Activation Of Peripheral Neurons Research Articles

Multi-Functional Small Molecule Alleviates Fracture Pain and Promotes Bone Healing.

Bone injuries such as fractures are one major cause of morbidities worldwide. A considerable number of fractures suffer from delayed healing, and the unresolved acute pain may transition to chronic and maladaptive pain. Current management of pain involves treatment with NSAIDs and opioids with substantial adverse effects. Herein, we tested the hypothesis that the purine molecule, adenosine, can simultaneously alleviate pain and promote healing in a mouse model of tibial fracture by targeting distinctive adenosine receptor subtypes in different cell populations. To achieve this, a biomaterial-assisted delivery of adenosine is utilized to localize and prolong its therapeutic effect at the injury site. The results demonstrate that local delivery of adenosine inhibited the nociceptive activity of peripheral neurons through activation of adenosine A1 receptor (ADORA1) and mitigated pain as demonstrated by weight bearing and open field movement tests. Concurrently, local delivery of adenosine at the fracture site promoted osteogenic differentiation of mesenchymal stromal cells through adenosine A2B receptor (ADORA2B) resulting in improved bone healing as shown by histological analyses and microCT imaging. This study demonstrates the dual role of adenosine and its material-assisted local delivery as a feasible therapeutic approach to treat bone trauma and associated pain.

A Fundamental Inequality Governing the Rate Coding Response of Sensory Neurons.

A fundamental inequality governing the spike activity of peripheral neurons is derived and tested against auditory data. This inequality states that the steady-state firing rate must lie between the arithmetic and geometric means of the spontaneous and peak activities during adaptation. Implications towards the development of auditory mechanistic models are explored.

What gets on the nerves of cardiac patients? Pathophysiological changes in cardiac innervation.

The autonomic nervous system regulates cardiac function by balancing the actions of sympathetic and parasympathetic inputs to the heart. Intrinsic cardiac neurocircuits integrate these autonomic signals to fine‐tune cardiac control, and sensory feedback loops regulate autonomic transmission in the face of external stimuli. These interconnected neural systems allow the heart to adapt to constantly changing circumstances that range from simple fluctuations in body position to running a marathon. The cardiac reflexes that serve to maintain homeostasis in health are disrupted in many disease states. This is often characterized by increased sympathetic and decreased parasympathetic transmission. Studies of cardiovascular disease reveal remodelling of cardiac neurocircuits at several functional and anatomical levels. Central circuits change so that sympathetic pathways become hyperactive, while parasympathetic circuits exhibit decreased activity. Peripheral sensory nerves also become hyperactive in disease, which increases patients’ risk for poor cardiac outcomes. Injury and disease also alter the types of neurotransmitters and neuropeptides released by autonomic nerves in the heart, and can lead to regional hyperinnervation (increased nerve density) or denervation (decreased nerve density) of cardiac tissue. The mechanisms responsible for neural remodelling are not fully understood, but neurotrophins and inflammatory cytokines are likely involved. Areas of active investigation include the role of immune cells and inflammation in neural remodelling, as well as the role of glia in modulating peripheral neuronal activity. Our growing understanding of autonomic dysfunction in disease has facilitated development of new therapeutic strategies to improve health outcomes.

Lasmiditan: the first neurally acting anti-migraine drug

Lasmiditan is the first neurally acting drug for the treatment of acute migraine. It is a highly selective, orally acting 5-HT1F agonist that was approved in November 2019, for the acute treatment of migraine in adults, with or without aura, by USFDA. Lesmiditan may help in terminating the acute attack of migraine by inhibiting the central and peripheral neuronal activity and the release of CGRP.

