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Taste cells are a heterogeneous population of sensory receptors that undergo continuous turnover. Different chemo‐sensitive cell lines rely on action potentials to release the neurotransmitter onto nerve endings. The electrical excitability is due to the presence of a tetrodotoxin‐sensitive, voltage‐gated sodium current (INa) similar to that found in neurons. Since the biophysical properties of neuronal INa change during development, we wondered whether the same also occurred in taste cells. Here, we used the patch‐clamp recording technique to study INa in salt‐sensing cells (sodium cells) of rat fungiform papillae. We identified these cells by exploiting the known blocking effect of amiloride on ENaC, the sodium (salt) receptor. Based on the amplitude of INa, which is known to increase during development, we subdivided sodium cells into two groups: cells with small sodium current (SSC cells; INa < 1 nA) and cells with large sodium current (LSC cells; INa > 1 nA). We found that: the voltage dependence of activation and inactivation significantly differed between these subsets; a slowly inactivating sodium current was more prominent in LSC cells; membrane capacitance in SSC cells was larger than in LSC cells. mRNA expression analysis of the α‐subunits of voltage‐gated sodium channels in fungiform taste buds supported the functional data. Lucifer Yellow labelling of recorded cells revealed that our electrophysiological criterion for distinguishing two broad groups of taste cells was in good agreement with morphological observations for cell maturity. Thus, all these findings are consistent with developmental changes in the voltage‐dependent properties of sodium‐taste cells. Key points: Taste cells are sensory receptors that undergo continuous turnover while they detect food chemicals and communicate with afferent nerve fibres.The voltage‐gated sodium current (INa) is a key ion current for generating action potentials in fully differentiated and chemo‐sensitive taste cells, which use electrical signalling to release neurotransmitters.Here we show that, during the maturation of rat taste cells involved in salt detection (sodium cells), the biophysical properties of INa, such as voltage dependence of activation and inactivation, change significantly.Our results help reveal how taste cells gain electrical excitability during turnover, a property critical to their operation as chemical detectors that relay sensory information to nerve fibres. [ABSTRACT FROM AUTHOR]

Key points: Age‐related hearing loss is a progressive hearing loss involving environmental and genetic factors, leading to a decrease in hearing sensitivity, threshold and speech discrimination.We compared age‐related changes in inner hair cells (IHCs) between four mouse strains with different levels of progressive hearing loss.The surface area of apical coil IHCs (9–12 kHz cochlear region) decreases by about 30–40% with age.The number of BK channels progressively decreases with age in the IHCs from most mouse strains, but the basolateral membrane current profile remains unchanged.The mechanoelectrical transducer current is smaller in mice harbouring the hypomorphic Cdh23 allele Cdh23ahl (C57BL/6J; C57BL/6NTac), but not in Cdh23‐repaired mice (C57BL/6NTacCdh23+), indicating that it could contribute to the different progression of hearing loss among mouse strains.The degree of efferent rewiring onto aged IHCs, most likely coming from the lateral olivocochlea fibres, was correlated with hearing loss in the different mouse strains. Inner hair cells (IHCs) are the primary sensory receptors of the mammalian cochlea, transducing acoustic information into electrical signals that are relayed to the afferent neurons. Functional changes in IHCs are a potential cause of age‐related hearing loss. Here, we have investigated the functional characteristics of IHCs from early‐onset hearing loss mice harbouring the allele Cdh23ahl (C57BL/6J and C57BL/6NTac), from late‐onset hearing loss mice (C3H/HeJ), and from mice corrected for the Cdh23ahl mutation (C57BL/6NTacCdh23+) with an intermediate hearing phenotype. There was no significant loss of IHCs in the 9–12 kHz cochlear region up to at least 15 months of age, but their surface area decreased progressively by 30–40% starting from ∼6 months of age. Although the size of the BK current decreased with age, IHCs retained a normal KCNQ4 current and resting membrane potential. These basolateral membrane changes were most severe for C57BL/6J and C57BL/6NTac, less so for C57BL/6NTacCdh23+ and minimal or absent in C3H/HeJ mice. We also found that lateral olivocochlear (LOC) efferent fibres re‐form functional axon‐somatic connections with aged IHCs, but this was seen only sporadically in C3H/HeJ mice. The efferent post‐synaptic SK2 channels appear prior to the establishment of the efferent contacts, suggesting that IHCs may play a direct role in re‐establishing the LOC‐IHC synapses. Finally, we showed that the size of the mechanoelectrical transducer (MET) current from IHCs decreased significantly with age in mice harbouring the Cdh23ahl allele but not in C57BL/6NTacCdh23+mice, indicating that the MET apparatus directly contributes to the progression of age‐related hearing loss. Key points: Age‐related hearing loss is a progressive hearing loss involving environmental and genetic factors, leading to a decrease in hearing sensitivity, threshold and speech discrimination.We compared age‐related changes in inner hair cells (IHCs) between four mouse strains with different levels of progressive hearing loss.The surface area of apical coil IHCs (9–12 kHz cochlear region) decreases by about 30–40% with age.The number of BK channels progressively decreases with age in the IHCs from most mouse strains, but the basolateral membrane current profile remains unchanged.The mechanoelectrical transducer current is smaller in mice harbouring the hypomorphic Cdh23 allele Cdh23ahl (C57BL/6J; C57BL/6NTac), but not in Cdh23‐repaired mice (C57BL/6NTacCdh23+), indicating that it could contribute to the different progression of hearing loss among mouse strains.The degree of efferent rewiring onto aged IHCs, most likely coming from the lateral olivocochlea fibres, was correlated with hearing loss in the different mouse strains. [ABSTRACT FROM AUTHOR]

Key points: Age‐related hearing loss (ARHL) is a very heterogeneous disease, resulting from cellular senescence, genetic predisposition and environmental factors (e.g. noise exposure).Currently, we know very little about age‐related changes occurring in the auditory sensory cells, including those associated with the outer hair cells (OHCs).Using different mouse strains, we show that OHCs undergo several morphological and biophysical changes in the ageing cochlea.Ageing OHCs also exhibited the progressive loss of afferent and efferent synapses.We also provide evidence that the size of the mechanoelectrical transducer current is reduced in ageing OHCs, highlighting its possible contribution in cochlear ageing. Outer hair cells (OHCs) are electromotile sensory receptors that provide sound amplification within the mammalian cochlea. Although OHCs appear susceptible to ageing, the progression of the pathophysiological changes in these cells is still poorly understood. By using mouse strains with a different progression of hearing loss (C57BL/6J, C57BL/6NTac, C57BL/6NTacCdh23+, C3H/HeJ), we have identified morphological, physiological and molecular changes in ageing OHCs (9–12 kHz cochlear region). We show that by 6 months of age, OHCs from all strains underwent a reduction in surface area, which was not a sign of degeneration. Although the ageing OHCs retained a normal basolateral membrane protein profile, they showed a reduction in the size of the K+ current and non‐linear capacitance, a readout of prestin‐dependent electromotility. Despite these changes, OHCs have a normal Vm and retain the ability to amplify sound, as distortion product otoacoustic emission thresholds were not affected in aged, good‐hearing mice (C3H/HeJ, C57BL/6NTacCdh23+). The loss of afferent synapses was present in all strains at 15 months. The number of efferent synapses per OHCs, defined as postsynaptic SK2 puncta, was reduced in aged OHCs of all strains apart from C3H mice. Several of the identified changes occurred in aged OHCs from all mouse strains, thus representing a general trait in the pathophysiological progression of age‐related hearing loss, possibly aimed at preserving functionality. We have also shown that the mechanoelectrical transduction (MET) current from OHCs of mice harbouring the Cdh23ahl allele is reduced with age, highlighting the possibility that changes in the MET apparatus could play a role in cochlear ageing. Key points: Age‐related hearing loss (ARHL) is a very heterogeneous disease, resulting from cellular senescence, genetic predisposition and environmental factors (e.g. noise exposure).Currently, we know very little about age‐related changes occurring in the auditory sensory cells, including those associated with the outer hair cells (OHCs).Using different mouse strains, we show that OHCs undergo several morphological and biophysical changes in the ageing cochlea.Ageing OHCs also exhibited the progressive loss of afferent and efferent synapses.We also provide evidence that the size of the mechanoelectrical transducer current is reduced in ageing OHCs, highlighting its possible contribution in cochlear ageing. [ABSTRACT FROM AUTHOR]

