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Exercise intolerance and exertional dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD) and are associated with worse prognosis and quality of life. Activation of pulmonary vagal afferents influences the ventilatory pattern and contributes to the sensation of dyspnoea. We tested the hypothesis that nebulized fentanyl, which might attenuate aberrant pulmonary afferent activity in FILD, reduces ventilation and dyspnoea while extending exercise endurance time (EET). In this randomized, single‐blind, placebo‐controlled study, eight FILD patients (two males, 71 ± 6 years of age) performed incremental cardiopulmonary cycle exercise tests following nebulization of either fentanyl citrate (100 µg) or 0.9% saline. Previous work indicated that this dose was unlikely to produce central effects. Comparisons between treatment conditions at rest were undertaken using Student's paired t‐test, and exercise data were evaluated with two‐way ANOVA with repeated measures. Dyspnoea was assessed using the Borg dyspnoea scale. Resting respiratory variables were not different following treatment with fentanyl and saline; however, resting heart rate was lower following fentanyl (P = 0.002) and remained lower throughout exercise compared with placebo (P = 0.008). Fentanyl did not increase EET (placebo 334 ± 117 s vs. fentanyl 348 ± 126 s, P = 0.250) although overall minute ventilation was reduced slightly (mean difference: −0.97 L/min, P = 0.022). There were no differences in ratings of dyspnoea intensity or unpleasantness between the conditions either at rest or at end‐exercise. Nebulized fentanyl did not improve EET or exercise dyspnoea but did decrease minute ventilation during exercise, although the extent of this reduction appears clinically insignificant. These findings suggest that nebulized fentanyl is unlikely to offer significant benefits for enhancing exercise capacity in FILD. [ABSTRACT FROM AUTHOR]

Background: Studies have examined the influence of postexercise blood flow restriction as a mechanism to activate muscle afferents and assess nonlocal muscle fatigue. Although these studies have assessed fatigue during maximal contractions, less is known about how these afferents may impact submaximal local muscle endurance, which was the purpose of the present study. Methods: Individuals completed two testing visits which involved completing a set of elbow flexion exercises to volitional failure on the nondominant followed by the dominant arm. During both trials, a pneumatic cuff was placed at the top of the nondominant arm before exercise. This cuff was inflated to either 0% (control) or 70% (experimental) of the individual's arterial occlusion pressure immediately after the set was completed. We then evaluated how this impacted local muscle endurance of the dominant arm using a Bayesian paired samples t‐test with an uninformed prior width of 0.707 centred on 0. Results: A total of 36 individuals completed the study (18 females). There was a greater discomfort present in the experimental trial when compared to the control trial (control: 4.5 standard deviation [SD]: 2.4); experimental: 5.8 [SD: 1.9]; BF10 = 61.46), but there were no differences in repetitions completed on the dominant arm (control: 43 [SD: 9], experimental: 43 [SD: 10]; BF10 = 0.179). Conclusion: Applying blood flow restriction postexercise induced sensations of discomfort but did not alter the local muscle endurance of the contralateral limb. These results suggest that increasing the activation of muscle afferents does not appear to alter the submaximal muscle endurance of a remote limb. [ABSTRACT FROM AUTHOR]

Key points Pairing motor cortex stimulation and spinal cord epidural stimulation produced large augmentation in motor cortex evoked potentials if they were timed to converge in the spinal cord., The modulation of cortical evoked potentials by spinal cord stimulation was largest when the spinal electrodes were placed over the dorsal root entry zone., Repeated pairing of motor cortex and spinal cord stimulation caused lasting increases in evoked potentials from both sites, but only if the time between the stimuli was optimal., Both immediate and lasting effects of paired stimulation are likely mediated by convergence of descending motor circuits and large diameter afferents onto common interneurons in the cervical spinal cord., Abstract Convergent activity in neural circuits can generate changes at their intersection. The rules of paired electrical stimulation are best understood for protocols that stimulate input circuits and their targets. We took a different approach by targeting the interaction of descending motor pathways and large diameter afferents in the spinal cord. We hypothesized that pairing stimulation of motor cortex and cervical spinal cord would strengthen motor responses through their convergence. We placed epidural electrodes over motor cortex and the dorsal cervical spinal cord in rats; motor evoked potentials (MEPs) were measured from biceps. MEPs evoked from motor cortex were robustly augmented with spinal epidural stimulation delivered at an intensity below the threshold for provoking an MEP. Augmentation was critically dependent on the timing and position of spinal stimulation. When the spinal stimulation was timed to coincide with the descending volley from motor cortex stimulation, MEPs were more than doubled. We then tested the effect of repeated pairing of motor cortex and spinal stimulation. Repetitive pairing caused strong augmentation of cortical MEPs and spinal excitability that lasted up to an hour after just 5 min of pairing. Additional physiology experiments support the hypothesis that paired stimulation is mediated by convergence of descending motor circuits and large diameter afferents in the spinal cord. The large effect size of this protocol and the conservation of the circuits being manipulated between rats and humans makes it worth pursuing for recovery of sensorimotor function after injury to the central nervous system. [ABSTRACT FROM AUTHOR]

