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Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3′,5′-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics. Linaclotide and plecanatide are synthetic peptide agonists of guanylate cyclase-C (GC-C), a transmembrane receptor that is predominantly located on intestinal epithelial cells. These medications have very low oral bioavailability, which, when combined with the expression profile of GC-C, provides a mechanism of action 'targeted to the gut'. Linaclotide has been shown to inhibit colonic nociceptors and reduce peripheral drive from the colon, resulting in reduced numbers of activated dorsal horn neurons within the spinal cord and reduced pain responses to noxious colorectal distension. These effects are greatest in animal models of chronic visceral hypersensitivity that drive the 'bottom-up' and/or 'top-down' sensitization relevant to irritable bowel syndrome (IBS). Activation of GC-C results in the generation and release of cyclic guanosine-3′,5′-monophosphate (cGMP) from intestinal epithelial cells. When released into the submucosal space through the basolateral membrane, extracellular cGMP acts as a neuromodulator to inhibit pain-sensing nerve fibers innervating the colon. cGMP has also been demonstrated to inhibit pain-sensing nerves from human donors. In all human Phase III clinical studies conducted to date in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC), linaclotide significantly improved abdominal pain, discomfort, and bloating. Recent preclinical studies also provide the prospect that linaclotide may offer a novel therapeutic option, not only for the treatment of chronic abdominal pain in IBS-C, but also comorbid bladder dysfunction and endometriosis-associated pain. [ABSTRACT FROM AUTHOR]

Abstract Like several other arthropod species, stick insects use their antennae for tactile exploration of the near-range environment and for spatial localisation of touched objects. More specifically, Carausius morosus continuously moves its antennae during locomotion and reliably responds to antennal contact events with directed movements of a front leg. Here we investigate the afferent projection patterns of antennal hair fields (aHF), proprioceptors known to encode antennal posture and movement, and to be involved in antennal movement control. We show that afferents of all seven aHF of C. morosus have terminal arborisations in the dorsal lobe (DL) of the cerebral (=supraoesophageal) ganglion, and descending collaterals that terminate in a characteristic part of the gnathal (=suboesophageal) ganglion. Despite differences of functional roles among aHF, terminal arborisation patterns show no topological arrangement according to segment specificity or direction of movement. In the DL, antennal motoneuron neurites show arborizations in proximity to aHF afferent terminals. Despite the morphological similarity of single mechanoreceptors of aHF and adjacent tactile hairs on the pedicel and flagellum, we find a clear separation of proprioceptive and exteroceptive mechanosensory neuropils in the cerebral ganglion. Moreover, we also find this functional separation in the gnathal ganglion. Highlights • Afferents of all seven antennal hair fields of stick insects have similar projection patterns in the cerebral ganglion and gnathal ganglion. • Hair field projections show no clear topological arrangement. • Hair field afferents are in proximity to antennal motoneuron projections in the dorsal lobe. • Antennal proprioceptive and exteroceptive mechanosensory neuropils are functionally separated in the cerebral ganglion and gnathal ganglion. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome and inflammatory bowel disease are major forms of chronic visceral pain, which affect over 15% of the global population. In order to identify new therapies, it is important to understand the underlying causes of chronic visceral pain. This review provides recent evidence demonstrating that inflammation or infection of the gastrointestinal tract triggers specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system. Specific changes in the expression and function of a variety of ion channels and receptors have been documented in inflammatory and chronic visceral pain conditions relevant to irritable bowel syndrome and inflammatory bowel disease. An increase in pro-nociceptive mechanisms enhances peripheral drive from the viscera and provides an underlying basis for enhanced nociceptive signalling during chronic visceral pain states. Recent evidence also highlights increases in anti-nociceptive mechanisms in models of chronic visceral pain, which present novel targets for pharmacological treatment of this condition. [ABSTRACT FROM AUTHOR]