Cortical plasticity following intramuscular lidocaine injection

ABSTRACT BACKGROUND AND OBJECTIVES: The manipulation of peripheral neuronal activity can alter the excitability of the primary motor cortex; however, it is not known whether this occurs after intramuscular injections of lidocaine. Therefore, the investigation focused on neurophysiological changes, assessed with transcranial magnetic stimulation, after lidocaine (0.5mL, 2%) injection in the first dorsal interosseous muscle of the dominant hand of healthy individuals. METHODS: Exploratory, double-blind, parallel laboratory study. Twenty-eight healthy subjects (mean age: 29.6 years, 15 women). Measurements with transcranial magnetic stimulation included resting motor threshold, motor evoked potential, intracortical facilitation, and short intracortical inhibition. Lidocaine injection (LID group) was compared to dry needling (DRY group), saline injection (SAL group), and no intervention (CTL group). Participants were randomly placed in each group. Muscle strength and measures of peripheral excitability (rheobase and chronaxie) were also evaluated to detect whether the interventions generated changes in the peripheral neuromuscular excitability. Evaluations were performed over four time points: immediately before and after intervention and 30 and 60 minutes after intervention. RESULTS: A generalized linear model was used to identify differences between the LID, DRY, and SAL groups and the CTL group. The results showed that motor evoked potentials were modified in the LID group (p<0.005). CONCLUSION: The injection of lidocaine into the first dorsal interosseous muscle in the dominant hand of healthy adults alters motor evoked potentials.

Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects.

Levcromakalim opens ATP-sensitive potassium channels (KATP channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. KATP channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans. To assess the local effect of KATP channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms. Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead (p > 0.05) and the forearms (p > 0.05). Intradermal injection of levcromakalim caused more flare (p < 0.001), skin temperature increase (p < 0.001), and skin blood flow increase (p < 0.001) compared to placebo in the forehead and the forearms. These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.

Evaluation of Liraglutide Effect on Serum Adipocytokines of Adults Male Wistar Rats with Insulin Resistance That Induced by High Fat Diet

Insulin resistance (IR) is the state in which insulin-stimulated glucose uptake is blunted in the insulin sensitive-tissue leading to state of prediabetes and T2DM, IR characterized by hyperglycemia and hyperinsulinemia in the fasting state, elevated glycosylated hemoglobin (HbA1c) level, hyperlipidemia, postprandial hyperglycemia, elevated plasma levels of pro-inflammatory markers and hypoadiponectinemia. Type 2 diabetes mellitus reported with peripheral insulin resistance (IR) and reduced production of insulin from pancreatic β-cells, IR elevates plasma fatty acids, decreasing glucose transportation to muscles and increased breakdown of fat finally leads to increased glucose production from the liver. This study was designed to evaluate the effect of liraglutide on serum adipocytokines of adult male rats with insulin resistance that induced by high fat diet, Chronic high fats diet feeding is a common cause of disturbing leptin signaling in hypothalamus leading to the state of hyperphagic obesity and leptin resistance. Liraglutide improve meal-stimulated insulin secretion so it's called incretin mimetic. It is glucagon like peptide-1 receptor agonist that adjust weight loss and glucose control via glucagon like peptide-1 receptors in the central nervous system or indirectly through activation of peripheral neurons. Current study utilized thirty-six adult male wistar rats (weighing 200-220gm), they were divided into two main groups: normal diet group (group A) that includes 12 rats receiving normal pellets and high fat diet group (group B and C) which has 24 rats feeding high fat diet pellets. Animals fed high fat diet pellets for 8 weeks to induce insulin resistance were divided into two groups: Group B received high fat diet pellets for 8 weeks then administered 0.5ml/kg normal saline intraperitoneal for four weeks. Group C received high fat diet pellets for 8 weeks then received 600μg/kg/day intraperitoneal liraglutide +0.5ml/kg normal saline four weeks along with high fat diet. High fat diet pellets caused a significant increase in body weight and blood glucose of high fat diet group. Liraglutide revealed a significant elevation in serum level of anti-inflammatory adipokines of group C. It also produces a significant reduction in serum level of pro-inflammatory cytokines of group C when compared with group B and control group. As conclusion, anti-inflammatory effects of liraglutide significantly elevate serum level of anti-inflammatory cytokines as well as significantly reduce serum level of pro-inflammatory cytokines.

