase CGRP content neuron cell bodies root ganglia (DRG)...

Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be successful treatment for different neurological disorders, with emerging novel indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; toxin able block pro-inflammatory molecules months after administration. Here we demonstrate extraordinary capacity neutralize complete paralysis pain insensitivity...

Neuropathic pain (NeP) in humans is often a life-long condition with no effective therapy available. The higher incidence of female gender NeP onset worldwide reported, and although the cause generally attributed to sex hormones, actual mechanisms players involved are still unclear. Glial immune cells take part development, orchestrate neuroimmune inflammatory response, releasing pro-inflammatory factors chemoattractant properties that activate resident recruit from circulation. neuro-immune...

As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of complex etiology neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher sensitivity greater NeP incidence in women. This "gender gap" our knowledge sex differences processing strongly limits sex-oriented treatment patients suffering from NeP. Besides, current investigation potential not addressed problem....

Xeomin® is a commercial formulation of botulinum neurotoxin type A (BoNT/A) clinically authorized for treating neurological disorders, such as blepharospasm, cervical dystonia, limb spasticity, and sialorrhea. We have previously demonstrated that spinal injection laboratory purified 150 kDa BoNT/A in paraplegic mice, after undergoing traumatic cord injury (SCI), was able to reduce excitotoxic phenomena, glial scar, inflammation, the development neuropathic pain facilitate regeneration motor...

Clinical use of neurotoxins from Clostridium botulinum is well established and continuously expanding, including in treatment pain conditions. Background: The serotype A (BoNT/A) has been widely investigated, current data demonstrate that it induces analgesia modulates nociceptive processing initiated by inflammation or nerve injury. Given concerning the B (BoNT/B) are limited, aim present study was to verify if also BoNT/B able not only counteract neuropathic pain, but interfere with...

Abstract Traumatic spinal cord injury has dramatic consequences and a huge social impact. We propose new mouse model of trauma that induces complete paralysis hindlimbs, still observable 30 days after injury. The contusion, performed without laminectomy deriving from the pressure exerted directly on bone, mimics more closely many features in humans. Spinal was injured at thoracic level 10 (T10) adult anesthetized female CD1 mice, mounted stereotaxic apparatus connected to precision impactor...

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by depletion of motor neurons (MNs), for which effective medical treatments are still required. Previous transcriptomic analysis revealed the up-regulation C-X-C motif chemokine receptor 2 (CXCR2)-mRNA in subset sporadic ALS patients and SOD1G93A mice. Here, we confirmed increase CXCR2 human cortex, showed that mainly localized cell bodies axons cortical neurons. We also investigated effects...

Recent preclinical and clinical evidence suggest that immune system has a role in the progression prognosis of Amyotrophic Lateral Sclerosis (ALS), but identification clear mechanism players remains to be elucidated. Here, we have investigated, 30 60 days (presymptomatic) 120 (symptomatic) old SOD1-G93A mice, systemic, peripheral, central innate adaptive inflammatory response, correlating it with neurodegeneration neuromuscular junction, sciatic nerves, spinal cord. Surprisingly, found very...

Physical activity in Amyotrophic Lateral Sclerosis (ALS) plays a controversial role. In some epidemiological studies, both recreational or professional sport exercise has been associated to an increased risk for ALS but the mechanisms underlying effects of have not fully elucidated either patients animal models.To better reproduce influence this environmental factor pathogenesis ALS, we exposed SOD1G93A low-copy male mice multiple sessions at asymptomatic and pre-symptomatic disease stages...

Epidemiological data and research highlight increased neuropathy chronic pain prevalence among females, spanning metabolic normometabolic contexts, including murine models. Prior findings demonstrated diverse immune neuroimmune responses between genders in neuropathic (NeP), alongside distinct protein expression sciatic nerves. This study unveils adipose tissue's (AT) role sex-specific NeP after peripheral nerve injury. Metabolic assessments, metabolomics, energy expenditure evaluations, AT...

Abstract The incidence of peripheral neuropathy development and chronic pain is strongly associated with the arrival senescence. gradual physiological decline that begins after mature stage produces myelin dysregulation pathological changes in nervous system, attributed to reduction proteins expression thinner sheath. Moreover elder subjects, when nerve damage occurs, regenerative processes are seriously compromised neuropathic (NeP) maintained. We previously demonstrated caloric restriction...