Background The complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls. Methods Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM. Results The FBF response (area under the curve; AUC) to 60 s of continuous PLM was attenuated in the HFrEF (25 ± 15 ml AUC) compared to controls (199 ± 34 ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (- 9 ± 10 ml AUC) in contrast to the controls (43 ± 25 ml AUC). Conclusions These data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation. [ABSTRACT FROM AUTHOR]

Highlights: [•] EW innervation come from PVH, LHA, Arc, PH and mammillary nuclei. [•] Prosencephalic sources of EW innervation are substantia innominata, lateral habenular nucleus and zona incerta. [•] Locus coeruleus and the lateral cerebellar nucleus, parvicellular part, are also sources of EW innervation. [•] BDA injected into PVH, LHA and PH showed anterogradely labeled fibers in a very close apposition to UCN 1-ir cells of EWcp. [ABSTRACT FROM AUTHOR]

Abstract: Brainstem A2/C2 catecholamine (CA) neurons within the solitary tract nucleus (NTS) influence many homeostatic functions, including food intake, stress, respiratory and cardiovascular reflexes. They also play a role in both opioid reward and withdrawal. Injections of opioids into the NTS modulate many autonomic functions influenced by catecholamine neurons including food intake and cardiac function. We recently showed that NTS-CA neurons are directly activated by incoming visceral afferent inputs. Here we determined whether opioid agonists modulate afferent activation of NTS-CA neurons using transgenic mice with EGFP expressed under the control of the tyrosine hydroxylase promoter (TH-EGFP) to identify catecholamine neurons. The opioid agonist Met-enkephalin (Met-Enk) significantly attenuated solitary tract-evoked excitatory postsynaptic currents (ST-EPSCs) in NTS TH-EGFP neurons by 80%, an effect reversed by wash or the mu opioid receptor-specific antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). Met-Enk had a significantly greater effect to inhibit afferent inputs onto TH-EGFP-positive neurons than EGFP-negative neurons, which were only inhibited by 50%. The mu agonist, DAMGO, also inhibited the ST-EPSC in TH-EGFP neurons in a dose-dependent manner. In contrast, neither the delta agonist DPDPE, nor the kappa agonist, U69,593, consistently inhibited the ST-EPSC amplitude. Met-Enk and DAMGO increased the paired pulse ratio, decreased the frequency, but not amplitude, of mini-EPSCs and had no effect on holding current, input resistance or current–voltage relationships in TH-EGFP neurons, suggesting a presynaptic mechanism of action on afferent terminals. Met-Enk significantly reduced both the basal firing rate of NTS TH-EGFP neurons and the ability of afferent stimulation to evoke an action potential. These results suggest that opioids inhibit NTS-CA neurons by reducing an excitatory afferent drive onto these neurons through presynaptic inhibition of glutamate release and elucidate one potential mechanism by which opioids could control autonomic functions and modulate reward and opioid withdrawal symptoms at the level of the NTS. [Copyright &y& Elsevier]

Abstract: Changes in airway temperature can result in respiratory responses such as cough, bronchoconstriction and mucosal secretion after cold exposure and hyperventilation after heat exposure. In the present investigation, we examined the activity of bronchopulmonary receptors in response to activators of thermo-sensitive transient receptor potential (TS-TRP) cation channels using an ex vivo rat lung preparation. Receptive fields in small bronchioles were probed with von Frey hair monofilaments, warm (50°C) or cold (8°C) saline or saline containing TS-TRP agonists. Among 233 fibers tested, 159 (68.2%) responded to heat (50°C). A large proportion of heat-responsive receptors (107/145) were also activated by capsaicin. Heat and capsaicin-evoked responses were both blocked by TRPV1 antagonist, capsazepine. Only 15.3% of airway receptors responded to cold, which was associated with sensitivity to TRPM8 agonist menthol but not to TRPA1 agonist cinnamaldehyde (CA). Moreover, cold-evoked responses was unaffected by TRPA1 antagonist HC-03001. Our observations suggest that TRPV1 and TRPM8 are involved in transducing heat and cold in the lower respiratory tract, respectively. [Copyright &y& Elsevier]