Key points: Outer hair cells (OHCs) enhance the sensitivity and the frequency tuning of the mammalian cochlea.Similar to the primary sensory receptor, the inner hair cells (IHCs), the mature functional characteristics of OHCs are acquired before hearing onset.We found that OHCs, like IHCs, fire spontaneous Ca2+‐induced action potentials (APs) during immature stages of development, which are driven by CaV1.3 Ca2+ channels.We also showed that the development of low‐ and high‐frequency hair cells is differentially regulated during pre‐hearing stages, with the former cells being more strongly dependent on experience‐independent Ca2+ action potential activity. Sound amplification within the mammalian cochlea depends upon specialized hair cells, the outer hair cells (OHCs), which possess both sensory and motile capabilities. In various altricial rodents, OHCs become functionally competent from around postnatal day 7 (P7), before the primary sensory inner hair cells (IHCs), which become competent at about the onset of hearing (P12). The mechanisms responsible for the maturation of OHCs and their synaptic specialization remain poorly understood. We report that spontaneous Ca2+ activity in the immature cochlea, which is generated by CaV1.3 Ca2+ channels, differentially regulates the maturation of hair cells along the cochlea. Under near‐physiological recording conditions we found that, similar to IHCs, immature OHCs elicited spontaneous Ca2+ action potentials (APs), but only during the first few postnatal days. Genetic ablation of these APs in vivo, using CaV1.3−/− mice, prevented the normal developmental acquisition of mature‐like basolateral membrane currents in low‐frequency (apical) hair cells, such as IK,n (carried by KCNQ4 channels), ISK2 and IACh (α9α10nAChRs) in OHCs and IK,n and IK,f (BK channels) in IHCs. Electromotility and prestin expression in OHCs were normal in CaV1.3−/− mice. The maturation of high‐frequency (basal) hair cells was also affected in CaV1.3−/− mice, but to a much lesser extent than apical cells. However, a characteristic feature in CaV1.3−/− mice was the reduced hair cell size irrespective of their cochlear location. We conclude that the development of low‐ and high‐frequency hair cells is differentially regulated during development, with apical cells being more strongly dependent on experience‐independent Ca2+ APs. Key points: Outer hair cells (OHCs) enhance the sensitivity and the frequency tuning of the mammalian cochlea.Similar to the primary sensory receptor, the inner hair cells (IHCs), the mature functional characteristics of OHCs are acquired before hearing onset.We found that OHCs, like IHCs, fire spontaneous Ca2+‐induced action potentials (APs) during immature stages of development, which are driven by CaV1.3 Ca2+ channels.We also showed that the development of low‐ and high‐frequency hair cells is differentially regulated during pre‐hearing stages, with the former cells being more strongly dependent on experience‐independent Ca2+ action potential activity. [ABSTRACT FROM AUTHOR]

Key points: An ex vivo preparation was developed to record from single sensory fibres innervating the glabrous skin of the mouse forepaw.The density of mechanoreceptor innervation of the forepaw glabrous skin was found to be three times higher than that of hindpaw glabrous skin.Rapidly adapting mechanoreceptors that innervate Meissner's corpuscles were severalfold more responsive to slowly moving stimuli in the forepaw compared to those innervating hindpaw skin.We found a distinct group of small hairs in the centre of the mouse hindpaw glabrous skin that were exclusively innervated by directionally sensitive D‐hair receptors.The directional sensitivity, but not the end‐organ anatomy, were the opposite to D‐hair receptors in the hairy skin.Glabrous skin hairs in the hindpaw are not ubiquitous in rodents, but occur in African and North American species that diverged more than 65 million years ago. Rodents use their forepaws to actively interact with their tactile environment. Studies on the physiology and anatomy of glabrous skin that makes up the majority of the forepaw are almost non‐existent in the mouse. Here we developed a preparation to record from single sensory fibres of the forepaw and compared anatomical and physiological receptor properties to those of the hindpaw glabrous and hairy skin. We found that the mouse forepaw skin is equipped with a very high density of mechanoreceptors; >3 times more than hindpaw glabrous skin. In addition, rapidly adapting mechanoreceptors that innervate Meissner's corpuscles of the forepaw were severalfold more sensitive to slowly moving mechanical stimuli compared to their counterparts in the hindpaw glabrous skin. All other mechanoreceptor types as well as myelinated nociceptors had physiological properties that were invariant regardless of which skin area they occupied. We discovered a novel D‐hair receptor innervating a small group of hairs in the middle of the hindpaw glabrous skin in mice. These glabrous skin D‐hair receptors were direction sensitive albeit with an orientation sensitivity opposite to that described for hairy skin D‐hair receptors. Glabrous skin hairs do not occur in all rodents, but are present in North American and African rodent species that diverged more than 65 million years ago. The function of these specialized hairs is unknown, but they are nevertheless evolutionarily very ancient. Our study reveals novel physiological specializations of mechanoreceptors in the glabrous skin that likely evolved to facilitate tactile exploration. Key points: An ex vivo preparation was developed to record from single sensory fibres innervating the glabrous skin of the mouse forepaw.The density of mechanoreceptor innervation of the forepaw glabrous skin was found to be three times higher than that of hindpaw glabrous skin.Rapidly adapting mechanoreceptors that innervate Meissner's corpuscles were severalfold more responsive to slowly moving stimuli in the forepaw compared to those innervating hindpaw skin.We found a distinct group of small hairs in the centre of the mouse hindpaw glabrous skin that were exclusively innervated by directionally sensitive D‐hair receptors.The directional sensitivity, but not the end‐organ anatomy, were the opposite to D‐hair receptors in the hairy skin.Glabrous skin hairs in the hindpaw are not ubiquitous in rodents, but occur in African and North American species that diverged more than 65 million years ago. [ABSTRACT FROM AUTHOR]

Key points Vestibular type I and type II hair cells and their afferent fibres send information to the brain regarding the position and movement of the head., The characteristic feature of type I hair cells is the expression of a low-voltage-activated outward rectifying K+ current, IK,L, whose biophysical properties and molecular identity are still largely unknown., In vitro, the afferent nerve calyx surrounding type I hair cells causes unstable intercellular K+ concentrations, altering the biophysical properties of IK,L., We found that in the absence of the calyx, IK,L in type I hair cells exhibited unique biophysical activation properties, which were faithfully reproduced by an allosteric channel gating scheme., These results form the basis for a molecular and pharmacological identification of IK,L., Abstract Type I and type II hair cells are the sensory receptors of the mammalian vestibular epithelia. Type I hair cells are characterized by their basolateral membrane being enveloped in a single large afferent nerve terminal, named the calyx, and by the expression of a low-voltage-activated outward rectifying K+ current, IK,L. The biophysical properties and molecular profile of IK,L are still largely unknown. By using the patch-clamp whole-cell technique, we examined the voltage- and time-dependent properties of IK,L in type I hair cells of the mouse semicircular canal. We found that the biophysical properties of IK,L were affected by an unstable K+ equilibrium potential ( VeqK+). Both the outward and inward K+ currents shifted VeqK+ consistent with K+ accumulation or depletion, respectively, in the extracellular space, which we attributed to a residual calyx attached to the basolateral membrane of the hair cells. We therefore optimized the hair cell dissociation protocol in order to isolate mature type I hair cells without their calyx. In these cells, the uncontaminated IK,L showed a half-activation at -79.6 mV and a steep voltage dependence (2.8 mV). IK,L also showed complex activation and deactivation kinetics, which we faithfully reproduced by an allosteric channel gating scheme where the channel is able to open from all (five) closed states. The 'early' open states substantially contribute to IK,L activation at negative voltages. This study provides the first complete description of the 'native' biophysical properties of IK,L in adult mouse vestibular type I hair cells. [ABSTRACT FROM AUTHOR]