Background One aspect of rehabilitation in swallowing disorders is to change liquid properties. The objective of our study was to test how liquid properties could improve oropharyngeal dysphagia and swallowing and ventilation coordination in an animal model. Methods Forty-two healthy male rats were distributed in six groups, including a control group. Rats were deprived of water for 24 h and then each group was administered liquid with different properties: tap water, sugar water, sparkling water, salt water, cold water, and acidic water. Rats were studied without and with oropharyngeal dysphagia achieved by unilateral section of the hypoglossal nerve. Swallowing and ventilation were analyzed by barometric plethysmograph. Key Results In healthy rats, swallowing occurred during expiratory time for all liquid properties. Most deglutitions were during expiratory time for all liquid properties (88±12%) and were not modified. There was an increase in VT/ TI during swallowing with sparkling water and cold water ( P<.05). In the operated groups, rats had significantly fewer swallows with tap water ( P<.05) and significantly more swallows with sparkling water ( P<.001), sugar water ( P<.001) and cold water ( P<.001) during expiratory time. The mean inspiratory volume ( VT/ TI) increased with sparkling water ( P<.05). Conclusion and Inferences Sparkling water seemed to improve swallowing and ventilation coordination in an animal model, to be confirmed in a study including patients with oropharyngeal dysphagia. [ABSTRACT FROM AUTHOR]

ABSTRACT The anatomical organization of the lateral prefrontal cortex (LPFC) afferents to the anterior part of the temporal lobe (ATL) remains to be clarified. The LPFC has two subdivisions, dorsal (dLPFC) and ventral (vLPFC), which have been linked to cognitive processes. The ATL includes several different cortical areas, namely, the temporal polar cortex and rostral parts of the perirhinal, inferotemporal, and anterior tip of the superior temporal gyrus cortices. Multiple sensory modalities converge in the ATL. All of them (except the rostral inferotemporal and superior temporal gyrus cortices) are components of the medial temporal lobe, which is critical for long-term memory processing. We studied the LPFC connections with the ATL by placing retrograde tracer injections into the ATL: the temporal polar ( n = 3), perirhinal (areas 35 and 36, n = 6), and inferotemporal cortices (area TE, n = 5), plus one additional deposit in the posterior parahippocampal cortex (area TF, n = 1). Anterograde tracer deposits into the dLPFC (A9 and A46, n = 2), the vLPFC (A46v, n = 2), and the orbitofrontal cortex (OF; n = 2) were placed for confirmation of those projections. The results showed that the vLPFC displays a moderate projection to rostral area TE and the dorsomedial portion of the temporal polar cortex; in contrast, the dLPFC connections with the ATL were weak. By comparison, the OFC and medial frontal cortices (MFC) showed dense connectivity with the ATL, namely, A13 with the temporopolar and perirhinal cortices. All areas of the MFC projected to the temporopolar cortex, albeit with a lower intensity. The functional significance of such paucity of LPFC afferents is unknown. J. Comp. Neurol. 523:2570-2598, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Traditionally, sensory signaling in the urinary bladder has been largely attributed to direct activation of bladder afferents. There is substantive evidence that sensory systems can be influenced by non-neuronal cells, such as the urothelium, which are able to respond to various types of stimuli that can include physiological, psychological and disease-related factors. The corresponding release of chemical mediators (through activation of a number of receptors/ion channels) can initiate signaling mechanisms between and within urothelial cells, as well as other cell types within the bladder wall including bladder nerves. However, the mechanisms underlying how various cell types in the bladder wall respond to normal filling and emptying, and are challenged by a variety of stressors (physical and chemical) are still not well understood. Alterations or defects in signaling mechanisms are likely to contribute to the pathophysiology of bladder disease with symptoms including urinary urgency, increased voiding frequency and pain. This review will discuss some of the components involved in control of lower urinary tract function, with an emphasis on the sensor and transducer roles of the urothelium. [ABSTRACT FROM AUTHOR]

