Adenosine-induced activation of esophageal nociceptors

Clinical studies implicate adenosine acting on esophageal nociceptive pathways in the pathogenesis of noncardiac chest pain originating from the esophagus. However, the effect of adenosine on esophageal afferent nerve subtypes is incompletely understood. We addressed the hypothesis that adenosine selectively activates esophageal nociceptors. Whole cell perforated patch-clamp recordings and single-cell RT-PCR analysis were performed on the primary afferent neurons retrogradely labeled from the esophagus in the guinea pig. Extracellular recordings were made from the isolated innervated esophagus. In patch-clamp studies, adenosine evoked activation (inward current) in a majority of putative nociceptive (capsaicin-sensitive) vagal nodose, vagal jugular, and spinal dorsal root ganglia (DRG) neurons innervating the esophagus. Single-cell RT-PCR analysis indicated that the majority of the putative nociceptive (transient receptor potential V1-positive) neurons innervating the esophagus express the adenosine receptors. The neural crest-derived (spinal DRG and vagal jugular) esophageal nociceptors expressed predominantly the adenosine A(1) receptor while the placodes-derived vagal nodose nociceptors expressed the adenosine A(1) and/or A(2A) receptors. Consistent with the studies in the cell bodies, adenosine evoked activation (overt action potential discharge) in esophageal nociceptive nerve terminals. Furthermore, the neural crest-derived jugular nociceptors were activated by the selective A(1) receptor agonist CCPA, and the placodes-derived nodose nociceptors were activated by CCPA and/or the selective adenosine A(2A) receptor CGS-21680. In contrast to esophageal nociceptors, adenosine failed to stimulate the vagal esophageal low-threshold (tension) mechanosensors. We conclude that adenosine selectively activates esophageal nociceptors. Our data indicate that the esophageal neural crest-derived nociceptors can be activated via the adenosine A(1) receptor while the placodes-derived esophageal nociceptors can be activated via A(1) and/or A(2A) receptors. Direct activation of esophageal nociceptors via adenosine receptors may contribute to the symptoms in esophageal diseases.     

Serotonergic neuromodulation of peripheral nociceptors

Nociception, the encoding and processing of noxious environmental stimuli by sensory neurons, functions to protect an organism from bodily damage. Activation of the terminal endings of certain sensory neurons, termed nociceptors, triggers a train of impulses to neurons in the spinal cord. Signals are integrated and processed in the dorsal spinal cord and then projected to the brain where they elicit the perception of pain. A number of neuromodulators that can affect nociceptors are released in the periphery during the inflammation that follows an initial injury. Serotonin (5-HT) is a one such proinflammatory mediator. This review discusses our current understanding of the neuromodulatory role of 5-HT, and specifically how this monoamine activates and sensitizes nociceptors. Potential therapeutic targets to treat pain are described.     

Supranodose vagotomy precludes reflex respiratory responses to serotonin in cats

Mediation of the respiratory reflex effects of an exogenous serotonin challenge goes beyond the lung vagi and is suggested to involve the nodose ganglia. In the present experiments the effects of an intravenous serotonin challenge on breathing pattern were studied in 8 pentobarbitone-chloralose anaesthetised cats. Bolus injection of serotonin oxalate (50 µg/kg) into the right femoral vein evoked prompt apnoea of 19.2 (±2.4)-second duration in all 8 cats while intact; the apnoea was much shorter after midcervical vagal section (8.1±0.9 s, p<0.001), and was abolished by supranodose vagotomy. In post-apnoeic breaths, the tidal volume was reduced from a baseline of 34.1±4.0 to 13.5±1.1 ml (p<0.001) prior to, and from a baseline of 43.9±5.4 to 33.8±6.6 ml (p<0.01) after midcervical vagotomy; the serotonin challenge did not affect tidal volume following supranodose vagal section (p=0.4). The increase in respiratory rate found in intact (p<0.001) and midcervically vagotomised cats (p<0.01) was eliminated by the neurotomy above the nodose ganglia. Supranodose vagotomy altered cardiovascular response to serotonin by replacing the fall in blood pressure with an increase. These data suggest that the sequelae of serotonin-induced pulmonary chemoreflex, i.e. respiratory arrest, cardiovascular changes and post-apnoeic pattern of breathing require intact nodose ganglia.     

Gut nociceptors: sentinels promoting host defense

Gut-innervating nociceptive neurons detect noxious mechanical and chemical stimuli within our gut, constituting the start of the'gut pain'pathway.In a recent pa...     

Ventrolateral medullary respiratory network participation in the expiration reflex in the cat.