Chronic heart failure (CHF) is a major public health problem. Tonic hyper-activation of sympathetic neural outflow is commonly observed in patients with CHF. Importantly, sympatho-excitation in CHF exacerbates its progression and is strongly related to poor prognosis and high mortality risk. Increases in both peripheral and central chemoreflex drive are considered markers of the severity of CHF. The principal peripheral chemoreceptors are the carotid bodies (CBs) and alteration in their function has been described in CHF. Mainly, during CHF the CB chemosensitivity is enhanced leading to increases in ventilation and sympathetic outflow. In addition to peripheral control of breathing, central chemoreceptors (CCs) are considered a dominant mechanism in ventilatory regulation. Potentiation of the ventilatory and sympathetic drive in response to CC activation has been shown in patients with CHF as well as in animal models. Therefore, improving understanding of the contribution of the peripheral and central chemoreflexes to augmented sympathetic discharge in CHF could help in developing new therapeutic approaches intended to attenuate the progression of CHF. Accordingly, the main focus of this review is to discuss recent evidence that peripheral and central chemoreflex function are altered in CHF and that they contribute to autonomic imbalance and progression of CHF. [ABSTRACT FROM AUTHOR]

Key points Remarkably little is known about how age affects the sensory signalling pathways in the gastrointestinal tract despite age-related gastrointestinal dysfunction being a prime cause of morbidity amongst the elderly population, High-threshold gastrointestinal sensory nerves play a key role in signalling distressing information from the gut to the brain., We found that ageing is associated with attenuated high-threshold afferent mechanosensitivity in the murine colon, and associated loss of TRPV1 channel function., These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease., Abstract Ageing has a profound effect upon gastrointestinal function through mechanisms that are poorly understood. Here we investigated the effect of age upon gastrointestinal sensory signalling pathways in order to address the mechanisms underlying these changes. In vitro mouse colonic and jejunal preparations with attached splanchnic and mesenteric nerves were used to study mechanosensory and chemosensory afferent function in 3-, 12- and 24-month-old C57BL/6 animals. Quantitative RT-PCR was used to investigate mRNA expression in colonic tissue and dorsal root ganglion (DRG) cells isolated from 3- and 24-month animals, and immunohistochemistry was used to quantify the number of 5-HT-expressing enterochromaffin (EC) cells. Colonic and jejunal afferent mechanosensory function was attenuated with age and these effects appeared earlier in the colon compared to the jejunum. Colonic age-related loss of mechanosensory function was more pronounced in high-threshold afferents compared to low-threshold afferents. Chemosensory function was attenuated in the 24-month colon, affecting TRPV1 and serotonergic signalling pathways. High-threshold mechanosensory afferent fibres and small-diameter DRG neurons possessed lower functional TRPV1 receptor responses, which occurred without a change in TRPV1 mRNA expression. Serotonergic signalling was attenuated at 24 months, but TPH1 and TPH2 mRNA expression was elevated in colonic tissue. In conclusion, we saw an age-associated decrease in afferent mechanosensitivity in the mouse colon affecting HT units. These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. [ABSTRACT FROM AUTHOR]

Key points Position sense at the human forearm can be measured in blindfolded subjects by matching positions of the arms or by a subject pointing to the perceived position of an unseen arm., Effects on position sense tested were: elbow muscle conditioning with a voluntary contraction, muscle vibration, loading the arm and elbow skin stretch., Conditioning contractions and vibration produced errors in a matching task, consistent with the action of muscle spindles as position sensors. Position errors in a pointing task were not consistent with the action of muscle spindles. Loading the arm or skin stretch had no effect in either matching or pointing tasks., It is proposed that there are two kinds of position sense: (i) indicating positions of different body parts relative to one another, using signals from muscle spindles; and (ii) indicating position of the body in extrapersonal space, using signals from exteroceptors, vision, touch and hearing., Abstract Human limb position sense can be measured in two ways: in a blindfolded matching task, position of one limb is indicated with the other limb. Alternatively, position of a limb, hidden from view, is indicated with a pointer, moved by pressing a lever. These experiments examined the sensory basis of position sense measured in these two ways. Position errors were measured in 14 subjects after elbow flexors or extensors had been conditioned with a half-maximum voluntary contraction. In agreement with previous studies, in the matching trials, position errors were distributed according to a pattern consistent with the action of muscle spindles as the position sensors. In the pointing trials, all errors lay in the direction of extension of the true position of the hidden arm and their distribution was inconsistent with influences arising in muscle spindles. Vibration of elbow muscles produced an illusion of muscle lengthening during a matching task, while during the pointing task no illusion was present. Finally, the matching-pointing error difference was preserved, even when one arm was loaded with a weight or skin over the elbow was stretched. It is proposed that there are two kinds of position sense. One is signalled by muscle spindles, indicating position of one part of the body relative to another. A second provides information about the position of the body in extrapersonal space and here we hypothesise that exteroceptors, including vision, touch and hearing, acting via a central map of the body, provide the spatial information. [ABSTRACT FROM AUTHOR]

Key points Sensory information from the urethra is essential to maintain continence and to achieve efficient micturition and when compromised by disease or injury can lead to substantial loss of function., Despite the key role urethral sensory information plays in the lower urinary tract, the relationship between physiological urethral stimuli, such as fluid flow, and the neural sensory response is poorly understood., This work systematically quantifies pudendal afferent responses to a range of fluid flows in the urethra in vivo and describes a previously unknown long-term neural accommodation phenomenon in these afferents. We present a compact mechanistic mathematical model that reproduces the pudendal sensory activity in response to urethral flow., These results have implications for understanding urinary tract dysfunction caused by neuropathy or nerve damage, such as urinary retention or incontinence, as well as for the development of strategies to mitigate the symptoms of these conditions., Abstract The pudendal nerve carries sensory information from the urethra that controls spinal reflexes necessary to maintain continence and achieve efficient micturition. Despite the key role urethral sensory feedback plays in regulation of the lower urinary tract, there is little information about the characteristics of urethral sensory responses to physiological stimuli, and the quantitative relationship between physiological stimuli and the evoked sensory activation is unknown. Such a relation is critical to understanding the neural control of the lower urinary tract and how dysfunction arises in disease states. We systematically quantified pudendal afferent responses to fluid flow in the urethra in vivo in the rat. We characterized the sensory response across a range of stimuli, and describe a previously unreported long-term neural accommodation phenomenon. We developed and validated a compact mechanistic mathematical model capable of reproducing the pudendal sensory activity in response to arbitrary profiles of urethral flows. These results describe the properties and function of urethral afferents that are necessary to understand how sensory disruption manifests in lower urinary tract pathophysiology. [ABSTRACT FROM AUTHOR]

Key points Anterior and posterior cerebral circulations have differential reactivity to changes in arterial blood gases, but the implications for the chemoreflex control of breathing are unclear., Indomethacin-induced blunting of cerebrovascular flow responsiveness did not affect central or peripheral respiratory chemoreflex magnitude using steady-state end-tidal forcing techniques., Posterior reactivity was related to hypoxic ventilatory decline, suggesting that CO2 washout from central chemoreceptors modulates hypoxic ventilatory dynamics., Our data indicate that steady-state end-tidal forcing techniques reduce the arterial-venous gradients, attenuating the effect of brain blood flow on ventilatory responses., Our study confirms the importance of measuring posterior cerebrovasculature when investigating the link between cerebral blood flow and the chemical control of breathing., Abstract Cerebrovascular reactivity impacts CO2-[H+] washout at the central chemoreceptors and hence has marked influence on the control of ventilation. To date, the integration of cerebral blood flow (CBF) and ventilation has been investigated exclusively with measures of anterior CBF, which has a differential reactivity from the vertebrobasilar system and perfuses the brainstem. We hypothesized that: (1) posterior versus anterior CBF would have a stronger relationship to central chemoreflex magnitude during hypercapnia, and (2) that higher posterior reactivity would lead to a greater hypoxic ventilatory decline (HVD). End-tidal forcing was used to induce steady-state hyperoxic (300 mmHg [ABSTRACT FROM AUTHOR]

