A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine

Unmyelinated tactile (CT) afferents are abundant in arm hairy skin and have been suggested to signal features of social affective touch. Here we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves, with the most distal receptive fields located on the proximal phalanx of the third finger for the superficial branch of the radial nerve, and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial (n=27), radial (n=8) and peroneal nerves (n=4). Moreover, we found that while CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared to C nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.

Transcranial Ultrasound Stimulation of the Anterior Cingulate Cortex Reduces Neuropathic Pain in Mice

Focused ultrasound (FUS) is a potential tool for treating chronic pain by modulating the central nervous system. Herein, we aimed to determine whether transcranial FUS stimulation of the anterior cingulate cortex (ACC) effectively improved chronic pain in the chronic compress injury mice model at different stages of neuropathic pain. The mechanical threshold of pain was recorded in the nociceptive tests. We found FUS stimulation elevated the mechanical threshold of pain in both short-term ( p < 0.01 ) and long-term ( p < 0.05 ) experiments. Furthermore, we determined protein expression differences in ACC between the control group, the intervention group, and the Sham group to analyze the underlying mechanism of FUS stimulation in improving neuropathic pain. Additionally, the results showed FUS stimulation led to alterations in differential proteins in long-term experiments, including cellular processes, cellular signaling, and information storage and processing. Our findings indicate FUS may effectively alleviate mechanical neuropathic pain via the ACC’s stimulation, especially in the chronic state.

Comparative studies of the constitutive models for tungsten heavy alloy (95W-3.5Ni-1.5Fe) at high strain rates

The plastic behaviors’ description of a tungsten heavy alloy (95W-3.5Ni-1.5Fe) at temperatures of 298–773 K and strain rates of 0.001–11,000 s−1 is systematically studied based on four constitutive models, that is, Zerilli-Armstrong model, modified Zerilli-Armstrong model, Mechanical Threshold Stress model, and modified Mechanical Threshold Stress model. The quasi-static compression experiments using an electronic universal testing machine and the dynamic compression experiments using a split Hopkinson pressure bar apparatus are employed to obtain the true stress–strain curves at a total of three temperatures (298 K, 573 K, and 773 K) and a wide range of strain rates (0.001–11,000 s−1). The parameters of the four constitutive models are obtained by the above fundamental experimental data and Grey Wolf Optimizer. The correlation coefficient and average absolute relative error are used to evaluate the predicted performance of these models. Modified Mechanical Threshold Stress model is found to have the highest predicted performance in describing the flow stress of the 95W-3.5Ni-1.5Fe alloy. Eventually, two compression experiments whose loading conditions are not in the fundamental experiments are conducted to validate the four models.

A Pusher and a Clip Applied to Hind Paws Under Isoflurane Sedation to Evaluate Neuropathic Pain in a CCI Model

: Rodent behavior assessments have been developed to evaluate pain. However, their fidgety activity and reactivity to human contact make it hard to activate animals in a consistent manner and get uniform and trustworthy responses. The present study was performed on prairie voles (aged 8 weeks). Sham (7 male prairie voles) and chronic constriction injury (CCI) (8 male prairie voles) rodents were investigated before surgery and four and seven days later. Each animal was assessed for nociceptive behavior. Pressure and mechanical threshold tests were conducted by the application of three different pushers to the center of hind paws and arterial clips to the toes while sedated with isoflurane. The CCI affected right lower extremity prominently increased nociceptive behavior scores four and seven days after the experiment, and the CCI affected right hind paw prominently decreased pressure and mechanical threshold tests four and seven days after the experiment . The pressure and mechanical thresholds were relevant to the scorings of nociceptive behavior in CCI model animals.

The Role of the Inflammatory and the Vascular Pathogenesis in a Model of Streptozotocin Induced Diabetic Neuropathy in Rats

Background Peripheral diabetic neuropathy (DN) is one of the major health problems facing the whole world. There is no treatment that could completely reverse or prevent progression of DN except for good glycemic control. The inflammatory and vascular pathways are two main domains that are incorporated in the pathogenesis of diabetic neuropathic pain (DNP) and DN. Thus, targeting both of them could be an appropriate way to delay progression of DN. Aim To investigate the role of the inflammatory and the vascular pathogenesis in diabetic mechanical allodynia. Method Twenty male Wistar rats were divided randomly into naïve and diabetic groups (n = 10). Diabetes was induced through i.p injection of single dose of streptozotocin (STZ) (50mg/kg), then 8 weeks after induction of diabetes, the sciatic content of tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) was assessed using ELISA technique. Additionally, the number of intercellular adhesion molecule-1 (ICAM-1) as well as CD31, the most specific vascular marker, positively stained vessels was counted manually in sciatic nerves cross sections. Whereas, DNP was assessed weekly throughout the experiment using 60%mechanical threshold of paw withdrawal test. Results There was a significant increase in the sciatic content of TNFα, VEGF and ICAM-1 positively stained vessels and a significant decrease in CD31 positively stained vessels in the diabetic group as compared to the naïve group. There was a correlation between TNFα, VEGF, ICAM-1, CD31 positively stained vessels in one side and the 60% mechanical threshold on the other side (r=-0.8, -0.9, -0.8 and 0.7 respectively). Conclusion The diabetic mechanical allodynia is negatively correlated to the sciatic nerve content TNFα, VEGF, ICAM-1 and positively correlated to the CD31.

Does Mechanical Threshold Inspiratory Muscle Training Promote Recovery and Improve Outcomes in Ventilator-Dependent ICU Patients? The IMPROVE Randomised Trial.

