Afferent Units Research Articles

Bioelastic state recovery for haptic sensory substitution.

The rich set of mechanoreceptors found in human skin1,2 offers a versatile engineering interface for transmitting information and eliciting perceptions3,4, potentially serving a broad range of applications in patient care5 and other important industries6,7. Targeted multisensory engagement of these afferent units, however, faces persistent challenges, especially for wearable, programmable systems that need to operate adaptively across the body8-11. Here we present a miniaturized electromechanical structure that, when combined with skin as an elastic, energy-storing element, supports bistable, self-sensing modes of deformation. Targeting specific classes of mechanoreceptors as the basis for distinct, programmed sensory responses, this haptic unit can deliver both dynamic and static stimuli, directed as either normal or shear forces. Systematic experimental and theoretical studies establish foundational principles and practical criteria for low-energy operation across natural anatomical variations in the mechanical properties of human skin. A wireless, skin-conformable haptic interface, integrating an array of these bistable transducers, serves as a high-density channel capable of rendering input from smartphone-based 3D scanning and inertial sensors. Demonstrations of this system include sensory substitution designed to improve the quality of life for patients with visual and proprioceptive impairments.

A Virtual Inner Ear Model Selects Ramped Pulse Shapes for Vestibular Afferent Stimulation.

Bilateral vestibular deficiency (BVD) results in chronic dizziness, blurry vision when moving the head, and postural instability. Vestibular prostheses (VPs) show promise as a treatment, but the VP-restored vestibulo-ocular reflex (VOR) gain in human trials falls short of expectations. We hypothesize that the slope of the rising ramp in stimulation pulses plays an important role in the recruitment of vestibular afferent units. To test this hypothesis, we utilized customized programming to generate ramped pulses with different slopes, testing their efficacy in inducing electrically evoked compound action potentials (eCAPs) and current spread via bench tests and simulations in a virtual inner model created in this study. The results confirmed that the slope of the ramping pulses influenced the recruitment of vestibular afferent units. Subsequently, an optimized stimulation pulse train was identified using model simulations, exhibiting improved modulation of vestibular afferent activity. This optimized slope not only reduced the excitation spread within the semicircular canals (SCCs) but also expanded the neural dynamic range. While the model simulations exhibited promising results, in vitro and in vivo experiments are warranted to validate the findings of this study in future investigations.

FEATURES OF THE IMMUNE SYSTEM STRUCTURE OF THE MUCOSA OF THE SMALL INTESTINE OF MICE

Afferent and efferent units of immune system of mucous membrane of the small intestine in white outbred rats have been studied light-and electron microscopically. On the basis of the received findings it was established that afferent unit stimulates and regulates T-, B - blast’s coo relation. Action of epithelium, stimulated T- and B - lymphocytes and cells of connective tissue has been integrated in efferent unit.

The Anatomical Distribution of Mechanoreceptors in Mouse Hind Paw Skin and the Influence of Integrin α1β1 on Meissner-Like Corpuscle Density in the Footpads.

Afferent neurons and their mechanoreceptors provide critical sensory feedback for gait. The anatomical distribution and density of afferents and mechanoreceptors influence sensory feedback, as does mechanoreceptor function. Electrophysiological studies of hind paw skin reveal the different types of afferent responses and their receptive fields, however, the anatomical distribution of mechanoreceptor endings is unknown. Also, the role of integrin α1β1 in mechanoreceptor function is unclear, though it is expressed by keratinocytes in the stratum basale where it is likely involved in a variety of mechanotransduction pathways and ion channel functionalities. For example, it has been shown that integrin α1β1 is necessary for the function of TRPV4 that is highly expressed by afferent units. The purpose of this study, therefore, was to determine and compare the distribution of mechanoreceptors across the hind paw skin and the footfall patterns of itga1-null and wild type mice. The itga1-null mouse is lacking the integrin α1 subunit, which binds exclusively to the β1 subunit, thus rendering integrin α1β1 nonfunctional while leaving the numerous other pairings of the β1 subunit undisturbed. Intact hind paws were processed, serially sectioned, and stained to visualize mechanoreceptors. Footfall patterns were analyzed as a first step in correlating mechanoreceptor distribution and functionality. Merkel cells and Meissner-like corpuscles were present, however, Ruffini endings and Pacinian corpuscles were not observed. Meissner-like corpuscles were located exclusively in the glabrous skin of the footpads and digit tips, however, Merkel cells were found throughout hairy and glabrous skin. The increased density of Merkel cells and Meissner-like corpuscles in footpads 1 and 3 and Meissner-like corpuscles in footpad 4 suggests their role in anteroposterior balance, while Meissner-like corpuscle concentrations in digits 2 and 5 support their role in mediolateral balance. Finally, a larger density of Meissner-like corpuscles in footpads 3 and 4 in male itga1-null mice compared to wild type controls paves the way for future site-specific single fiber in vivo recordings to provide insight into the role of integrin α1β1 in tactile mechanotransduction.