The experience of pain is strongly affected by descending control systems originating in the brainstem ventrolateral periaqueductal grey (VL-PAG), which control the spinal processing of nociceptive information. A- and C-fibre nociceptors detect noxious stimulation, and have distinct and independent contributions to both the perception of pain quality (fast and slow pain, respectively) and the development of chronic pain. Evidence suggests a separation in the central processing of information arising from A- vs. C-nociceptors; for example, inhibition of the cyclooxygenase-1 (COX-1)-prostaglandin system within the VL-PAG alters spinal nociceptive reflexes evoked by C-nociceptor input in vivo via descending pathways, leaving A-nociceptor-evoked reflexes largely unaffected. As the spinal neuronal mechanisms underlying these different responses remain unknown, we determined the effect of inhibition of VL-PAG COX-1 on dorsal horn wide dynamic-range neurons evoked by C- vs. A-nociceptor activation. Inhibition of VL-PAG COX-1 in anaesthetised rats increased firing thresholds of lamina IV-V wide dynamic-range dorsal horn neurons in response to both A- and C-nociceptor stimulation. Importantly, wide dynamic-range dorsal horn neurons continued to faithfully encode A-nociceptive information, even after VL-PAG COX-1 inhibition, whereas the encoding of C-nociceptor information by wide dynamic-range spinal neurons was significantly disrupted. Dorsal horn neurons with stronger C-nociceptor input were affected by COX-1 inhibition to a greater extent than those with weak C-fibre input. These data show that the gain and contrast of C-nociceptive information processed in individual wide dynamic-range dorsal horn neurons is modulated by prostanergic descending control mechanisms in the VL-PAG. [ABSTRACT FROM AUTHOR]

The Na+-Ca2+ exchanger (NCX) appears to play an important role in the regulation of the high K+-evoked Ca2+ transient in putative nociceptive dorsal root ganglion (DRG) neurons. The purpose of the present study was to (1) characterize the properties of NCX activity in subpopulations of DRG neurons, (2) identify the isoform(s) underlying NCX activity, and (3) begin to assess the function of the isoform(s) in vivo. In retrogradely labelled neurons from the glabrous skin of adult male Sprague-Dawley rats, NCX activity, as assessed with fura-2-based microfluorimetry, was only detected in putative nociceptive IB4+neurons. There were two modes of NCX activity: one was evoked in response to relatively large and long lasting (~325 nM for >12 s) increases in the concentration of intracellular Ca2+ ([Ca2+]i), and a second was active at resting [Ca2+]i > ~150 nM. There also were two modes of evoked activity: one that decayed relatively rapidly (<5 min) and a second that persisted (>10 min). Whereas mRNA encoding all three NCX isoforms (NCX1-3) was detected in putative nociceptive cutaneous neurons with single cell PCR, pharmacological analysis and small interfering RNA (siRNA) knockdown of each isoform in vivo suggested that NCX2 and 3 were responsible for NCX activity. We stern blot analyses suggested that NCX isoforms were differentially distributed within sensory neurons. Functional assays of excitability, action potential propagation, and nociceptive behaviour suggest NCX activity has little influence on excitability per se, but instead influences axonal conduction velocity, resting membrane potential, and nociceptive threshold. Together these results indicate that the function of NCX in the regulation of [Ca2+]i in putative nociceptive neurons may be unique relative to other cells in which these exchanger isoforms have been characterized and it has the potential to influence sensory neuron properties at multiple levels. [ABSTRACT FROM AUTHOR]

Key points When a blindfolded subject holds his or her arm at a particular angle, its reported position shifts over time; this is known as proprioceptive drift., Here, we show that in relation to position sense at the elbow, the direction of perceived shifts is consistent with adaptation in discharge levels of sensory receptors in elbow muscles., Raising or lowering receptor discharge levels by similar amounts in opposing muscles at the elbow using muscle conditioning abolishes proprioceptive drift, but large position errors may result., The present experiments provide an explanation for proprioceptive drift and indicate that, in a forearm position-matching task, the brain is not concerned with actual discharge levels from arm muscles, but with their difference., Abstract These experiments on the human forearm are based on the hypothesis that drift in the perceived position of a limb over time can be explained by receptor adaptation. Limb position sense was measured in 39 blindfolded subjects using a forearm-matching task. A property of muscle, its thixotropy, a contraction history-dependent passive stiffness, was exploited to place muscle receptors of elbow muscles in a defined state. After the arm had been held flexed and elbow flexors contracted, we observed time-dependent changes in the perceived position of the reference arm by an average of 2.8° in the direction of elbow flexion over 30 s (Experiment 1). The direction of the drift reversed after the arm had been extended and elbow extensors contracted, with a mean shift of 3.5° over 30 s in the direction of elbow extension (Experiment 2). The time-dependent changes could be abolished by conditioning elbow flexors and extensors in the reference arm at the test angle, although this led to large position errors during matching (±10°), depending on how the indicator arm had been conditioned (Experiments 3 and 4). When slack was introduced in the elbow muscles of both arms, by shortening muscles after the conditioning contraction, matching errors became small and there was no drift in position sense (Experiments 5 and 6). These experiments argue for a receptor-based mechanism for proprioceptive drift and suggest that to align the two forearms, the brain monitors the difference between the afferent signals from the two arms. [ABSTRACT FROM AUTHOR]

Key points Hypoxia activates peripheral chemoreceptors producing an increase in breathing and arterial pressure., In conditions of sustained hypoxia, an increase in ventilation and arterial blood pressure is observed that persists after the return to normoxia., We show in rats that sustained hypoxia for 24 h produces glutamate-dependent changes in the activity of expiratory and sympathetic neurones of the rostral ventrolateral medulla, which are essential for the control of respiratory and sympathetic activities., These neuronal changes induced by sustained hypoxia are critical for the emergence of coupled active expiration and augmented sympathetic activity., These findings contribute to a better understanding of cardiorespiratory adjustments associated with sustained hypoxia in individuals experiencing high altitudes., Abstract Individuals experiencing sustained hypoxia (SH) exhibit adjustments in the respiratory and autonomic functions by neural mechanisms not yet elucidated. In the present study we evaluated the central mechanisms underpinning the SH-induced changes in the respiratory pattern and their impact on the sympathetic outflow. Using a decerebrated arterially perfused in situ preparation, we verified that juvenile rats exposed to SH (10% O2) for 24 h presented an active expiratory pattern, with increased abdominal, hypoglossal and vagal activities during late-expiration (late-E). SH also enhanced the activity of augmenting-expiratory neurones and depressed the activity of post-inspiratory neurones of the Bötzinger complex (BötC) by mechanisms not related to changes in their intrinsic electrophysiological properties. SH rats exhibited high thoracic sympathetic activity and arterial pressure levels associated with an augmented firing frequency of pre-sympathetic neurones of the rostral ventrolateral medulla (RVLM) during the late-E phase. The antagonism of ionotropic glutamatergic receptors in the BötC/RVLM abolished the late-E bursts in expiratory and sympathetic outputs of SH rats, indicating that glutamatergic inputs to the BötC/RVLM are essential for the changes in the expiratory and sympathetic coupling observed in SH rats. We also observed that the usually silent late-E neurones of the retrotrapezoid nucleus/parafacial respiratory group became active in SH rats, suggesting that this neuronal population may provide the excitatory drive essential to the emergence of active expiration and sympathetic overactivity. We conclude that short-term SH induces the activation of medullary expiratory neurones, which affects the pattern of expiratory motor activity and its coupling with sympathetic activity. [ABSTRACT FROM AUTHOR]