The mechanisms underlying bladder sensation and the way we experience sensations during normal voiding and in pathology is complex and not well understood. During storage and emptying, mechanical changes occurring in number of cell types within the bladder wall (i.e. the uroepithelium and bladder afferents) can have a major influence on our sensory systems. In this review, we discuss bladder sensation with a focus on coding events in the periphery. [ABSTRACT FROM AUTHOR]

What's known on the subject? and What does the study add? It is well known that urinary bladder sensation requires the activation by ATP of ionotropic purinergic P2X3/P2X2/3 receptors located in bladder afferent C-fibres. Furthermore, in rat models of neurogenic bladder hyperactivity the release of ATP from the bladder urothelium is greater than ATP release in neurally intact rats. Therefore, the activation of purinergic receptors in bladder sensory fibres seems to be a sentinel event for the development of bladder hyperactivity after spinal cord injury. We found that inhibition of P2X3/P2X2/3 purinergic receptors decreased the frequency of sensory field potentials evoked by activation of bladder noxious pathways. At the same time, the pharmacological blockade of these receptors significantly decreased the frequency of non-voiding contractions in rats with neurogenic bladder hyperactivity. The present study uncovers sensory purinergic receptors as potential therapeutic targets to treat neurogenic bladder hyperactivity, especially when the release of ATP from the urothelium is elevated. OBJECTIVE To evaluate the role of bladder sensory purinergic P2X3 and P2X2/3 receptors on modulating the activity of lumbosacral neurones and urinary bladder contractions in vivo in normal or spinal cord-injured (SCI) rats with neurogenic bladder overactivity., MATERIALS AND METHODS SCI was induced in female rats by complete transection at T8-T9 and experiments were performed 4 weeks later, when bladder overactivity developed. Non-transected rats were used as controls (normal rats)., Neural activity was recorded in the dorsal horn of the spinal cord and field potentials were acquired in response to intravesical pressure steps via a suprapubic catheter. Field potentials were recorded under control conditions, after stimulation of bladder mucosal purinergic receptors with intravesical ATP (1 m m), and after intravenous injection of the P2X3/P2X2/3 antagonist AF-353 (10 mg/kg and 20 mg/kg)., Cystometry was performed in urethane-anaesthetised rats intravesically infused with saline. AF-353 (10 mg/kg) was systemically applied after baseline recordings; the rats also received a second dose of AF-353 (20 mg/kg). Changes in the frequency of voiding (VC) and non-voiding (NVC) contractions were evaluated., RESULTS SCI rats had significantly higher frequencies for field potentials and NVC than NL rats. Intravesical ATP increased field potential frequency in control but not SCI rats, while systemic AF-353 significantly reduced this parameter in both groups., AF-353 also reduced the inter-contractile interval in control but not in SCI rats; however, the frequency of NVC in SCI rats was significantly reduced., CONCLUSION The P2X3/P2X2/3 receptors on bladder afferent nerves positively regulate sensory activity and NVCs in overactive bladders. [ABSTRACT FROM AUTHOR]