Mapping quantal touch using 7 Tesla functional magnetic resonance imaging and single-unit intraneural microstimulation.

Using ultra-high field 7 Tesla (7T) functional magnetic resonance imaging (fMRI), we map the cortical and perceptual responses elicited by intraneural microstimulation (INMS) of single mechanoreceptive afferent units in the median nerve, in humans. Activations are compared to those produced by applying vibrotactile stimulation to the unit's receptive field, and unit-type perceptual reports are analyzed. We show that INMS and vibrotactile stimulation engage overlapping areas within the topographically appropriate digit representation in the primary somatosensory cortex. Additional brain regions in bilateral secondary somatosensory cortex, premotor cortex, primary motor cortex, insula and posterior parietal cortex, as well as in contralateral prefrontal cortex are also shown to be activated in response to INMS. The combination of INMS and 7T fMRI opens up an unprecedented opportunity to bridge the gap between first-order mechanoreceptive afferent input codes and their spatial, dynamic and perceptual representations in human cortex.

Impaired excitability of renal afferent innervation after exposure to the inflammatory chemokine CXCL1.

Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patch-clamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e., <5 APs following current injection. Of the labeled renal afferents treated with vehicle, 58.9% exhibited a tonic firing pattern vs. 7.8%, in unlabeled, nonrenal neurons (P < 0.05). However, after exposure to CXCL1, significantly more phasic neurons were found among labeled renal neurons; hence the occurrence of tonic neurons with sustained firing upon electrical stimulation decreased (35.6 vs. 58.9%, P < 0.05). The firing frequency among tonic neurons was not statistically different between control and CXCL1-treated neurons. However, the lower firing frequency of phasic neurons was even further decreased with CXCL1 exposure [control: 1 AP/600 ms (1-2) vs. CXCL1: 1 AP/600 ms (1-1); P < 0.05; median (25th-75th percentile)]. Hence, CXCL1 shifted the firing pattern of renal afferents from a predominantly tonic to a more phasic firing pattern, suggesting that CXCL1 reduced the sensitivity of renal afferent units upon stimulation.

Low-threshold mechanoreceptive skin Aδ and C afferent units contribute to an inhibitory effect of touch on nociceptive somatocardiac reflexes via the spinal μ-opioid system

Low-threshold mechanoreceptive skin Aδ and C afferent units contribute to an inhibitory effect of touch on nociceptive somatocardiac reflexes via the spinal μ-opioid system

Abstract P220: Congestive Heart Failure in the Rat Induces Subtle Renal Damage via Neurogenic Pathways