Key points The carotid body (CB) is a key chemoreceptor organ that mediates the hyperventilatory response to hypoxia, and contributes to the process of acclimatisation to chronic hypoxaemia., Knowledge of CB physiology at the cellular and molecular levels has advanced considerably in recent times thanks to studies on lower mammals; however, information on humans is practically absent. Here we describe the properties of human CB cells in slice preparations or after enzymatic dispersion., Besides glomus (type I) and glia-like, sustentacular (type II) cells, adult human CBs contain nestin-positive neural progenitor cells. The human CB also expresses high levels of glial cell line-derived neurotrophic factor. These properties are maintained at an advanced age., Human glomus cells contain a relatively high density of voltage-dependent Na+, Ca2+ and K+ channels. Membrane depolarisation with high extracellular K+ induces an increase of cytosolic [Ca2+] and quantal catecholamine release., Human glomus cells are responsive to hypoxia and hypoglycaemia, both of which induce an increase in cytosolic [Ca2+] and transmitter release. Chemosensory responses of glomus cells are also preserved at an advanced age., These findings on the cellular and molecular physiology of the CB provide novel perspectives for the systematic study of pathologies involving this organ in humans., Abstract The carotid body (CB) is the major peripheral arterial chemoreceptor in mammals that mediates the acute hyperventilatory response to hypoxia. The CB grows in response to sustained hypoxia and also participates in acclimatisation to chronic hypoxaemia. Knowledge of CB physiology at the cellular level has increased considerably in recent times thanks to studies performed on lower mammals, and rodents in particular. However, the functional characteristics of human CB cells remain practically unknown. Herein, we use tissue slices or enzymatically dispersed cells to determine the characteristics of human CB cells. The adult human CB parenchyma contains clusters of chemosensitive glomus (type I) and sustentacular (type II) cells as well as nestin-positive progenitor cells. This organ also expresses high levels of the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF). We found that GDNF production and the number of progenitor and glomus cells were preserved in the CBs of human subjects of advanced age. Moreover, glomus cells exhibited voltage-dependent Na+, Ca2+ and K+ currents that were qualitatively similar to those reported in lower mammals. These cells responded to hypoxia with an external Ca2+-dependent increase of cytosolic Ca2+ and quantal catecholamine secretion, as reported for other mammalian species. Interestingly, human glomus cells are also responsive to hypoglycaemia and together these two stimuli can potentiate each other's effects. The chemosensory responses of glomus cells are also preserved at an advanced age. These new data on the cellular and molecular physiology of the CB pave the way for future pathophysiological studies involving this organ in humans. [ABSTRACT FROM AUTHOR]

Key points The brain keeps a representation of which things are part of our body. This sense of ownership is easily manipulated using brushing of the skin or movement of a limb to create an illusion of ownership over an inanimate object, such as a rubber hand., We induced a sense of ownership of an artificial finger using movement of the index finger without vision of the hands. As cutaneous receptors had been anaesthetised, this illusion depended on proprioceptive signals from muscle receptors., In addition, we found a new grasp illusion in which perceived distance between the index fingers decreases when subjects hold an artificial finger., These results increase understanding of how the brain generates our body representation and may help in understanding diseases in which the sense of ownership is disrupted., Abstract Body 'ownership' defines which things belong to us and can be manipulated by signals from cutaneous or muscle receptors. Whether signals from muscle proprioceptors on their own influence perceived ownership is unknown. We used finger-joint movement to induce illusory ownership of an artificial finger without vision. We coupled the subject's index finger to an artificial finger 12 cm above it. The experimenter held the subject's other index finger and thumb on the artificial finger and passively moved them congruently or incongruently for 3 min with the index finger and the grasping index finger and thumb intact or anaesthetised. When intact, congruent movement (19 subjects) reduced perceived vertical distance between index fingers to 1.0 (0.0, 2.0) cm [median (IQR)] from 3.0 (3.0, 4.0) cm with incongruent movement ( P < 0.01). Simply grasping the artificial finger reduced perceived spacing between the grasping and test index fingers from 6.0 (5.0, 9.0) cm to 3.0 (3.0, 6.0) cm ( P < 0.01), a new grasp illusion. Digital anaesthesia eliminated this grasp effect, after which congruent movement still reduced the perceived spacing between the index fingers to 1.0 (0.0, 2.75) cm compared to 4.0 (3.25, 6.0) cm with incongruent movement ( P < 0.001). Subjects more strongly agreed that they were holding their own finger after congruent but not incongruent movement ( P < 0.01). We propose that the brain generates possible scenarios and tests them against available sensory information. This process can function without vision or motor commands, and with only one channel of somatic information. [ABSTRACT FROM AUTHOR]

Key points The lanceolate sensory nerve ending of hair follicles is known to contain small (∼50 nm), clear vesicles similar to those of presynaptic terminals, but of unknown function., We show that the sensory terminals spontaneously take up and release the fluorescent styryl dye FM1-43, and also provide other evidence that the dye flux is primarily by recycling of these synaptic-like vesicles (SLVs)., FM1-43 labelling is Ca2+ dependent, and its release is sensitive to α-latrotoxin, which is known to deplete synaptic vesicles at neuromuscular junctions., Responses of hair follicle afferents are not significantly affected by FM1-43 at a concentration (10 μ m) sufficient to label the endings, so the mechanotransduction channel that has previously been shown to be blocked by FM1-43 permeation in hair cells of the inner ear and in cultured dorsal root ganglion cells is either not responsible for sensory transduction in the lanceolate ending or is in some way protected from exposure to the dye., The sensory terminals are relatively enriched in glutamate, presumably within the vesicles., Exogenous glutamate increases FM1-43 labelling, whereas the labelling is strongly inhibited by PCCG-13, a specific blocker of a non-canonical phospholipase D-linked metabotropic glutamate receptor, but not by canonical ionotropic or metabotropic glutamate receptor blockers. It is also inhibited by FIPI, a novel phospholipase D inhibitor., The system of SLVs is closely similar to that we have previously described in the muscle spindle, and where we further demonstrated the regulatory action of glutamate on the sensory response to maintained stretch., We conclude that an SLV-mediated glutamatergic system is present in the mechanosensory endings of the primary afferents of lanceolate endings, and it appears to function in a similar way to the autoregulatory system of the muscle spindle., Abstract Our aim in the present study was to determine whether a glutamatergic modulatory system involving synaptic-like vesicles (SLVs) is present in the lanceolate ending of the mouse and rat hair follicle and, if so, to assess its similarity to that of the rat muscle spindle annulospiral ending we have described previously. Both types of endings are formed by the peripheral sensory terminals of primary mechanosensory dorsal root ganglion cells, so the presence of such a system in the lanceolate ending would provide support for our hypothesis that it is a general property of fundamental importance to the regulation of the responsiveness of the broad class of primary mechanosensory endings. We show not only that an SLV-based system is present in lanceolate endings, but also that there are clear parallels between its operation in the two types of mechanosensory endings. In particular, we demonstrate that, as in the muscle spindle: (i) FM1-43 labels the sensory terminals of the lanceolate ending, rather than the closely associated accessory (glial) cells; (ii) the dye enters and leaves the terminals primarily by SLV recycling; (iii) the dye does not block the electrical response to mechanical stimulation, in contrast to its effect on the hair cell and dorsal root ganglion cells in culture; (iv) SLV recycling is Ca2+ sensitive; and (v) the sensory terminals are enriched in glutamate. Thus, in the lanceolate sensory ending SLV recycling is itself regulated, at least in part, by glutamate acting through a phospholipase D-coupled metabotropic glutamate receptor. [ABSTRACT FROM AUTHOR]