The management of pancreatic pain is a significant clinical problem so understanding of how sensory signals are generated in pancreatic tissue is fundamental. We aimed to characterize mechanosensitive and chemosensitive properties of pancreatic spinal and vagal afferents in vitro. Spinal and vagal afferent preparations from Sprague–Dawley rats were established incorporating the left splanchnic nerve or vagus nerves respectively. The common bile duct was cannulated for distension of the pancreatic duct with fluid. Nerve discharge evoked by blunt probing, duct distension or electrical stimulation was obtained from teased nerve bundles using standard extra-cellular recording. Discharge from 197 spinal afferent bundles was recorded, of which 57% displayed spontaneous activity. Blunt probing revealed 61 mechanosensitive receptive fields which were associated primarily with arteries/blood vessels (33/61) and the parenchyma (22/61). All mechanosensitive responses were slowly adapting, with 33% continuing to discharge after termination of the stimulus and 60% displaying a response threshold <10 g. Application of chemical mediators (bradykinin, histamine, 5-hydroxytryptamine, cholecystokinin octapeptide) evoked a response from 31/57 units, with 33% excitatory and 23% inhibitory. Spontaneous discharge was recorded from 72% of 135 vagal bundles. Mechanosensitive receptive fields were not identified in the pancreas but were evident in adjacent organs. No spinal or vagal afferent response to duct distension was obtained. In conclusion, pancreatic mechanosensitive spinal afferents are common, in contrast to pancreatic mechanosensitive vagal afferents indicating that pancreatic sensory innervation is predominantly spinal. Chemosensitive spinal afferent nerve endings are present in the pancreas and respond to a variety of inflammatory and physiological mediators. [ABSTRACT FROM AUTHOR]

Vagal, spinal and intestino-fugal fibres all potentially transmit mechanosensory afferent information from the gastrointestinal tract. We aimed to characterize the relative mechanosensitivity of these three different afferent populations supplying the rat jejunum. Afferent nerve discharge was recorded from pentobarbitone-anaesthetized rats during different distension protocols. Saline ramp distension (1 mL min−1) and barostat ramp distension (2 mmHg 4 s−1) each evoked biphasic responses but with the latter significantly attenuated especially at low distending pressures. Barostat controlled phasic distensions (10–50 mmHg, 25 s) evoked an afferent response with a peak at the onset of distension adapting to a pleateau level that was maintained and comparable to the barostat ramp responses at the corresponding pressures. Chronic subdiaphragmatic vagotomy significantly attenuated the low pressure component of the response to balloon ramp distension and both peak and plateau responses to phasic distension. Single unit analysis showed an absence of low threshold afferent activity after vagotomy while the response to fibres with wide-dynamic range and high threshold sensitivity were preserved hexamethonium had no effect on the responses to either ramp or phasic distension. These findings suggest that the nature of the distension stimulus is critical in determining the pattern of response observed from the various subpopulations of afferents supplying the bowel wall. [ABSTRACT FROM AUTHOR]

Background: Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here, we determined whether these pathways differ also in their chemosensitivity to bradykinin. Methods: Using a novel in vitro mouse colon preparation, serosal afferents were recorded from the LSN and PN and distinguished based on their mechanosensitivity to von Frey filaments (70–4000 mg) and insensitivity to colonic stretch (1–5 g) or fine mucosal stroking (10 mg). Bradykinin was applied into a ring around mechanoreceptive fields. Results: The LSN and PN afferents had different dynamic responses to mechanical stimuli: PN afferents required lower intensity stimuli, evoked larger responses, and displayed more maintained responses than LSN afferents. Bradykinin (1 μmol L−1) excited 66% (27 of 41) of LSN afferents. Responses to probing were potentiated after bradykinin. The concentration-dependent (EC50: 0.16 μmol L−1) response was reversed by the B2-receptor antagonist HOE-140 (10 nmol L−1). Twelve bradykinin responsive afferents were mechanically insensitive. More LSN serosal afferents responded to bradykinin than PN afferents (11%, P < 0.001) , with larger responses ( P < 0.05). No mechanically insensitive PN afferents were recruited by bradykinin. Conclusions: Bradykinin potently stimulates most splanchnic serosal afferents via B2-receptors, but few pelvic afferents. Mechanically insensitive afferents recruited by bradykinin are exclusive to the LSN. [ABSTRACT FROM AUTHOR]