Abstract: Cruciate ligaments provide sensory information that cause excitatory as well as inhibitory effects to the activity of the muscles around the knee. The aim of the study was to determine whether these muscular reflexes are reestablished after anterior cruciate ligament (ACL) re-construction. Wire electrodes were inserted during arthroscopy into the normal posterior cruciate ligament (PCL) and the reconstructed ACL in 11 patients who had a successful ACL re-construction 8months to 12years earlier. After the anesthesia had subsided, the PCL was stimulated electrically through the electrodes and the sensory threshold was determined. Stimulus amplitudes were increased to 1.5–2.0 times the sensory threshold, and inhibitory reflexes could be elicited from PCL in the quadriceps during active extension and in the hamstrings muscles during active flexion in all patients. Subsequently the ACL re-constructions were stimulated. The sensory threshold was 3.4 times higher in the ACL than in the PCL. Stimulus amplitudes were increased to 1.5–2.0 times the sensory threshold, and a typical inhibitory reflex could be elicited in 9 patients. The latency was the same as for the reflex from the PCL. The stimulus amplitudes necessary to elicit reflexes from the ACL re-constructions were 2, 9 times higher than amplitudes that elicited reflexes from the PCL. Sensation and afferent reflex activity required a much stronger stimulus in the ACL graft compared to normal PCL. We suggest that the reason for this is that the ACL grafts were not reinnervated, and that the reflexes were elicited by spread of stimulus current to the PCL. [ABSTRACT FROM AUTHOR]

Abstract: Standing and walking require a plethora of sensorimotor interactions that occur throughout the nervous system. Sensory afferent feedback plays a crucial role in the rhythmical muscle activation pattern, as it affects through spinal reflex circuits the spinal neuronal networks responsible for inducing and maintaining rhythmicity, drives short-term and long-term re-organization of the brain and spinal cord circuits, and contributes to recovery of walking after locomotor training. Therefore, spinal circuits integrating sensory signals are adjustable networks with learning capabilities. In this review, I will synthesize the mechanisms underlying phase-dependent modulation of spinal reflexes in healthy humans as well as those with spinal or cerebral lesions along with findings on afferent regulation of spinal reflexes and central pattern generator in reduced animal preparations. Recovery of walking after locomotor training has been documented in numerous studies but the re-organization of spinal interneuronal and cortical circuits need to be further explored at cellular and physiological levels. For maximizing sensorimotor recovery in people with spinal or cerebral lesions, a multidisciplinary approach (rehabilitation, pharmacology, and electrical stimulation) delivered during various sensorimotor constraints is needed. [ABSTRACT FROM AUTHOR]

Abstract: Cardio-respiratory effects of intravenous injection of somatostatin were investigated in anaesthetized, spontaneously breathing rats that were: (i) neurally intact and subsequently bilaterally vagotomized in the neck, or (ii) midcervically vagotomized with later vagotomized at the supranodosal level, or (iii) midcervically vagotomized and subjected to section of the carotid sinus nerves (CSNs). Intravenous injection of 100μg/kg of somatostatin before and after midcervical vagotomy-induced immediate slowing down of the respiratory rate and decreased tidal volume, mean arterial blood pressure (MAP) and heart rate. Supranodose vagotomy did not abolish somatostatin-induced respiratory depression. CSNs section eliminated all respiratory effects of somatostatin challenge. In all the neural states, somatostatin caused significant falls in mean arterial blood pressure and heart rate. The results of this study suggest that hypoventilation induced by intravenous somatostatin administration occurs outside vagal afferentation to the medulla and is mediated via carotid body afferents. Sino-aortic chemoreceptors and baroreceptors do not contribute to bradycardia and a fall in blood pressure. These cardiovascular effects are presumably mediated due to excitation of somatostatin receptors within the heart and/or in the brain. [Copyright &y& Elsevier]