The expiration reflex is a distinct airway defensive response characterized by a brief, intense expiratory effort and coordinated adduction and abduction of the laryngeal folds. This study addressed the hypothesis that the ventrolateral medullary respiratory network participates in the reflex. Extracellular neuron activity was recorded with microelectrode arrays in decerebrated, neuromuscular-blocked, ventilated cats. In 32 recordings (17 cats), 232 neurons were monitored in the rostral (including B?tzinger and pre-B?tzinger complexes) and caudal ventral respiratory group. Neurons were classified by firing pattern, evaluated for spinal projections, functional associations with recurrent laryngeal and lumbar nerves, and firing rate changes during brief, large increases in lumbar motor nerve discharge (fictive expiration reflex, FER) elicited during mechanical stimulation of the vocal folds. Two hundred eight neurons were respiratory modulated, and 24 were nonrespiratory; 104 of the respiratory and 6 of the nonrespiratory-modulated neurons had altered peak firing rates during the FER. Increased firing rates of bulbospinal neurons and expiratory laryngeal premotor and motoneurons during the expiratory burst of FER were accompanied by changes in the firing patterns of putative propriobulbar neurons proposed to participate in the eupneic respiratory network. The results support the hypothesis that elements of the rostral and caudal ventral respiratory groups participate in generating and shaping the motor output of the FER. A model is proposed for the participation of the respiratory network in the expiration reflex.     

Kv3.4 channel function and dysfunction in nociceptors

Recently, we reported the isolation of the Kv3.4 current in dorsal root ganglion (DRG) neurons and described dysregulation of this current in a spinal cord injury (SCI) model of chronic pain. These studies strongly suggest that rat Kv3.4 channels are major regulators of excitability in DRG neurons from pups and adult females, where they help determine action potential (AP) repolarization and spiking properties. Here, we characterized the Kv3.4 current in rat DRG neurons from adult males and show that it transfers 40–70% of the total repolarizing charge during the AP across all ages and sexes. Following SCI, we also found remodeling of the repolarizing currents during the AP. In the light of these studies, homomeric Kv3.4 channels expressed in DRG nociceptors are emerging novel targets that may help develop new approaches to treat neuropathic pain.     

Central processing of input signals arising from myelinated and nonmyelinated nociceptors: In vivo studies

Nociceptive information is transmitted to the spinal cord via A-and C-fiber nociceptors. These different groups of nociceptors convey different qualities of the pain signal and play different roles in chronic pain states. It is of considerable importance, therefore, to compare the respective central processing. To do this, we have developed a technique allowing us to preferentially activate either A-or C-heat nociceptors. This article describes functional anatomical approaches used to study spinal brainstem loops and their roles in determining the pain experience. It will focus on (i) A-vs C-nociceptive inputs to control centers in the midbrain periaqueductal gray and the hypothalamus, including interactions between these afferent signals, and (ii) differential descending control of A-vs C-nociceptor-evoked spinal nociception. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 342–349, July–August, 2006.     

Leptospirotic etiology in pulmonary and upper respiratory tract pathology

A number of 3,200 febrile patients who presented upon admission to hospital primary pulmonary or upper respiratory tract impairment either as single forms of manifestation or associated to other syndromes were tested. The cases were screened by the rapid slide agglutination reaction with heat inactivated Patoc antigen and leptospirotic etiology was confirmed by the ultramicroscopic agglutination reaction with 18 live circulating pathogenic antigens. 64 leptospirosis cases with pulmonary impairment were confirmed and in 52 cases the upper respiratory tract was involved. Particular aspects of leptospirosis with pulmonary impairment: 71.8% of cases had a clinical diagnosis of interstitial pneumonia; 89% of cases presented important chest x-ray modifications; in an approximately equal number of cases the pulmonary involvement was the single manifestation or was associated with other syndromes; icterohaemorrhagiae, wolffi and pomona were the frequently encountered infecting serotypes. Particular aspects for leptospirosis involving the upper respiratory tract: 84.6% of cases had a clinical diagnosis of acute rhino-pharyngotracheitis; in 86.5% of cases the upper respiratory tract impairment was the single feature; the infecting serotypes were in decreasing order of frequency as follows: icterohaemorrhagiae, pomona, wolffi, canicola, grippotyphosa.     

The variability of pulmonary gas exchange and respiratory pattern

Very-low-frequency (VLF) fluctuations, whose nature is probably determined by rhythms of energy processes, are known to determine the variability of respiratory and heart rates. It is still unclear to which type of wave processes (chaotic or regular) these rhythm patterns belong. The goal of this study was to investigate the rhythms of pulmonary gas exchange and the variability of the respiratory pattern, as well as to find their possible relation. To analyze the variability of ventilation indices in the VLF band, pneumograms were recorded for 30 min and then the pulmonary gas exchange indices (Ve, pulmonary ventilation; V_O2 V_{O_2 }, oxygen consumption; V_CO2 V_{CO_2 }, carbon dioxide release) were recorded for 30 min using the breath-by-breath method in ten healthy subjects. Spectral analysis carried out using the fast Fourier transform revealed two groups of major peaks: the first one was in the range from 0.2 to 0.3 Hz (the time interval of 3–5 s), which was in good agreement with the respiratory rate varied from 12 to 20 per min in tested subjects; the second was from 0.002 to 0.0075 Hz, which corresponded to the VLF band. The data make it possible to draw a conclusion about the stability of the wave processes found. Apparently, the slow-wave pattern of the pulmonary gas exchange indices belongs to the quasi-periodic oscillation type, reflecting synchronization of oscillators with incommensurable frequencies when the two-frequency pattern dominates. The first oscillator is the chemoreceptor mechanism of the regulation of ventilation, the nature of the second one is still unclear. Taking into consideration that V_O2 V_{O_2 } and V_CO2 V_{CO_2 } depend on energy demand, one can suppose that energy processes form (an)other oscillator(s) of periodic processes.