Most glutamatergic neurons in the brain express one of two vesicular glutamate transporters, vGlut1 or vGlut2. Cortical glutamatergic neurons highly express vGlut1, whereas vGlut2 predominates in subcortical areas. In this study immunohistochemical detection of vGlut1 or vGlut2 was used in combination with tryptophan hydroxylase (TPH) to characterize glutamatergic innervation of the dorsal raphe nucleus (DRN) of the rat. Immunofluorescence labeling of both vGlut1 and vGlut2 was punctate and homogenously distributed throughout the DRN. Puncta labeled for vGlut2 appeared more numerous then those labeled for vGlut1. Ultrastructural analysis revealed axon terminals containing vGlut1 and vGlut2 formed asymmetric-type synapses 80% and 95% of the time, respectively. Postsynaptic targets of vGlut1- and vGlut2-containing axons differed in morphology. vGlut1-labeled axon terminals synapsed predominantly on small-caliber (distal) dendrites (42%, 46/110) or dendritic spines (46%, 50/110). In contrast, vGlut2-containing axons synapsed on larger caliber (proximal) dendritic shafts (> 0.5 µm diameter; 48%, 78/161). A fraction of both vGlut1- or vGlut2-labeled axons synapsed onto TPH-containing dendrites (14% and 34%, respectively). These observations reveal that different populations of glutamate-containing axons innervate selective dendritic domains of serotonergic and non-serotonergic neurons, suggesting they play different functional roles in modulating excitation within the DRN. [ABSTRACT FROM AUTHOR]

Visceral hypersensitivity in the upper gastrointestinal tract is a potential pathomechanism of functional dyspepsia. The herbal preparation STW 5 (Iberogast®) provides symptomatic relief for this condition. We aimed to investigate whether STW 5 modulates intestinal afferent sensitivity.The herbal preparation STW 5 or vehicle (30.8% ethanol) were administered orally in male Wister rats. After 2 h animals were anaesthetized and extracellular multi-unit intestinal afferent nerve recordings were secured from the neurovascular bundle of the mesentery in the proximal jejunum. Afferent discharge to ramp distension of the intestinal loop (0–60 cm H2O) and dose–response curves for i.v. bradykinin (10, 20 and 40 μg kg−1) and 5-HT (5, 10, 20 and 40 μg kg−1) were recorded.Baseline discharge was not different between the vehicle and treatment group. Ramp distension was followed by a pressure dependent increase in afferent nerve discharge that was decreased following STW 5 pretreatment for all distending pressures reaching 147 ± 8 impulses s−1 (imp s−1) following STW 5vs171 ± 5 imp s−1 following vehicle at 60 cm H2O (mean ± SEM;P < 0.05). A dose-dependent increase in afferent discharge was observed for 5-HT and bradykinin. Following STW 5 pretreatment, afferent discharge was reduced at all doses of 5-HT to 110 ± 5 at the maximum dose after STW 5 and 128 ± 3 imp s−1 in controls (allP < 0.05). Afferent discharge to bradykinin was similarly reduced at 20 and 40 μg kg−1 but not at 10 μg kg−1 of bradykinin with a discharge rate of 176 ± 7 imp s−1 following STW 5 and 200 ± 6 imp s−1 in controls at 40 μg kg−1 (P < 0.05).The preparation STW 5 reduces intestinal afferent nerve discharge following chemical and mechanical stimuli, while baseline discharge is not affected. This effect of STW 5 on afferent sensitivity may contribute to its therapeutic relief of dyspeptic symptoms. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine the sensitivity to opioid-receptor agonists of mesenteric afferents supplying the small intestine and to characterize the subpopulations of any responsive fibres. Mesenteric afferent discharge was recorded electrophysiologically in response to cumulative doses (1–400 μg kg–1) of the μ-receptor agonist [D-ala,2 N- me-Phe4,Gly5-ol]-enkephalin (DAMGO), the δ-receptor agonist [D-ala,2 D-leu5]-enkephalin (DADLE) and the κ-receptor agonist U-50488. DAMGO and DADLE, but not U-50488, markedly stimulated whole nerve mesenteric afferent discharge (P < 0.05) that was unrelated to intestinal motor events. Subpopulations of afferent fibres responding to DAMGO were examined using waveform analysis to identify single units from within the whole mesenteric nerve bundles. One population was CCK-sensitive (15/15 fibres) and the other was a subpopulation of mechanosensitive afferents that responded to distension (17/28). 5-HT-sensitive afferents did not respond to DAMGO (0/11). We conclude that specific subpopulations of mesenteric afferents respond to μ- and possibly δ- but not κ-receptor agonists. This sensitivity to opioids may contribute to the antinociceptive property of vagal afferents. [ABSTRACT FROM AUTHOR]