Background: Cardiomyopathy in experimental renal insufficiency is putatively influenced by neurogenic pathways of renal origin. We wondered if cardiac neurogenic effects in congestive heart failure could likewise harm the kidney. We hypothesized that increased renal sympathetic nerve activity (RSNA) in rats with congestive heart failure after myocardial infarction (CHF) induces renal structural damage. Methods: 21 day after induction of CHF renal morphology was evaluated by immunohistology (interstitial and glomerular mononuclear cell infiltration (ED1), cell proliferation (PCNA), collagen I,III,IV,V,VI, laminin und fibronectin). RSNA was assessed by volume challenge (VE) to decrease RSNA. CHF and control rats were investigated with and without renal denervation (DNX). Blood pressure (BP), heart rate (HR) and RSNA were recorded. Nodose ganglion neurons (NGN) with vagal cardiac afferents were cultured for 1 day. Whole cell recordings were obtained and current-voltage relationships established. Cells were characterized by osmomechanical stress with a mannitol solution. Results: In CHF rats with intact renal nerves (nonDNX) formation of collagen I occurred, that was reduced after DNX (12.2+0.7 %area vs. 9.1+1.1 %area*, n=6, * p&lt;0.05). VE-induced RSNA decreases were impaired in CHF vs controls suggesting increased RSNA (-α 34+8% vs. -α[[Unable to Display Character: &amp;#61472;]]54+6% *, n=6, * p&lt;0.05). NGN from CHF exhibited altered conductance in response to mechanical stress as compared to controls (change in holding current at -80 mV: control_normoosmotic: -144±30 pA; control_hypoos.: -282±34 pA vs CHF_normosmotic: - 230±55 pA; CHF_hypos.: -540±100* pA; *p&lt;0.05 CHF vs. control). Conclusion: CHF induced subtle renal structural damage due to increased renal sympathetic tone which was likely due to altered NGN mechanosensitivity. Afferent nerve units from cardiovascular organs obviously form a complex sympathomodulatory network.

Activation of intestinal spinal afferent endings by changes in intra-mesenteric arterial pressure.

A major class of mechano-nociceptors to the intestine have mechanotransduction sites on extramural and intramural arteries and arterioles ('vascular afferents'). These sensory neurons can be activated by compression or axial stretch of vessels. Using isolated preparations we showed that increasing intra-arterial pressure, within the physiological range, activated mechano-nociceptors on vessels in intact mesenteric arcades, but not in isolated arteries. This suggests that distortion of the branching vascular tree is the mechanical adequate stimulus for these sensory neurons, rather than simple distension. The same rises in pressure also activated intestinal peristalsis in a partially capsaicin-sensitive manner indicating that pressure-sensitive vascular afferents influence enteric circuits. The results identify the mechanical adequate stimulus for a major class of mechano-nociceptors with endings on blood vessels supplying the gut wall; these afferents have similar endings to ones supplying other viscera, striated muscle and dural vessels. Spinal sensory neurons innervate many large blood vessels throughout the body. Their activation causes the hallmarks of neurogenic inflammation: vasodilatation through the release of the neuropeptide calcitonin gene-related peptide and plasma extravasation via tachykinins. The same vasodilator afferent neurons show mechanical sensitivity, responding to crushing, compression or axial stretch of blood vessels - responses which activate pain pathways and which can be modified by cell damage and inflammation. In the present study, we tested whether spinal afferent axons ending on branching mesenteric arteries ('vascular afferents') are sensitive to increased intravascular pressure. From a holding pressure of 5mmHg, distension to 20, 40, 60 or 80mmHg caused graded, slowly adapting increases in firing of vascular afferents. Many of the same afferent units showed responses to axial stretch, which summed with responses evoked by raised pressure. Many vascular afferents were also sensitive to raised temperature, capsaicin and/or local compression with von Frey hairs. However, responses to raised pressure in single, isolated vessels were negligible, suggesting that the adequate stimulus is distortion of the arterial arcade rather than distension per se. Increasing arterial pressure often triggered peristaltic contractions in the neighbouring segment of intestine, an effect that was mimicked by acute exposure to capsaicin (1μm) and which was reduced after desensitisation to capsaicin. These results indicate that sensory fibres with perivascular endings are sensitive to pressure-induced distortion of branched arteries, in addition to compression and axial stretch, and that they contribute functional inputs to enteric motor circuits.

Types of skin afferent fibers and spinal opioid receptors that contribute to touch-induced inhibition of heart rate changes evoked by noxious cutaneous heat stimulation.