Evaluation of Liraglutide Effect on Serum Adipocytokines of Adults Male Wistar Rats with Insulin Resistance That Induced by High Fat Diet

Insulin resistance (IR) is the state in which insulin-stimulated glucose uptake is blunted in the insulin sensitive-tissue leading to state of prediabetes and T2DM, IR characterized by hyperglycemia and hyperinsulinemia in the fasting state, elevated glycosylated hemoglobin (HbA1c) level, hyperlipidemia, postprandial hyperglycemia, elevated plasma levels of pro-inflammatory markers and hypoadiponectinemia.&#x0D; Type 2 diabetes mellitus reported with peripheral insulin resistance (IR) and reduced production of insulin from pancreatic β-cells, IR elevates plasma fatty acids, decreasing glucose transportation to muscles and increased breakdown of fat finally leads to increased glucose production from the liver.&#x0D; This study was designed to evaluate the effect of liraglutide on serum adipocytokines of adult male rats with insulin resistance that induced by high fat diet, Chronic high fats diet feeding is a common cause of disturbing leptin signaling in hypothalamus leading to the state of hyperphagic obesity and leptin resistance. Liraglutide improve meal-stimulated insulin secretion so it's called incretin mimetic. It is glucagon like peptide-1 receptor agonist that adjust weight loss and glucose control via glucagon like peptide-1 receptors in the central nervous system or indirectly through activation of peripheral neurons.&#x0D; Current study utilized thirty-six adult male wistar rats (weighing 200-220gm), they were divided into two main groups: normal diet group (group A) that includes 12 rats receiving normal pellets and high fat diet group (group B and C) which has 24 rats feeding high fat diet pellets. Animals fed high fat diet pellets for 8 weeks to induce insulin resistance were divided into two groups: Group B received high fat diet pellets for 8 weeks then administered 0.5ml/kg normal saline intraperitoneal for four weeks. Group C received high fat diet pellets for 8 weeks then received 600μg/kg/day intraperitoneal liraglutide +0.5ml/kg normal saline four weeks along with high fat diet.&#x0D; High fat diet pellets caused a significant increase in body weight and blood glucose of high fat diet group. Liraglutide revealed a significant elevation in serum level of anti-inflammatory adipokines of group C. It also produces a significant reduction in serum level of pro-inflammatory cytokines of group C when compared with group B and control group.&#x0D; As conclusion, anti-inflammatory effects of liraglutide significantly elevate serum level of anti-inflammatory cytokines as well as significantly reduce serum level of pro-inflammatory cytokines.

Assessment of Peripheral Neuronal Activity with Nerve Conduction Studies in Iron Deficiency Anaemia Patients from Rural Areas of Bankura District of West Bengal

Assessment of Peripheral Neuronal Activity with Nerve Conduction Studies in Iron Deficiency Anaemia Patients from Rural Areas of Bankura District of West Bengal

Assessment of peripheral neuronal activity with Nerve Conduction Studies in subclinical hypothyroidfemales from rural area of Bankura district of West Bengal

Objective : Like overt cases, whether subclinical hypothyroidism also causes supressed neuronal transmission is still debated . In this study, we tried to explore whether neuronal transmission is impaired in peripheral nerves in subclinical hypothyroidism with the help of Nerve Conduction Studies. Methods: 30 subclinical hypothyroid cases and 30 age sex matched euthyroid control were examined. All the subjects were assessed for Nerve Conduction velocity (NCV).Latency ,amplitude of CMAP(Compound Motor Action Potential) and conduction velocity of peripheral nerves like median and ulnar of both hands were considered. Findings were compared between groups by unpaired Students T- test andassociation among thyroid function parameters and NCV findings were tested by Pearsons co efficient of correlation (r value). Every where p< 0.05 was considered as significant. Results: Subclinical hypothyroids showed significantly higher distal latencies but lower conduction velocities of both median and ulnar nerves than the euthyroid controls (p<0.05 in each case). Amplitude of CMAP of both the nerves were not significantly different between the groups.Level of T3 was found to have a significant negative correlation withdistal latencies of Median and ulnar nerves (r value = -0.51 and -0.38 respectively, P<0.05 in each case) whereas a positive correlation with their conduction velocities (r- value = 0.27 and 0.55 respectively, p< 0.05 in each case). TSH however did not show any significant correlation with NCV parameters. Conclusion: Subclinical hypothyroidism may cause impairment in peripheral nerve conduction but the severity of such neurodeficit is not correlated with the level of TSH but with the level of T3.