Key points Ablation of TRPV1+/peptidergic or of MrgprD+/non-peptidergic nociceptors produces modality-specific deficits in the behavioural responses to heat and mechanical stimuli, respectively. Noxious heat-induced dorsal horn Fos expression is also eliminated, despite the heat responsiveness of the non-peptidergic nociceptors., To assess whether this modality-specific contribution is manifest at the level of individual spinal neurons, we made extracellular recordings from mouse dorsal horn after selective ablation of the two nociceptor populations., Intrathecal capsaicin, which ablated the TRPV1+ nociceptors, abolished responsiveness of superficial and deep dorsal horn neurons to noxious heat, with no change in response to noxious mechanical stimulation., Ablation of MrgprD+ afferents did not alter the response to noxious heat but reduced the firing of dorsal horn neurons in response to noxious mechanical stimulation., These findings argue strongly that TRPV1+ and MrgprD+ nociceptors provide modality-specific contributions to the response properties of spinal cord neurons., Abstract We previously demonstrated that genetic and/or pharmacological ablation of the TRPV1+/peptidergic or the MrgprD+/non-peptidergic subset of nociceptors produced selective, modality-specific deficits in the behavioural responses to heat and mechanical stimuli, respectively. To assess whether this modality-specific contribution is also manifest at the level of spinal cord neuron responsiveness, here we made extracellular recordings from lumbar dorsal horn neurons of the mouse in response to graded thermal and mechanical stimulation. We found that, following intrathecal injection of capsaicin to eliminate the central terminals of TRPV1+ nociceptors, neurons in the region of laminae I and V of the spinal cord lost responsiveness to noxious heat (whether generated by a contact heat probe or diode laser), with no change in their response to noxious mechanical stimulation. In contrast, ablation of MrgprD+ afferents did not alter the response to noxious heat, but reduced the firing of superficial dorsal horn nociceptive-specific neurons in response to graded mechanical stimulation and decreased the relative number of wide dynamic range neurons that were exclusively mechanosensitive. Neither ablation procedure reduced the number of dorsal horn neurons that responded to noxious cold. These findings support the conclusion that TRPV1+ nociceptors are necessary and probably sufficient for noxious heat activation of dorsal horn neurons and that, despite their polymodal properties, TRPV1+ and MrgprD+ nociceptors provide modality-specific contributions to the response properties of spinal cord neurons. [ABSTRACT FROM AUTHOR]

Key points [ABSTRACT FROM AUTHOR]

Key points [ABSTRACT FROM AUTHOR]

Non-technical summary The hair cell, or sensory receptor of the inner ear, achieves high sensitivity by amplifying its mechanical inputs. The mechanism of amplification depends on the concerted opening and closing of mechanically sensitive ion channels in the hair bundle, a cluster of actin-containing rods that protrude from the cell's top surface. When a hair cell is stimulated simultaneously at two frequencies, channel gating also produces distortion products or responses at other frequencies. Using a sensitive interferometer to measure the motions of stereocilia, we have found that hydrodynamic forces act within the hair bundle to suppress these spurious signals. The hair bundle has evidently evolved an effective means of amplifying input signals while reducing the effect of distortions. [ABSTRACT FROM AUTHOR]

Non-technical summary Specialized nerve endings in the walls of various blood vessels are sensitive to alterations in the distending pressure. An increase in the blood pressure inside several arteries, including aorta, carotid and coronary arteries, generates sensory activity which causes reflex changes in the heart and circulation to reduce blood pressure. They operate as a negative feedback control and stabilise blood pressure. In this study we show that stimulation of pressure receptors in the walls of the pulmonary artery (low pressure) results in responses that differ from those originating from high pressure arteries. Instead of causing decreases in blood pressure and vascular resistance, their effect is to increase them. We also show that the effects on nervous activity to the kidney are different; stimulation of arterial receptors decreases renal nerve activity whereas stimulation of pulmonary arterial receptors increases it. There is interaction between the two reflexes. In other words, the level of stimulation of one reflex affects the responses from the other. We suggest that pulmonary arterial receptors are likely to have important physiological and pathophysiological consequences; they could contribute to causing the blood pressure increase during exercise as well as being involved in blood pressure control as the body changes orientation. They may also be involved in blood pressure control in heart failure and in the high pulmonary arterial pressures that are seen, for example, at high altitudes. [ABSTRACT FROM AUTHOR]

We addressed the hypothesis that single vagal afferent C-fibres can be stimulated via either the adenosine A1 or A2A receptor subtypes. The effect of adenosine on the nerve terminals of vagal sensory nerve subtypes was evaluated in an ex vivo perfused guinea pig lung preparation using extracellular recording techniques. Adenosine (10 μm) consistently evoked action potential discharge in lung C-fibre terminals arising from the nodose ganglia, but failed to evoke action potential discharge in most jugular ganglion C-fibres. Adenosine also failed to activate stretch-sensitive nodose A-fibres in the lungs. The selective A1 antagonist DPCPX (0.1 μm) or the selective A2A antagonist SCH 58261 (0.1 μm) partially inhibited the nodose C-fibre activation by adenosine, and the combination of both antagonists almost completely inhibited the response. The adenosine-induced action potential discharge in nodose C-fibres was mimicked by either the selective A1 agonist CCPA (1 μm) or the selective A2A agonist CGS 21680 (1 μm). Single cell PCR techniques revealed that adenosine A1 and A2A receptor mRNA was expressed in individual nodose neurons retrogradely labelled from the lungs. The gramicidin-perforated patch clamp technique on neurons retrogradely labelled from the lungs was employed to study the functional consequence of adenosine receptor agonists directly on neuronal membrane properties. Both the selective A1 agonist CCPA (1 μm) and the selective A2A agonist CGS 21680 (1 μm) depolarized the airway-specific, capsaicin-sensitive, nodose neurons to action potential threshold. The data support the hypothesis that adenosine selectively depolarizes vagal nodose C-fibre terminals in the lungs to action potential threshold, by stimulation of both adenosine A1 and A2A receptor subtypes located in the neuronal membrane. [ABSTRACT FROM AUTHOR]

An in vitro preparation of the guinea-pig cornea was used to study the effects of the K+ channel blockers 4-aminopyridine (4-AP), tetraethylammonium (TEA) and Ba2+ on nerve terminal impulses (NTIs) recorded extracellularly from cold sensory receptors. These receptors have an ongoing discharge of NTIs that is increased by cooling and decreased by heating. The K+ channel blocker 4-AP reduced the negative amplitude of the diphasic (positive–negative) NTIs, whereas TEA and Ba2+ prolonged the duration of the negative component. As the shape of the NTI is determined by the first derivative (d V/d t) of the membrane voltage change, these changes in the negative component are consistent with the blockade of K+ channels that contribute to action potential repolarization. Only TEA changed the basal activity of the receptors, increasing the likelihood of burst discharges. Ba2+ selectively reduced the response of the receptors to heating, whereas neither 4-AP nor TEA modified the response to heating or to cooling. The findings indicate that K+ channels blocked by 4-AP, TEA and Ba2+ contribute to action potential repolarization in corneal cold receptors, and that ionic mechanisms that underlie the reduction in NTI frequency in response to heating differ from those that increase activity in response to cooling. [ABSTRACT FROM AUTHOR]