BackgroundIn anesthetized rats and conscious humans, a gentle touch using a soft disc covered with microcones (with a texture similar to that of a finger), but not with a flat disc, inhibits nociceptive somatocardiac reflexes. Such an inhibitory effect is most reliably evoked when touch is applied to the skin ipsilateral and closest to nociceptive inputs. However, the mechanism of this inhibition is not completely elucidated. We aimed to clarify the types of cutaneous afferent fibers and spinal opioid receptors that contribute to antinociceptive effects of microcone touch.ResultsThe present study comprised two experiments with urethane-anesthetized rats. In the first experiment, unitary activity of skin afferent fibers was recorded from the saphenous nerve, and responses to a 10-min touch using a microcone disc and a flat disc (control) were compared. Greater discharge rate during microcone touch was observed in low-threshold mechanoreceptive Aδ and C afferent units, whereas many Aβ afferents responded similarly to the two types of touch. In the second experiment, the effect of an intrathecal injection of opioid receptor antagonists on the inhibitory effects of microcone touch on heart rate responses to noxious heat stimulation was examined. The magnitude of the heart rate response was significantly reduced by microcone touch in rats that received saline or naltrindole (δ-opioid receptor antagonist) injections. However, such an inhibition was not observed in rats that received naloxone (non-selective opioid receptor antagonist) or Phe-Cys-Tyr-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; μ-opioid receptor antagonist) injections.ConclusionsMicrocone touch induced greater responses of low-threshold mechanoreceptive Aδ and C afferent units than control touch. The antinociceptive effect of microcone touch was abolished by intrathecal injection of μ-opioid receptor antagonist. These results suggest that excitation of low-threshold mechanoreceptive Aδ and C afferents produces the release of endogenous μ-opioid ligands in the spinal cord, resulting in the inhibition of nociceptive transmission that contributes to somatocardiac reflexes.

Discriminative and affective touch: sensing and feeling.

The multimodal properties of the human somatosensory system continue to be unravelled. There is mounting evidence that one of these submodalities-touch-has another dimension, providing not only its well-recognized discriminative input to the brain, but also an affective input. It has long been recognized that touch plays an important role in many forms of social communication and a number of theories have been proposed to explain observations and beliefs about the "power of touch." Here, we propose that a class of low-threshold mechanosensitive C fibers that innervate the hairy skin represent the neurobiological substrate for the affective and rewarding properties of touch.

Tactile sensory system: encoding from the periphery to the cortex

Specialized mechanoreceptors in the skin respond to mechanical deformation and provide the primary input to the tactile sensory system. Although the morphology of these receptors has been documented, there is still considerable uncertainty as to the relation between cutaneous receptor morphology and the associated physiological responses to stimulation. Labelled-line models of somatosensory processes in which specific mechanoreceptors are associated with particular sensory qualities fail to account for the evidence showing that all types of tactile afferent units respond to a varying extent to most types of natural stimuli. Neurophysiological and psychophysical experiments have provided the framework for determining the relation between peripheral afferent or cortical activity and tactile perception. Neural codes derived from these afferent signals are evaluated in terms of their capacity to predict human perceptual performance. One particular challenge in developing models of the tactile sensory system is the dual use of sensory signals from the skin. In addition to their perceptual function they serve as inputs to the sensorimotor control system involved in manipulation. Perceptions generated through active touch differ from those resulting from passive stimulation of the skin because they are the product of self-generated exploratory processes. Recent research in this area has highlighted the importance of shear forces in these exploratory movements and has shown that fingertip skin is particularly sensitive to shear generated during both object manipulation and tactile exploration.

Stomatin‐domain protein interactions with acid‐sensing ion channels modulate nociceptor mechanosensitivity