NGF and Its Receptors in the Regulation of Inflammatory Response.

There is growing interest in the complex relationship between the nervous and immune systems and how its alteration can affect homeostasis and result in the development of inflammatory diseases. A key mediator in cross-talk between the two systems is nerve growth factor (NGF), which can influence both neuronal cell function and immune cell activity. The up-regulation of NGF described in inflamed tissues of many diseases can regulate innervation and neuronal activity of peripheral neurons, inducing the release of immune-active neuropeptides and neurotransmitters, but can also directly influence innate and adaptive immune responses. Expression of the NGF receptors tropomyosin receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) is dynamically regulated in immune cells, suggesting a varying requirement for NGF depending on their state of differentiation and functional activity. NGF has a variety of effects that can be either pro-inflammatory or anti-inflammatory. This apparent contradiction can be explained by considering NGF as part of an endogenous mechanism that, while activating immune responses, also activates pathways necessary to dampen the inflammatory response and limit tissue damage. Decreases in TrkA expression, such as that recently demonstrated in immune cells of arthritis patients, might prevent the activation by NGF of regulatory feed-back mechanisms, thus contributing to the development and maintenance of chronic inflammation.

Auditory deprivation modifies the expression of brain-derived neurotrophic factor and tropomyosin receptor kinase B in the rat auditory cortex

The development and plasticity of central auditory system can be influenced by the change of peripheral neuronal activity. However, the molecular mechanism participating in the process remains elusive. Brain-derived neurotrophic factor (BDNF) binding with its functional receptor tropomyosin receptor kinase B (TrkB) has multiple effects on neurons. Here we used a rat model of auditory deprivation by bilateral cochlear ablation, to investigate the changes in expression of BDNF and TrkB in the auditory cortex after auditory deprivation that occurred during the critical period for the development of central auditory system. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry methods were adopted to detect the mRNA and protein expression levels of BDNF and TrkB in the auditory cortex at 2, 4, 6 and 8 weeks after surgery, respectively. The change in the expression of BDNF and TrkB mRNAs and proteins followed similar trend. In the bilateral cochlear ablation groups, the BDNF-TrkB expression level initially decreased at 2 weeks but increased at 4 weeks followed by the reduction at 6 and 8 weeks after cochlear removal, as compared to the age-matched sham control groups. In conclusion, the BDNF-TrkB signaling is involved in the plasticity of auditory cortex in an activity-dependent manner.

The gut-brain axis: is intestinal inflammation a silent driver of Parkinson\u2019s disease pathogenesis?

The state of the intestinal environment can have profound effects on the activity of the central nervous system through the physiological contributions of the microbiota, regulation of intestinal barrier function, and altered activity of peripheral neurons. The common language employed for much of the gut-brain communication is the modulation of immune activity. Chronic proinflammatory immune activity is increasingly being recognized as a fundamental element of neurodegenerative disorders, and in Parkinson’s disease, inflammation in the intestine appears particularly relevant in pathogenesis. We review the evidence that intestinal dysfunction is present in Parkinson’s disease and that it may reflect the earliest manifestations of Parkinson’s disease pathology, and we link these findings to dysregulated immune activity. Based on this, we present a model for Parkinson’s disease pathogenesis in which the disorder originates in the intestine and progresses with inflammation as its underlying mechanism. More in-depth investigations into the physiological mechanisms underlying peripheral pre-motor symptoms in Parkinson’s disease are expected to lead to the development of novel diagnostic and therapeutic measures that can slow or limit progression of the disease to more advanced stages involving debilitating motor and cognitive symptoms.