Asphyxia, which occurs during obstructive sleep apnoeic events, alters the baroreceptor reflex and this may lead to hypertension. We have recently reported that breathing an asphyxic gas resets the baroreceptor–vascular resistance reflex towards higher pressures. The present study was designed to determine whether this effect was caused by the reduced oxygen tension, which affects mainly peripheral chemoreceptors, or by the increased carbon dioxide, which acts mainly on central chemoreceptors. We studied 11 healthy volunteer subjects aged between 20 and 55 years old (6 male). The stimulus to the carotid baroreceptors was changed using graded pressures of −40 to +60 mmHg applied to a neck chamber. Responses of vascular resistance were assessed in the forearm from changes in blood pressure (Finapres) divided by brachial blood flow velocity (Doppler) and cardiac responses from the changes in RR interval and heart rate. Stimulus–response curves were defined during (i) air breathing, (ii) hypoxia (12% O2 in N2), and (iii) hypercapnia (5% CO2 in 95% O2). Responses during air breathing were assessed both prior to and after either hypoxia or hypercapnia. We applied a sigmoid function or third order polynomial to the curves and determined the maximal differential (equivalent to peak sensitivity) and the corresponding carotid sinus pressure (equivalent to ‘set point’). Hypoxia resulted in an increase in heart rate but no significant change in mean blood pressure or vascular resistance. However, there was an increase in vascular resistance in the post-stimulus period. Hypoxia had no significant effect on baroreflex sensitivity or ‘set point’ for the control of RR interval, heart rate or mean arterial pressure. Peak sensitivity of the vascular resistance response to baroreceptor stimulation was significantly reduced from −2.5 ± 0.4 units to −1.4 ± 0.1 units ( P < 0.05) and this was restored in the post-stimulus period to −2.6 ± 0.5 units. There was no effect on ‘set point’. Hypercapnia, on the other hand, resulted in a decrease in heart rate, which remained reduced in the post-stimulus period and significantly increased mean blood pressure. Baseline vascular resistance was significantly increased and then further increased in the post-control period. Like hypoxia, hypercapnia had no effect on baroreflex control of RR interval, heart rate or mean arterial pressure. There was, also no significant change in the sensitivity of the vascular resistance responses, however, ‘set point’ was significantly increased from 74.7 ± 4 to 87.0 ± 2 mmHg ( P < 0.02). This was not completely restored to pre-stimulus control levels in the post-stimulus control period (82.2 ± 3 mmHg). These results suggest that the hypoxic component of asphyxia reduces baroreceptor–vascular resistance reflex sensitivity, whilst the hypercapnic component is responsible for increasing blood pressure and reflex ‘set point’. Hypercapnia appears to have a lasting effect after the removal of the stimulus. Thus the effect of both peripheral and central chemoreceptors on baroreflex function may contribute to promoting hypertension in patients with obstructive sleep apnoea. [ABSTRACT FROM AUTHOR]

Different classes of ion channels have been implicated in sensing cold temperatures at mammalian thermoreceptor nerve endings. A major candidate is TRPM8, a non-selective cation channel of the transient receptor potential family, activated by menthol and low temperatures. We investigated the role of TRPM8 in cold sensing during transient expression in mouse cultured hippocampal neurones, a tissue that lacks endogenous expression of thermosensitive TRPs. In the absence of synaptic input, control hippocampal neurones were not excited by cooling. In contrast, all TRPM8-transfected hippocampal neurones were excited by cooling and menthol. However, in comparison to cold-sensitive trigeminal sensory neurones, hippocampal neurones exhibited much lower threshold temperatures, requiring temperatures below 27°C to fire action potentials. These results directly demonstrate that expression of TRPM8 in mammalian neurones induces cold sensing, albeit at lower temperatures than native TRPM8-expressing neurones, suggesting the presence of additional modulatory mechanisms in the cold response of sensory neurones. [ABSTRACT FROM AUTHOR]

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 also differ in their chemosensitivity and receptor expression. Using an in vitro mouse colon preparation, individual primary afferents were tested with selective P2X and transient receptor potential vanilloid receptor 1 (TRPV1) receptor ligands. Afferent cell bodies in thoracolumbar and lumbosacral dorsal root ganglia (DRG) were retrogradely labelled from the colon and analysed for P2X3- and TRPV1-like immunoreactivity (LI). Forty per cent of LSN afferents responded to α,β-methylene adenosine 5′-triphosphate (α,β-meATP; 1 m m), an effect that was concentration dependent and reversed by the P2X antagonist pyridoxyl5-phosphate 6-azophenyl-2′,4′-disulphonic acid (PPADS) (100 μ m). Significantly fewer PN afferents (7%) responded to α,β-meATP. Correspondingly, 36% of colonic thoracolumbar DRG neurones exhibited P2X3-LI compared with only 19% of colonic lumbosacral neurones. Capsaicin (3 μ m) excited 61% of LSN afferents and 47% of PN afferents; 82% of thoracolumbar and 50% of lumbosacral colonic DRG neurones displayed TRPV1-LI. Mechanically insensitive afferents were recruited by α,β-meATP or capsaicin, and were almost exclusive to the LSN. Capsaicin-responsive LSN afferents displayed marked mechanical desensitization after responding to capsaicin, which did not occur in capsaicin-responsive PN afferents. Therefore, colonic LSN and PN pathways differ in their chemosensitivity to known noxious stimuli and their corresponding receptor expression. As these pathways relay information that may relate to symptoms in functional gastrointestinal disease, these results may have implications for the efficacy of therapies targeting receptor modulation. [ABSTRACT FROM AUTHOR]

Fifty-nanometre diameter, clear, synaptic-like vesicles (SLVs) are found in primary mechanosensory nerve terminals of vertebrate and invertebrate animals. We have investigated their role in mechanosensory function using the muscle spindle primary endings of rat Ia afferents as a model. Uptake and release of the synaptic vesicle marker FM1-43 indicated that SLVs recycle like synaptic vesicles and do so in a Ca2+-sensitive manner. Mechanical stimulation increased SLV recycling, increasing both dye uptake and release. Immunogold/electronmicroscopy showed that, like the central synaptic endings, Ia peripheral endings are enriched with glutamate. Moreover, exogenous glutamate enhanced stretch-induced Ia excitability. Enhanced excitability persisted in the presence of antagonists to the commonest ionotropic and metabotropic glutamate receptors (kynurenate, MCPG, CPPG and MAP4). However, excitation by glutamate was abolished by (R,S)-3,5-dihydroxyphenylglycine (DHPG), and rather more effectively by (2R,1′-S,2′-R,3′-S)-2-(2′-carboxy-3′-phenylcyclopropyl) glycine (PCCG-13). PCCG-13 also significantly reduced stretch-activated excitability in the absence of exogenous glutamate. These data indicate that SLVs recycle at rest, releasing glutamate, and that mechanical activity increases this process. The blockade with DHPG and PCCG-13 suggests that endogenous glutamate release acts, at least in part, through the recently described phospholipase D-linked metabotropic Glu receptor to maintain the excitability of the sensory endings. [ABSTRACT FROM AUTHOR]

The carotid body (CB) chemoreceptors may play an important role in the enhanced hypoxic ventilatory response induced by chronic intermittent hypoxia (CIH). We studied the effects of cyclic hypoxic episodes of short duration on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes (PO2 ∼ 75 Torr) repeated during 8 h for 2-4 days. Cats were anaesthetized with sodium pentobarbitone (40 mg kg-1 I.R, followed by 8-12 mg i.v.), and ventilatory and cardiovascular responses to NaCN (0.1-100 µg kg-1 i.v.) and several isocapnic levels of oxygen (PO2 ∼ 20-740 Torr) were studied. After studying the reflex responses, we recorded the CB chemosensory responses induced by the same stimuli. Results showed that CIH for 4 days selectively enhanced cat CB ventilatory (VT and VI) responses to hypoxia, while responses to NaCN remained largely unchanged. Similarly, basal CB discharges and responses to acute hypoxia (PO2 < 100 Torr) were larger in CIH than in control cats, without modification of the responses to NaCN. Exposure to CIH did not increase hasal arterial pressure, heart rate, or their changes induced by acute hypoxia or hyperoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low-/high-frequency ratio and an increase of the power spectral distribution of low frequencies of heart rate variability. Thus, the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia, as well as to modified heart rate variability due to early changes in autonomic activity. [ABSTRACT FROM AUTHOR]