Acid-sensing ion channels (ASICs) and their interaction partners of the stomatin family have all been implicated in sensory transduction. Single gene deletion of asic3, asic2, stomatin, or stoml3 all result in deficits in the mechanosensitivity of distinct cutaneous afferents in the mouse. Here, we generated asic3−/−:stomatin−/−, asic3−/−:stoml3−/− and asic2−/−:stomatin−/− double mutant mice to characterize the functional consequences of stomatin–ASIC protein interactions on sensory afferent mechanosensitivity. The absence of ASIC3 led to a clear increase in mechanosensitivity in rapidly adapting mechanoreceptors (RAMs) and a decrease in the mechanosensitivity in both Aδ- and C-fibre nociceptors. The increased mechanosensitivity of RAMs could be accounted for by a loss of adaptation which could be mimicked by local application of APETx2 a toxin that specifically blocks ASIC3. There is a substantial loss of mechanosensitivity in stoml3−/− mice in which ∼35% of the myelinated fibres lack a mechanosensitive receptive field and this phenotype was found to be identical in asic3−/−:stoml3−/− mutant mice. However, Aδ-nociceptors showed much reduced mechanosensitivity in asic3−/−:stoml3−/− mutant mice compared to asic3−/− controls. Interestingly, in asic2−/−:stomatin−/− mutant mice many Aδ-nociceptors completely lost their mechanosensitivity which was not observed in asic2−/− or stomatin−/− mice. Examination of stomatin−/−:stoml3−/− mutant mice indicated that a stomatin/STOML3 interaction is unlikely to account for the greater Aδ-nociceptor deficits in double mutant mice. A key finding from these studies is that the loss of stomatin or STOML3 in asic3−/− or asic2−/− mutant mice markedly exacerbates deficits in the mechanosensitivity of nociceptors without affecting mechanoreceptor function.

OnabotulinumtoxinA significantly attenuates bladder afferent nerve firing and inhibits ATP release from the urothelium

To investigate the direct effect of onabotulinumtoxinA (OnaBotA) on bladder afferent nerve activity and release of ATP and acetylcholine (ACh) from the urothelium. Bladder afferent nerve activity was recorded using an in vitro mouse preparation enabling simultaneous recordings of afferent nerve firing and intravesical pressure during bladder distension. Intraluminal and extraluminal ATP, ACh, and nitric oxide (NO) release were measured using the luciferin-luciferase and Amplex(®) Red assays (Molecular Probes, Carlsbad, CA, USA), and fluorometric assay kit, respectively. OnaBotA (2U), was applied intraluminally, during bladder distension, and its effect was monitored for 2 h after application. Whole-nerve activity was analysed to classify the single afferent units responding to physiological (low-threshold [LT] afferent <15 mmHg) and supra-physiological (high-threshold [HT] afferent >15 mmHg) distension pressures. Bladder distension evoked reproducible pressure-dependent increases in afferent nerve firing. After exposure to OnaBotA, both LT and HT afferent units were significantly attenuated. OnaBotA also significantly inhibited ATP release from the urothelium and increased NO release. These data indicate that OnaBotA attenuates the bladder afferent nerves involved in micturition and bladder sensation, suggesting that OnaBotA may exert its clinical effects on urinary urgency and the other symptoms of overactive bladder syndrome through its marked effect on afferent nerves.

Investigation of VHI Affected by the Density of Mechanoreceptive units for Virtual Sensation

Abstract The velvet hand illusion (VHI) is an innovative tactile illusion that enables a human to perceive a velvety sensation by gently rubbing the hands on both sides of wire mesh string through a frame. In order to enhance tactile displays presentation ability, VHI’s mechanism is applied through a series of psychophysical experiments. In this paper, we have investigated the effects of several physical parameters on intensity variation of VHI in subjects’ fingers and fingertips, such as wire distance D and a dimensionless ratio of wire stroke r to wire distance r/D in passive touch based on psychophysical experiment. We obtain D = 45 mm and r/D ≈ 1 as optimum values for VHI intensity for wire distance and the ratio, respectively. Furthermore, as the result of comparison between the present result and the previous result for palm, we conclude that a combination of mechanoreceptive afferent units, SAI, SAII and FAI, are involved in VHI. VHI mechanism is induced when movement of wires is accepted through FAI under constant compressive stimulus for SAI and no shearing force for SAII. This result indicates that VHI can be generated by normal pin matrix type tactile displays because no stimulation of SAII is required.