Abstract: Sensory nerves of the urinary bladder consist of small diameter Aδ and C fibers running in the hypogastic and pelvic nerves. Neuroanatomical studies have revealed a complex neuronal network within the bladder wall. Electrophysiological recordings in vitro and in vivo have revealed several distinct classes of afferent fibers that may signal a wide range of bladder stimulations including physiological bladder filling, noxious distension, cold, chemical irritation and inflammation. The exact mechanisms that underline mechanosensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels (e.g., TTX-resistant Na+ channels, Kv channels and hyperpolarization-activated cyclic nucleotide-gated cation channels) and receptors (e.g., TRPV1, TRPM8, TRPA1, P2X2/3, etc) have been identified at bladder afferent terminals and implicated in the generation and modulation of afferent signals. Experimental investigations have revealed that expression and/or function of these ion channels and receptors may be altered in animal models and patients with overactive and painful bladder disorders. Some of these ion channels and receptors may be potential therapeutic targets for bladder diseases. [Copyright &y& Elsevier]

Abstract: The use of isolated in vitro spinal cord preparations to examine the underlying networks that control locomotion has become popular. It is also well known that afferent feedback can excite and modulate these networks. However, it is often difficult to selectively activate classes of afferents that subserve specific modalities using in vitro preparations. Here, we describe a technique where afferent receptors that detect temperature were selectively activated. To accomplish this we used an in vitro preparation of the mouse where the spinal cord was isolated (T5-cauda equina) with one hind limb left attached. We designed a special chamber allowing the hind paw to be placed in such a way that it remained attached to the spinal cord but received a separate supply of artificial cerebrospinal fluid (aCSF). This allowed us to alter the temperature of the hind limb compartment without affecting the temperature of the central compartment containing the spinal cord. We also demonstrate using this approach that agonists which activate receptors which detect noxious heat could be intradermally injected into the hind limb without it diffusing into the central compartment. [Copyright &y& Elsevier]

Abstract: Imposed static hip stretches substantially modulate the soleus H-reflex in people with an intact or injured spinal cord while stretch of the hip flexors affect the walking pattern in lower vertebrates and humans. The aim of this study was to assess the effects of dynamic hip stretches on the soleus H-reflex in supine spinal cord injured (SCI) subjects. Sinusoidal movements were imposed on the right hip joint at 0.2Hz by a Biodex system. H-reflexes from the soleus muscle were recorded as the leg moved in flexion or extension. Stimuli were sent only once in every hip movement cycle that each lasted 5s. Torque responses were recorded at the hip, knee, and ankle joints. A hip phase-dependent soleus H-reflex modulation was present in all subjects. The reflex was facilitated during hip extension and suppressed during hip flexion. There were no significant differences in pre- or post-stimulus soleus background activity between the two conditions. Oscillatory responses were present as the hip was maximally flexed. Sinusoidal hip stretches modulated the soleus H-reflex in a manner similar to that previously observed following static hip stretches. The amount of reflex facilitation depended on the angle of hip extension. Further research is needed on the afferent control of spinal reflex pathways in health and disease in order to better understand the neural control of movement in humans. This will aid in the development of rehabilitation strategies to restore motor function in these patients. [Copyright &y& Elsevier]