Background: In ventilator-dependent ICU patients, inspiratory muscle training may improve inspiratory muscle strength and accelerate liberation from the ventilator, but optimal training parameters are yet to be established and little is known about the impact of inspiratory muscle training on quality of life or dyspnea. Thus we sough to ascertain whether inspiratory muscle training, commenced while ventilator-dependent, would improve outcomes for ICU patients invasively ventilated for 7 days or longer.Methods: In this randomized trial with assessor-blinding and intention-to-treat analysis, 70 participants (mechanically ventilated ≥7 days) were randomized to receive once- daily supervised high-intensity inspiratory muscle training with a mechanical threshold device in addition to usual care, or usual care (control). Primary outcomes were inspiratory muscle strength (maximum inspiratory pressure % predicted) and endurance (fatigue resistance index) at ventilator-liberation and 1 week later, and quality of life (SF-36v2, EQ-5D). Secondary outcomes included dyspnea, physical function, duration of ventilation and in-hospital mortality.Results: 33 participants were randomly allocated to the training group and 37 to control. There were no statistically significant differences in strength (maximum inspiratory pressure) (95% CI -7.4 to 14.0) or endurance (fatigue resistance index) (95% CI -0.003 to 0.436). Quality of life improved significantly more in the training group than control (EQ5D 17.2; 95% CI 1.3-33.0) (SF36-PCS 6.97; 96%CI 1.96-12.00). Only the training group demonstrated significant reductions in dyspnea (-1.5 at rest, -1.9 during exercise). There were no between-group differences in duration of ventilation or other measures. In-hospital mortality was higher in the control group than the training group (9 vs 4, 24% vs 12%, p=0.23).Conclusions: In ventilator-dependent patients, mechanical threshold loading inspiratory muscle training improves quality of life and dyspnea, even in the absence of strength improvements or acceleration of ventilator liberation. Trial registration: ACTRN12610001089022 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12610001089022Trial protocol: http://bmjopen.bmj.com/content/2/2/e000813.full

Modified Molecular Chain Displacement Analysis Employing Electro-Mechanical Threshold Energy Condition for Direct Current Breakdown of Low-Density Polyethylene

In an HVDC environment, space charge accumulated in polymeric insulators causes severe electric field distortion and degradation of breakdown strength. To analyze the breakdown characteristics, here, the space charge distribution was numerically evaluated using the bipolar charge transport (BCT) model, considering the temperature gradient inside the polymeric insulator. In particular, we proposed an electro-mechanical threshold energy condition, resulting in the modified molecular chain displacement model. The temperature gradient accelerates to reduce the breakdown strength with the polarity-reversal voltage, except during the harshest condition, when the temperature of the entire polymeric insulator was 70 °C. The energy imbalance inside the insulator caused by polarity-reversal voltage reduced the breakdown strength by 82%. Finally, this numerical analysis model can be used universally to predict the breakdown strength of polymeric insulators in various environments, and help in evaluating the electrical performance of polymeric insulators.

A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine.

Numerous microneurography studies in the human peroneal nerve have suggested that CT afferents are lacking in the more distal parts of the limbs. Here we recorded from unmyelinated low-threshold mechanosensitive afferents in the peroneal and radial nerves, with the most distal receptive fields located on the proximal phalanx of the third finger for the superficial branch of the radial nerve, and near the lateral malleolus for the peroneal nerve. We found that the physiological properties with regard to conduction velocity and mechanical threshold, as well as their tuning to brush velocity, were similar in CT units across the antebrachial, radial and peroneal nerves. Moreover, we found that while CT afferents are readily found during microneurography of the arm nerves, they appear to be much more sparse in the lower leg compared to C nociceptors. We continued to explore CT afferents with regard to their chemical sensitivity and found that they could not be activated by topical application to their receptive field of either the cooling agent menthol or the pruritogen histamine. In light of previous studies showing the combined effects that temperature and mechanical stimuli have on these neurons, including a lack of responsiveness to heat, these findings add to the growing body of research suggesting that CT afferents constitute a unique class of sensory afferents with highly specialized mechanisms for transducing gentle touch.

Spontaneous, Voluntary, and Affective Behaviours in Rat Models of Pathological Pain

In pain patients affective and motivational reactions as well as impairment of daily life activities dominate the clinical picture. In contrast, many rodent pain models have been established on the basis of mechanical hypersensitivity testing. Up to today most rodent studies on pain still rely on reflexive withdrawal responses only. This discrepancy has likely contributed to the low predictive power of preclinical pain models for novel therapies. Here, we used a behavioural test array for rats to behaviourally evaluate five aetiologically distinct pain models consisting of inflammatory-, postsurgical-, cephalic-, neuropathic- and chemotherapy-induced pain. We assessed paralleling clinical expressions and comorbidities of chronic pain with an array of behavioural tests to assess anxiety, social interaction, distress, depression, and voluntary/spontaneous behaviours. Pharmacological treatment of the distinct pain conditions was performed with pathology-specific and clinically efficacious analgesics as gabapentin, sumatriptan, naproxen, and codeine. We found that rats differed in their manifestation of symptoms depending on the pain model and that pathology-specific analgesics also reduced the associated behavioural parameters. Based on all behavioural test performed, we screened for tests that can discriminate experimental groups on the basis of reflexive as well as non-sensory, affective parameters. Together, we propose a set of non-evoked behaviours with a comparable predictive power to mechanical threshold testing for each pain model.