Differential Effects of Peripheral Vibration on Motor-Evoked Potentials in Acute Stages of Stroke

The excitability of sensorimotor cortex and spinal motoneurones can be modulated by afferent signals arising from the periphery. Low- and high-frequency vibrations activate separate classes of afferent units in the periphery. Low-frequency vibrations (2-100 Hz) activate the type I fast adapting afferent units (FA-I), whereas high-frequency vibrations (60-1000 Hz) preferentially activate the type II units (FA-II). Muscle spindles are also sensitive to high-frequency mechanical vibrations. Motor-evoked potentials (MEP) generated in response to transcranial magnetic stimulation (TMS) can be modulated by afferent signals. However, it is not clear whether these interactions take place at cortical or spinal cord levels. Cerebrovascular attacks resulting in stroke generally affect both sensory and motor systems. In eight stroke patients with partial motor deficit in the first two weeks of the incident we studies the effects of low- (30 Hz) and high- (130 Hz) frequency mechanical vibrations on the MEPs obtained in response to TMS. Recordings from the abductor digiti minimi muscle were carried out by TMS of both lesioned and intact hemispheres. Six patients were tested again four to eight weeks after the initial assessment. The results also were compared with data obtained from eight control subjects. MEPs were evoked by 50% above threshold intensities and for each testing condition initially five control MEPs were recorded. This was followed by consecutive MEPs obtained during vibration (N= 5) and between vibrations (N= 5), and the traces were averaged and analyzed. In normal subjects both low- (30 Hz) and high- (130 Hz) frequency vibration resulted in shortening of MEP latencies. In patients, there was a similar effect on the affected side with 30 Hz, but not with 130 Hz. Stimulation of the intact hemisphere during high-frequency vibration in the second test revealed a latency shortening, which could be due to central reorganization. The amplitude of MEPs showed a stronger facilitation in the presence of low-frequency vibration in the early stage of stroke compared with normal subjects. However, in the second test the level of facilitation was reduced, indicating an effect at the cortical level. The results suggest that a cerebrovascular accident influences the modulatory effects of afferent inputs at both spinal and cortical levels, and in time, as reorganization takes place, these altered influences settle towards normal levels.

Site of stimulation effects on the prevalence of the tactile motion aftereffect

The motion aftereffect (MAE) refers to the apparent motion of a stationary stimulus following adaptation to a continuously moving stimulus. There is a growing consensus that the fast adapting (FA) rather than the slowly adapting (SA) afferent units mediate the tactile version of the MAE. The present study investigated which FA units underlie the tactile MAE by measuring its prevalence, duration, and vividness on different skin areas that vary in their composition of FA units. Specifically, the right cheek, volar surface of the forearm, and volar surface of the hand were adapted using a ridged cylindrical drum, which rotated at 60 rpm for 120 s. Although there was no difference in duration or vividness between the skin surfaces tested, the tactile MAE was reported twice as often on the hand compared to the cheek and forearm, which did not differ significantly from one another. This suggests that the FA I units in the glabrous skin and the hair follicle and/or the FA I and field units in the hairy skin contribute to the tactile MAE.

Bradykinin and thromboxane A2reciprocally interact to synergistically stimulate cardiac spinal afferents during myocardial ischemia

Myocardial ischemia is a complex process leading to the simultaneous release of a number of mediators, including thromboxane A(2) (TxA(2)) and bradykinin (BK), that activate cardiac spinal afferents. The present study tested the hypothesis that TxA(2) and BK reciprocally interact to excite ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) of anesthetized cats. Fifty-two ischemically sensitive afferents (conduction velocity = 0.27-3.35 m/s, 7 Adelta-fibers and 45 C-fibers) were identified. Repeated injections (1 microg) of BK into the left atrium (LA) 4 min after the administration of U-46619 (5 microg into the LA), a TxA(2) mimetic, induced a significantly larger cardiac afferent response than the first response to BK (0.61 +/- 0.14 to 1.95 +/- 0.29 vs. 0.66 +/- 0.09 to 2.75 +/- 0.34 impulses/s, first injection vs. second injection, n = 8). Conversely, blockade of TxA(2) receptors with BM-13,177 (30 mg/kg iv) attenuated the responses of eight other afferents to BK (1 microg into the LA) by 45%. In contrast, repeated BK (1 microg into the LA) induced consistent discharge activity in six separate afferents. We then observed that the coadministration of U-46619 (5 microg) and BK (1 microg into the LA) together caused a total response that was significantly higher than the predicted response by the simple addition of the individual responses. BK (1 microg) facilitated eight cardiac afferent responses to U-46619 (5 microg into the LA) by 64%. In contrast, repeated U-46619 (5 microg into the LA) without intervening BK stimulation evoked consistent responses in seven other ischemically sensitive afferents. Finally, inhibition of cyclooxygenase with indomethacin (5 mg/kg iv) eliminated the potentiating effects of BK on the cardiac afferent response to U-46619 (5 microg into the LA) but did not alter the afferent response to U-46619. These data suggest that BK and TxA(2) reciprocally interact to stimulate ischemically sensitive cardiac afferent endings leading to synergistic afferent responses and that the BK sensitization effect is mediated by cyclooxygenase products.