Abstract: Introduction: A limited number of drugs are available for the treatment of functional dyspepsia and irritable bowel syndrome. The efficacy of STW 5 (Iberogast®) was previously shown in clinical trials. Since visceral hypersensitivity seems to be the prime pathomechanism of functional gastro-intestinal disorders, the aim of this study was to explore whether STW 5 reduces intestinal afferent sensitivity in the upper gastrointestinal tract. Methods: Two groups of male Wistar rats were pretreated with either the herbal preparation STW 5 or its vehicle (30.8% ethanol). Then, after 2h, general anesthesia was induced by pentobarbitone (60mgkg−1 i.p.) and extracellular multi-unit afferent recordings were obtained from mesenteric afferents innervating the proximal jejunum. The intestinal afferent nerve response to increasing doses of 5-HT and bradykinin were quantified as well as afferent discharge following a ramp distension of the adjacent intestinal loop from 0 to 60cm H2O. Results: Afferent discharge to 5-HT and bradykinin increased dose-dependently. Following the different doses of 5-HT, the peak in afferent nerve discharge was always reduced after pretreatment with STW 5 compared to controls with a response of 110±5imps−1 after STW 5 and 128±3 in vehicle controls at the maximum dose (40μgkg−1; ; mean±SEM). For bradykinin, afferent responses were reduced following STW 5 at the 20 and 40μgkg−1 dose but not at 10μgkg−1 (40μgkg−1: 176±7imps−1 following STW 5 versus 200±6imps−1 in controls; ). The ramp distension of the intestinal loop stimulated a rise in intestinal afferent nerve discharge that was always lower in the STW 5 pretreated group compared to vehicle controls with the exception of the discharge rate at the pressure level of 0 and 20cm H2O (all other pressures up to 60cm H2O ). Conclusions: Sensitivity of intestinal afferents to mechanical and chemical stimuli is reduced following treatment with the herbal preparation STW 5. This mechanism may help to explain why STW 5 relieves dyspeptic and bowel symptoms in patients. [Copyright &y& Elsevier]

Abstract: Objective: To investigate whether a short-duration reduction of input to the motor cortex affects excitability in the hand region of the motor cortex. Methods: Subjects (n =10) received sets of transcranial magnetic stimulation of the motor cortex (TMS) and peripheral ulnar nerve stimulation. Stimuli were delivered before and after 20min of inactivity of the test hand. The evoked compound muscle action potentials were recorded in two relaxed intrinsic hand muscles using surface EMG. Results: Motor evoked potential size (MEP; expressed relative to the maximal M-wave) increased by ∼30–40 in both hand muscles (P =0.012) following inactivity. The enlarged MEP was not associated with changes in F-wave size, a marker of motoneurone excitability, or changes in intracortical inhibition and facilitation measured with paired-pulse TMS. Conclusions: MEP growth most likely reflects an increase in motor cortical excitability. The increased excitability appears to be more associated with reduced voluntary drive to and from the motor cortex rather than reduced afferent input from the periphery. Significance: These results have important implications for any investigation of motor cortical excitability in relaxed subjects. The outcome of an experimental intervention is the net result of the intervention itself and alterations in cortical excitability produced by the subjects’ inactivity. [Copyright &y& Elsevier]

Abstract: A novel in vitro bladder preparation was used to examine effect of various stimuli (stretch, von Frey hair compression, stroking of receptive fields, applications of chemical stimuli to the mucosa) on electrophysiological recordings from guinea pig bladder afferents in vitro. Several functionally distinct classes of bladder sensory neurons were distinguished. These include stretch-sensitive afferents—muscle mechanoreceptors which behaved as “in-series tension receptors” and tension-mucosal mechanoreceptors, which could be activated by stretch, mucosal stroking with light von Frey hair (0.1–2mN) and by hypertonic solutions (1M mannitol and 490–850mM NaCl) applied locally to their receptive fields in the mucosa. In addition, we have recorded stretch-insensitive afferents—mucosal mechanoreceptors and chemoreceptors. The non-selective P2X/P2Y purinoreceptor antagonist, PPADS (30μM) did not affect stretch-induced firing by low threshold muscle mechanoreceptors but significantly inhibited α,β-methylene ATP (30μM)-induced contractions and associated afferent firing. Transduction by low threshold stretch-sensitive muscle mechanoreceptors does not appear to involve exocytotic synaptic transmission since it occurs in Ca2+-free (with 1mM EDTA and 6mM Mg2+) Krebs solution. The data suggest that the endogenous transmitter ATP is not involved in mechanotransduction by this specific class of low threshold muscle mechanoreceptors in the guinea pig bladder; rather they appear to transduce mechanical stimuli directly, possibly via stretch-activated ion channels. Mechanisms of activation of other classes of mechanoreceptors and chemoreceptors remain to be established. [Copyright &y& Elsevier]