Ca2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca2+ calmodulin kinases

The antidepressant-sensitive norepinephrine (NE) transporter (NET) inactivates NE released during central and peripheral neuronal activity by transport into presynaptic cells. Altered NE clearance due to dysfunction of NET has been associated with the development of mental illness and cardiovascular diseases. NET activity in vivo is influenced by stress, neuronal activity, hormones and drugs. We investigated the mechanisms of Ca2+ regulation of NET and found that Ca2+ influenced both Vmax and Km for NE transport into cortical synaptosomes. Changes in extracellular Ca2+ triggered rapid and bidirectional surface trafficking of NET expressed in cultured cells. Deletion of residues 28–47 in the NET NH2-terminus abolished the Ca2+ effect on surface trafficking. Mutagenesis studies identified Thr30 in this region as the essential residue for both Ca2+- dependent phosphorylation and trafficking of NET. Depolarization of excitable cells increased surface NET in a Thr30 dependent manner. A proteomic analysis, RNA interference, and pharmacological inhibition supported roles of CaMKI and CaMKII in Ca2+-modulated NE transport and NET trafficking. Depolarization of primary noradrenergic neurons in culture with elevated K+ increased NET surface expression in a process that required external Ca2+ and depended on CaMK activity. Hippocampal NE clearance in vivo was also stimulated by depolarization, and inhibitors of CaMK signaling prevented this stimulation. In summary, Ca2+ signaling influenced surface trafficking of NET through a CaMK-dependent mechanism requiring Thr30.

Direct effects of recurrent hypoglycaemia on adrenal catecholamine release.

In Type 1 and advanced Type 2 diabetes mellitus, elevation of plasma epinephrine plays a key role in normalizing plasma glucose during hypoglycaemia. However, recurrent hypoglycaemia blunts this elevation of plasma epinephrine. To determine whether recurrent hypoglycaemia affects peripheral components of the sympatho-adrenal system responsible for epinephrine release, male rats were administered subcutaneous insulin daily for 3 days. These recurrent hypoglycaemic animals showed a smaller elevation of plasma epinephrine than saline-injected controls when subjected to insulin-induced hypoglycaemia. Electrical stimulation of an adrenal branch of the splanchnic nerve in recurrent hypoglycaemic animals elicited less release of epinephrine and norepinephrine than in controls, without a change in adrenal catecholamine content. Responsiveness of isolated, perfused adrenal glands to acetylcholine and other acetylcholine receptor agonists was also unchanged. These results indicate that recurrent hypoglycaemia compromised the efficacy with which peripheral neuronal activity stimulates adrenal catecholamine release and demonstrate that peripheral components of the sympatho-adrenal system were directly affected by recurrent hypoglycaemia.

Neuronal activation by mucosal biopsy supernatants from irritable bowel syndrome patients is linked to visceral sensitivity.

Based on the discomfort/pain threshold during rectal distension, irritable bowel syndrome (IBS) patients may be subtyped as normo- or hypersensitive. We previously showed that mucosal biopsy supernatants from IBS patients activated enteric and visceral afferent neurons. We tested the hypothesis that visceral sensitivity is linked to the degree of neuronal activation. Normo- and hypersensitive IBS patients were distinguished by their discomfort/pain threshold to rectal balloon distension with a barostat. Using potentiometric and Ca(2+) dye imaging, we recorded the response of guinea-pig enteric submucous and mouse dorsal root ganglion (DRG) neurons, respectively, to mucosal biopsy supernatants from normosensitive (n=12 tested in enteric neurons, n=9 tested in DRG) and hypersensitive IBS patients (n=9, tested in both types of neurons). In addition, we analysed the association between neuronal activation and individual discomfort/pain pressure thresholds. The IBS supernatants evoked Ca(2+) transients in DRG neurons and spike discharge in submucous neurons. Submucous and DRG neurons showed significantly stronger responses to supernatants from hypersensitive IBS patients as reflected by higher spike frequency or stronger [Ca(2+)]i transients in a larger proportion of neurons. The neuroindex as a product of spike frequency or [Ca(2+)]i transients and proportion of responding neurons correlated significantly with the individual discomfort/pain thresholds of the IBS patients. Supernatants from hypersensitive IBS patients caused stronger activation of enteric and DRG neurons. The level of activation correlated with the individual discomfort/pain threshold pressure values. These findings support our hypothesis that visceral sensitivity is linked to activation of peripheral neurons by biopsy supernatants.