The effects of peripheral nerve lesions on the membrane and synaptic properties of motoneurones have been extensively studied. However, minimal information exists about how these alterations finally influence discharge activity and motor output under physiological afferent drive. The aim of this work was to evaluate the effect of hypoglossal (XIIth) nerve crushing on hypoglossal motoneurone (HMN) discharge in response to the basal inspiratory afferent drive and its chemosensory modulation by CO2. The evolution of the lesion was assessed by recording the compound muscle action potential evoked by XIIth nerve stimulation, which was lost on crushing and then recovered gradually to control values from the second to fourth weeks post-lesion. Basal inspiratory activities recorded 7 days post-injury in the nerve proximal to the lesion site, and in the nucleus, were reduced by 51.6% and 35.8%, respectively. Single unit antidromic latencies were lengthened by lesion, and unusually high stimulation intensities were frequently required to elicit antidromic spikes. Likewise, inspiratory modulation of unitary discharge under conditions in which chemoreceptor drive was varied by altering end-tidal CO2 was reduced by more than 60%. Although the general recruitment scheme was preserved after XIIth nerve lesion, we noticed an increased proportion of low-threshold units and a reduced recruitment gain across the physiological range. Immunohistochemical staining of synaptophysin in the hypoglossal nuclei revealed significant reductions of this synaptic marker after nerve injury. Morphological and functional alterations recovered with muscle re-innervation. Thus, we report here that nerve lesion induced changes in the basal activity and discharge modulation of HMNs, concurrent with the loss of afferent inputs. Nevertheless, we suggest that an increase in membrane excitability, reported by others, and in the proportion of ... [ABSTRACT FROM AUTHOR]

In a previous study, we established that leptin acts on chemosensitive intestinal vagal mechanoreceptors and that its excitatory effects are blocked by the endogenous interleukin-1 β receptor antagonist (Il-1ra). To determine how interleukin-1 β (Il-1 β) is involved in the action of leptin, we studied the effects of this drug on the single vagal afferent activities of intestinal mechanoreceptors in anaesthetized cats. For this purpose, the activity of 34 intestinal vagal mechanoreceptors was recorded via glass microelectrodes implanted in the nodose ganglion. Il-1 β (1 µg) administered into the artery irrigating the upper part of the intestine activated both the 16 leptin-activated units (type 1 units; P < 0.01) and the 12 leptin-inhibited units (type 2 units; P < 0.001), but had no effect on the six leptin-insensitive units. Cholecystokinin (CCK, 10 µg) induced an activatory response only in the two types of Il-1 β-sensitive units. When Il-1 β was administered after CCK, its excitatory effects on type 1 units were enhanced, whereas the excitatory effects on type 2 units were abolished. Pre-treatment with Il-1 ra (250 µg) blocked all the effects of Il-1 β and the excitatory effects of leptin on type 1 units, whereas it enhanced the inhibitory effects of leptin on type 2 units. It can therefore be concluded that (i) leptin acts on intestinal vagal mechanoreceptors via Il-1 β in the case of the type 1 units and independently of Il-1 β in the case of the type 2 units, and (ii) type 1 and type 2 units belong to two different populations of vagal afferents that transmit different information about ingestion or inflammation to the CNS, depending on the chemical environment. [ABSTRACT FROM AUTHOR]

Velocity changes following single and double conditioning impulses were studied by microneurography in single human C fibres to provide information about axonal membrane properties. C units were identified as mechano-responsive (n = 19) or mechano-insensitive (12) nociceptors, cold-sensitive (8) or sympathetic fibres (9), and excited by single, double and triple electrical stimuli to the skin at mean rates of 0.25-2 Hz. The interval between single or paired (20 ms apart) conditioning stimuli and test stimulus was then varied between 500 and 2 ms, and recovery curves of velocity change against inter-spike interval constructed, allowing for changes in these variables with distance. All fibres exhibited an initial (4-24 ms) relative refractory phase, and a long-lasting (>500 ms) 'H2' phase of reduced velocity, attributed to activation of Na[sup+]/K[sup+]-ATPase. Mechanoresponsive nociceptors exhibited an intermediate phase of either supernormality or subnormality, depending on stimulation rate. Mechano-insensitive nociceptors behaved similarly, but all were supernormal at 1 Hz. Sympathetic units exhibited only a long-lasting supernormality, while cold fibres exhibited a briefer supernormal and a late subnormal phase (H1), similar to A fibres. A preconditioning impulse doubled H2 and increased H1, but did not augment supernormality or the subnormality of similar time course. Like A fibre supernormality, these phenomena were explained by a passive cable model, so that they provide an estimate of membrane time constant. Nociceptor membrane time constants (median 110 ms, n = 17) were rather insensitive to membrane potential, indicating few active voltage-dependent potassium channels, whereas sympathetic time constants were longer and reduced by activity-dependent hyperpolarisation. [ABSTRACT FROM AUTHOR]

The mammalian utricular sensory receptors are commonly believed to be non-spiking cells with electrical activity limited to graded membrane potential changes. Here we provide evidence that during the first post-natal week, the sensory hair cells of the rat utricle express a tetrodotoxin (TTX)-sensitive voltage-gated Na[sup+] current that displays most of the biophysical and pharmacological characteristics of neuronal Na[sup+] current. Single-cell RT-PCR reveals that several α-subunit isoforms of the Na[sup+] channels are co-expressed within a single hair cell, with a major expression of Nav1.2 and Nav1.6 subunits. In neonatal hair cells, 30% of the Na[sup+] channels are available for activation at the resting potential. Depolarizing current injections in the range of the transduction currents are able to trigger TTX-sensitive action potentials. We also provide evidence of a TTX-sensitive activity-dependent brain-derived neurotrophic factor (BDNF) release by early post-natal utricle explants. Developmental analysis shows that Na[sup+] currents decrease dramatically from post-natal day 0 (PO) to P8 and become almost undetectable at P21. Concomitantly, depolarizing stimuli fail to induce both action potential and BDNF release at P20. The present findings reveal that vestibular hair cells express neuronal-like TTX-sensitive Na[sup+] channels able to generate Nat-driven action potentials only during the early post-natal period of development. During the same period an activity-dependent BDNF secretion by utricular explants has been demonstrated. This could be an important mechanism involved in vestibular sensory system differentiation and synaptogenesis. [ABSTRACT FROM AUTHOR]

The article discusses the highlights of a symposium on sensory end organs presented at the 2013 Annual Meeting of the Society for Neuroscience held in San Diego, California on November 9-13. Nirupa Chaudhari, Paul Fuchs and Susan Carlton are cited as featured speakers at the event. Also discussed are signal processing in the peripheral sensory receptors and organs, efferent modulation of signals, and the labelled line sensory coding concept.

The article offers information related to the neuronal firing which is the physiological substrate of sensory-perceptual experiences. Topics discussed include the codes employed by neuronal populations to carry sensory information; transformations in stimulus representation within pathways that lead from sensory receptors to high-level cerebral cortical regions; and study of the features of the visual image that make a given neuron fire.

The article presents evidence-based literature on the interaction between peripheral and central respiratory chemoreceptors. There are studies which support the mechanism by which carotid body denervation (CBD) and the bicarbonate infusion affected carbon dioxide (CO2) sensitivity and multiplication of a hypoxia-induced carotid body response. Another set of studies of both the intact and CBD human support the role of hyperaddition in this interaction.

The article deals with studies which examine how the carotid body sensed hypoxia and translated this into increased chemosensory activity. It notes a 1988 study which found that isolated type I cells from rabbit carotid bodies expressed potassium (K+) channels that were selectively inhibited by acute hypoxia. Another study showed that human type I cells exhibit voltage-gated sodium (Na+), K+ and calcium (Ca2+) currents and respond to acute hypoxia based on the membrane hypothesis.

The authors present their response to commentaries regarding the interaction between peripheral and central respiratory chemoreceptors. They believe that the modified rebreathing technique is questionable based on the carotid body activity in hyperoxia, the carbon dioxide (CO2 mechanism in tissues and arteries, and the hypoxic response. They cite inconsistencies of the hybrid model of interaction with data from experimental animals.

The authors present their response to a commentary on an article which described the interaction between peripheral respiratory chemoreceptors and systemic effects of carbon dioxide (CO2). They cite the limitations of studies on these subject which prompted them to develop an artificially perfused experimental rat without intact autonomic and vagal influences. They claim that hypoadditivity in this experimental set-up are similar to and supported by other studies.

The authors present their response to a commentary by Teppema & Smith and Wilson & Day regarding hyperadditive interaction between central and peripheral respiratory chemoreceptors. The notion that carotid body denervation removes the tonic drive from the carotid bodies was supported by the authors. They agreed to the proposition that species differences and experimental models and scenarios devised to test the interaction are subject to limitations.