Abstract: The mushroom bodies are a morphologically diverse sensory integration and learning and memory center in the brains of various invertebrate species, of which those of insects are the best described. Insect mushroom bodies are composed of numerous tiny intrinsic neurons (Kenyon cells) that form calyces with their dendrites and a pedunculus and lobes with their axons. The identities of conserved Kenyon cell subpopulations and the correlations between morphological and functional specializations of the mushroom bodies are just beginning to be elucidated, providing insight into mechanisms of mushroom body evolution. Comparisons of mushroom body organization in different insect lineages reveal trends in the evolution of subcompartments correlated with the elaboration, reduction, acquisition or loss of Kenyon cell subpopulations. Furthermore, these changes often appear correlated with variation in type and strength of afferent input and in behavioral ecology. These and other features of mushroom body organization suggest a striking convergence with mammalian cortex, with Kenyon cell subpopulations displaying evolutionary modularity in a manner reminiscent of cortical areas. [Copyright &y& Elsevier]

Abstract: Afferent projections to the tuberal lateral hypothalamus (tLH), where excitatory amino acid application is most effective in eliciting feeding, and to the anterior, posterior and medial regions of the hypothalamus were studied using reverse microdialysis of N-methyl-d-aspartic acid (NMDA) and Fluorogold (FG). NMDA at 660μM delivered for 10min was effective in stimulating food intake only when administered into the tLH, causing a mean intake of 9.3g compared to less than 1g in any other site. Subsequent administration of FG through the dialysis probe retrogradely in labeled neurons in brain structures associated with the feeding response including the frontal cortex, amygdala, nucleus accumbens (NA), preoptic areas, substantia nigra, ventral tegmental area (VTA), parabrachial nucleus, and the nucleus of the solitary tract (NST). Labeling after anterior and posterior LH infusion of FG was similar to that seen after tLH delivery with some apparent differences, whereas FG administration into the medial hypothalamus produced a distinctly different pattern of labeling compared to the other groups. Some of the observed labeling appeared to be almost exclusively associated with the tLH where NMDA elicits feeding. In particular, amygdala, preoptic area and shell of the accumbens labeling was noticeably denser in tLH eaters than in all other groups. These findings are consistent with the role of LH glutamate and NMDA receptors in the regulation of food intake and identify afferents to the region which possibly mediate endogenous LH glutamate''s effects on feeding. [Copyright &y& Elsevier]

Abstract: This study was carried out to identify lamprey neurones relaying trigeminal sensory inputs to reticulospinal cells. Double labeling with fluorescent tracers was used in vitro. Fluorescein-conjugated dextran amines were applied to the proximal stump of the cut trigeminal nerve on both sides, and Texas Red-conjugated dextran amines were injected unilaterally in the middle (MRRN) or the posterior (PRRN) rhombencephalic reticular nuclei. Texas Red retrogradely labeled cells were found ipsi- and contralateral to each injection. Any of these cells with the soma or at least a major dendrite among the fluorescein-labeled trigeminal afferent axons was considered a candidate relay cell. Of these two possibilities, only cells with their soma among the fluorescein-labeled trigeminal afferents were found. The candidate relay cells projecting to the MRRN were mostly clustered at the caudal vestibular nerve level within the trigeminal descending tract, whereas the majority of those projecting to the PRRN were located more caudally. The diameter of candidate relay cells ranged from 9.2 to 24.6 μm and 9.2 to 46.1 μm, after MRRN and PRRN injections, respectively. A possible relay function for these cells was tested with electrophysiological experiments. The intracellular responses to trigeminal nerve stimulation were recorded in reticulospinal cells under control conditions and after ejections of a combination of glutamate ionotropic receptor antagonists over the candidate relay cells in small areas along the sulcus limitans. The synaptic responses elicited in MRRN reticulospinal cells were maximally depressed when ejections were made at the level of the vestibular nerve, in accord with the anatomical data. The synaptic responses in PRRN reticulospinal cells showed maximal depression when ejections were made slightly more caudally. Altogether, these results suggest that cells located within the trigeminal descending tract and projecting to reticular nuclei are likely to be the sensory trigeminal relays to reticulospinal neurones in lampreys. [Copyright &y& Elsevier]