Reactive oxygen species activate the group IV muscle afferents in resting and exercising muscle in rats

We tested the hypothesis that the reactive oxygen species (ROS) produced at rest and mostly during muscle contraction may stimulate the group IV muscle afferents. In rats, afferent activity was recorded in the peroneal nerve innervating the tibialis anterior muscle. Group IV afferents were identified from measurements of their conduction velocity and response to lactic acid. Comparing the group IV response to an intramuscular injection of buffered isotonic NaCl solution, we searched for the effects of a ROS donor (H2O2) or a ROS inhibitor (superoxide dismutase, SOD) on the baseline afferent activity in resting muscles. We also explored the consequences of a pre-treatment with SOD on the afferent nerve response to H2O2 injection or electrical muscle stimulation (MS). In other animals, we measured the changes in intramuscular level of a marker of oxidative stress (isoprostanes) after each test agent. H2O2 injection markedly activated all recorded group IV afferents. SOD injection lowered the baseline activity of 50 out of 70 afferent units, suppressed the afferent response to H2O2 injection, and delayed and reduced the MS-induced activation of all recorded units. Intramuscular isoprostanes level significantly increased after H2O2 injection or MS, the oxidative stress being absent in muscles pre-treated with SOD. We concluded that ROS influence both the spontaneous and contraction-induced activities of the group IV muscle afferents and are a potent stimulus of muscle metaboreceptors.

Facilitatory Interactions between 5‐HT and Thromboxane A2 in Stimulation of Ischemically Sensitive Cardiac Sympathetic Afferents

We have demonstrated that the endogenously produced mediators serotonin (5‐HT) and thromboxane A2 (TxA2) contribute to activation of cardiac afferents during ischemia. In the present study we hypothesized facilitatory interactions between these two metabolites in stimulation of cardiac afferents during ischemia. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T2 ‐ T5) of anesthetized cats. Twenty ischemically sensitive afferents (CV= 0.28 ‐ 3.62 m/s, 4 Ad‐ and 16 C‐fibers) were identified. We observed that a repeat injection of 5‐HT (40 μg/kg) into left atrium (LA), 4 min after LA 2.5 μg of U46619, a TxA2 mimetic, induced a significantly larger cardiac afferent response than the first 5‐HT response (0.46±0.08 to 1.06±0.11 vs.0.45±0.13 to 1.90±0.18 imp/s, first vs. second injection, n=3). In a control group, repeated 5‐HT (40 μg/kg, LA) evoked consistent responses in three other ischemically sensitive afferents. Furthermore, LA administration of 5‐HT (40 μg/kg) and U46619 (2.5 μg) caused a larger response than simple addition of the individual responses (n=5). Additionally, the responses of three cardiac afferents to repeat U46619 (2.5 μg, LA) were enhanced compared with the U46619 response before 5‐HT, while the responses of three other cardiac afferents to repeated U46619 stimulation were consistent. Finally, blockade of the 5‐HT3 receptors with tropisetron (200 μg/kg, iv) attenuated the responses of three cardiac afferent to U46619 (2.5 μg, LA) by 52%. These preliminary data suggest that 5‐HT and TxA2 each facilitate the responses of ischemically sensitive cardiac afferent endings to the actions of other metabolite (Supported by NIH HL66217).