Micromolar copper modifies electrical properties and spontaneous discharges of nodose ganglion neurons in vitro

Copper plays a key role in aerobic cell physiology mainly related to mitochondrial metabolism. This element is also present at higher than basal levels in some central nuclei and indeed, current evidence support copper's role as a neuromodulator in the central nervous system. More recent data indicate that copper may also affect peripheral neuronal activity, but so far, there are not detailed descriptions of what peripheral neuronal characteristics are targeted by copper. Here, we studied the effect of physiological concentration of CuCl2 (μM range) on the activity of peripheral neurons using a preparation of nodose ganglion in vitro. By mean of conventional intracellular recordings passive and active electrical membrane properties were studied. Extracellular copper modified (in a redox-independent manner) the resting membrane potential and the input resistance of the nodose ganglion neurons, increasing the excitability in most of the tested neurons. These results suggest that Cu(2+) modulates the activity of nodose ganglion neurons and support nodose ganglion in vitro preparation as a simple model to study the subcellular mechanisms involved in the Cu(2+) effects on neuron electrical properties.

Activities and functions of peripheral neurons in the enteric nervous system ofAplysiaandLymnaea

In order to explore the functions of the peripheral neurons in the enteric nervous system (ENS) of the gastropods, Aplysia and Lymnaea, we investigated the correlation between peripheral neuronal activities and movements of the digestive tract. In Aplysia, movements of the gizzard were distinguished into two types of contraction: a large constriction of the whole gizzard following bursting activities of the neurons on the gizzard and EJP-like potentials in the musculature; and a small contraction of a restricted part of the gizzard following a slow muscle potential. When TTX was applied to isolated gizzard preparation, the bursting activities were blocked and the EJP-like potentials and the subsequent constriction disappeared, whereas the slow potentials in the musculature and partial contractions appeared to be unaffected. Therefore, it was suggested that the peripheral neurons on the gizzard were motor neurons for constriction, while the partial contraction was thought to be myogenic. In Lymnaea, we recorded periodic bursting activities in the enteric nervous system that were followed by EJP-like potentials and gastrointestinal movements. The results show that, in both species, there may exist motor neurons in the ENS that are responsible for neurogenic movements of the digestive tract.

Coordinated Peripheral Neuronal Activities Among the Different Regions of the Digestive Tract in Aplysia

Peripheral neuronal somata are scattered throughout the enteric nervous system (ENS) in Aplysia. We found that somata on the outer surface of the digestive tract were more densely distributed on the stomatogastric ring and the posterior gizzard than on other regions. In preparations with or without the central nervous system, two types of synchronous bursting activity were recorded from the nerves of the ENS. Some of the synchronous bursts were recorded from nerves on the crop and stomatogastric ring, whereas others were recorded from nerves on the crop, stomatogastric ring, and gizzard. Experiments using preparations in which the different regions were separated suggested that the former bursts originated in neurons on the crop and the latter originated in neurons on the gizzard. Axonal projections of neurons on the different regions were examined by backfilling and analysis of the direction of impulse conduction. Blocking chemical synapses in separated gizzards depressed EPSP-like potentials and eliminated the bursting activities. When chemical synapses on the crop and stomatogastric ring but not on the gizzard were blocked in a whole digestive tract preparation, bursting activity recorded from nerves on all the regions was decreased, although the frequency of the bursting rhythm did not change. Stimulation of a neuron on the crop elicited bursts in nerves on the gizzard. These results suggest that chemical synaptic connections and a feedback loop along the digestive tract coordinate the synchrony of bursting activity originating in the gizzard.

Extrinsic regulation on the two types of peripheral neuronal activities in the digestive tract of Aplysia

Extrinsic regulation on the two types of peripheral neuronal activities in the digestive tract of Aplysia