This study characterizes aspects of the anatomy and physiology of auditory receptors and certain interneurons in the cricket Gryllus rubens. We identified an `L''-shaped ascending interneuron tuned to frequencies >15 kHz (57 dB SPL threshold at 20 kHz). Also identified were two intrasegmental `omega''-shaped interneurons that were broadly tuned to 3–65 kHz, with best sensitivity to frequencies of the male calling song (5 kHz, 52 dB SPL). The temporal sensitivity of units excited by calling song frequencies were measured using sinusoidally amplitude modulated stimuli that varied in both modulation rate and depth, parameters that vary with song propagation distance and the number of singing males. Omega cells responded like low-pass filters with a time constant of 42 ms. In contrast, receptors significantly coded modulation rates up to the maximum rate presented (85 Hz). Whereas omegas required ∼65% modulation depth at 45 Hz (calling song AM) to elicit significant synchrony coding, receptors tolerated a ∼50% reduction in modulation depth up to 85 Hz. These results suggest that omega cells in G. rubens might not play a role in detecting song modulation per se at increased distances from a singing male. [Copyright &y& Elsevier]

In this paper available knowledge on effects from joint and ligament afferents on spinal neurones and pathways are briefly reviewed, and possible functional implications discussed. Ligament afferents may contribute to joint stability, muscle coordination and proprioception through direct polysynaptic reflex effects onto ascending pathways and skeletomotoneurones, and/or indirectly via reflex actions on the γ-muscle spindle system. Theoretical and experimental evidence indicate that ligament afferents, together with afferents from other joint structures, muscles and the skin, provide the CNS with information on movements and posture through ensemble coding mechanisms, rather than via modality specific private pathways. The existence and functional relevance of ligamentomuscular protective reflexes, that are triggered when the ligament is threatened by potentially harmful loads, has been seriously questioned. It seems more likely that peripheral sensory inputs from ligament afferents participate in a continuous control of the muscle activity through feedforward, or preprogramming, mechanisms. In line with these ideas it has been suggested that ligament mechanoreceptors have an important role in muscle coordination and in the reflex regulation of the functional joint stability, by contributing to the preprogramming of the muscle stiffness through reflex modulation of the γ-muscle spindle system. [Copyright &y& Elsevier]

Dynamic shoulder stability is dependent on muscular coordination and sensory inputs. In the shoulder, mechanoreceptors are found in the coracoacromial ligament, the rotator cuff tendons, the musculotendinous junctions of the rotator cuff and in the capsule. The number of receptors in the capsule is small compared to the number in the other shoulder structures. Proprioceptive information from numerous receptors in muscles and tendons is mediated via fast conducting nervefibers and probably contribute more to kinaestethic sensation than information from capsule and ligaments. Therefore it seems likely that the joint receptors have a more distinct role for the kinaestethic sense than muscle receptors. In cats a direct reflex from the afferents innervating the shoulder to the muscles around the shoulder has been presented. The reflex had an extremely short latency (2.7–3.1 ms). In man, a very long latency (300 ms) excitatory reflex has been found when nerves in the capsule were stimulated electrically during shoulder surgery. In addition, when the anterior-inferior capsule was excited in conscious humans with modest amplitude electrical stimuli during muscle activity, a strong inhibition was found with an average latency of 33 ms. Stimulation of the sensory nerves in the coracoacromial ligament has also been found to modify muscle activity strongly. Even though our understanding of the control of shoulder motion is incomplete, it is clear that sensory inputs can strongly modify muscle activity around the shoulder. This has implications for rehabilitation and shoulder surgery. [Copyright &y& Elsevier]

Radiotherapy for malignant tumours often elicits anorexia or loss of appetite as an adverse effect. However, the mechanism for this is poorly understood. The present study was undertaken to investigate if visceral afferents are responsible for reduction of food intake following X-ray irradiation. Rats were exposed bilaterally to X-ray (10 MV) irradiation with total doses of 1.5, 3 and 6 Gy, using a high-energy electron linear accelerator at a dose rate of 4.9 Gy min−1. X-ray irradiation of the whole body, abdomen or head with doses of 1.5, 3 and 6 Gy reduced food intake in a dose-dependent manner. The reduction of food intake after X-ray irradiation of the whole body or abdomen was significantly greater than when only the head was irradiated. Reduction of food intake was observed for the first 4 days after 6 Gy X-ray irradiation of the abdomen, while it was observed only on the first day after the same 6-Gy irradiation of the abdomen in animals whose small-diameter afferents were ablated by capsaicin pre-treatment. These results suggested that the abdominal afferent nerves at least contribute to the reduction of food intake observed on second to fourth days after 6-Gy abdominal irradiation. Taken together, the present evidence suggests that the reduction of food intake following X-ray irradiation of the whole body or the abdomen is partly mediated via abdominal afferent nerves. Moreover, the results of X-ray irradiation to the head suggest that X-ray irradiation directly influences the central nervous system to reduce food intake. [Copyright &y& Elsevier]

The activity of single myelinated afferents was recorded from dorsal roots L4–5 in normal Sprague–Dawley rats and animals that developed mechanical hypersensitivity following ischemic injury to the sciatic nerve. The mechanical response properties and conduction velocity of afferents conducting through the injury site (about 50% of units) were similar to controls. However, the majority of afferents not conducting through the injury site exhibited ongoing activity. The results suggest that mechanical allodynia may be at least partly due to the central integration of activity arising from these two populations of afferents in neuropathic rats. [ABSTRACT FROM AUTHOR]

• From five different retrograde dyes, Di-8-ANEPPQ was the best in labeling cardiac afferents. • 2D and 3D reconstruction of cardiac vagal and spinal afferents were imaged. • Cardiac vagal and spinal afferents had homogeneous and bilateral distribution. • Cardiac sensory neurons constituted at least 5–6% of vagal afferents. • Majority of cardiac afferents were small-sized with nociceptor marker TRPV1 expression. The identity of sensory neurons innervating the heart tissue and the extent of information reported to the brain via these neurons are poorly understood. In order to evaluate the multidimensional distribution and abundance of the cardiac spinal and vagal afferents, we assessed the retrograde labeling efficiency of various tracers, and mapped the cardiac afferents qualitatively and quantitatively at the bilateral nodose ganglia (NGs) and dorsal root ganglia (DRGs). From the five different retrograde tracers evaluated, Di-8-ANEPPQ yielded reproducibly the highest labeling efficiency of cardiac afferents. We demonstrated specific cardiac afferents at NGs and C4 to T11 DRG segments. Next, the 2D reconstruction of the tissue sections and 3D imaging of the whole NGs and DRGs revealed homogeneous and bilateral distribution of cardiac afferents. The quantitative analyses of the labeled cardiac afferents demonstrated approximately 5–6% of the soma in NGs that were equally distributed bilaterally. The neuronal character of Di-8-ANEPPQ labeled cells were validated by coimmunostaning with pan-neuronal marker Tuj-1. In addition, the cell diameters of labeled cardiac sensory neurons were found smaller than 20 μm, implying the nociceptor phenotype confirmed by co-labeling with TRPV1 and Di-8-ANEPPQ. Importantly, co-labeling with two distinct tracers Di-8-ANEPPQ and WGA-647 demonstrated exclusively the same cardiac afferents in DRGs and NGs, validating our findings. Collectively, our findings revealed the cardiac afferents in NGs bilaterally and DRGs with the highest labeling efficiency reported, spatial distribution and quantitation at both 2D and 3D levels, furthering our understanding of this novel neuron population. [ABSTRACT FROM AUTHOR]