Sensitive Afferents Research Articles

Effects of exercise induced muscle damage on cardiovascular responses to isometric muscle contractions and post-exercise circulatory occlusion

PurposeThe aim of the present study was to investigate whether exercise-induced muscle damage (EIMD) influences cardiovascular responses to isometric exercise and post-exercise circulatory occlusion (PECO). We hypothesized that EIMD would increase muscle afferent sensitivity and, accordingly, increase blood pressure responses to exercise and PECO.MethodsEleven male and nine female participants performed unilateral isometric knee extension at 30% of maximal voluntary contraction (MVC) for 3-min. A thigh cuff was rapidly inflated to 250 mmHg for two min PECO, followed by 3 min recovery. Heart rate and blood pressure were monitored beat-by-beat, with stroke volume and cardiac output estimated from the Modelflow algorithm. Measurements were taken before and 48 h after completing eccentric knee-extension contractions to induce muscle damage (EIMD).ResultsEIMD caused 21% decrease in MVC (baseline: 634.6 ± 229.3 N, 48 h: 504.0 ± 160 N), and a 17-fold increase in perceived soreness using a visual-analogue scale (0–100 mm; VASSQ) (both p < 0.001). CV responses to exercise and PECO were not different between pre and post EIMD. However, mean arterial pressure (MAP) was higher during the recovery phase after EIMD (p < 0.05). Significant associations were found between increases in MAP during exercise and VASSQ, Rate of Perceived Exertion (RPE) and Pain after EIMD only (all p < 0.05).ConclusionThe MAP correlations with muscle soreness, RPE and Pain during contractions of damaged muscles suggests that higher afferent activity was associated with higher MAP responses to exercise.

Using macular velocity measurements to relate parameters of bone conduction to vestibular compound action potential responses

To examine mechanisms responsible for vestibular afferent sensitivity to transient bone conducted vibration, we performed simultaneous measurements of stimulus-evoked vestibular compound action potentials (vCAPs), utricular macula velocity, and vestibular microphonics (VMs) in anaesthetized guinea pigs. Results provide new insights into the kinematic variables of transient motion responsible for triggering mammalian vCAPs, revealing synchronized vestibular afferent responses are not universally sensitive to linear jerk as previously thought. For short duration stimuli (< 1 ms), the vCAP increases magnitude in close proportion to macular velocity and temporal bone (linear) acceleration, rather than other kinematic elements. For longer duration stimuli, the vCAP magnitude switches from temporal bone acceleration sensitive to linear jerk sensitive while maintaining macular velocity sensitivity. Frequency tuning curves evoked by tone-burst stimuli show vCAPs increase in proportion to onset macular velocity, while VMs increase in proportion to macular displacement across the entire frequency bandwidth tested between 0.1 and 2 kHz. The subset of vestibular afferent neurons responsible for synchronized firing and vCAPs have been shown previously to make calyceal synaptic contacts with type I hair cells in the striolar region of the epithelium and have irregularly spaced inter-spike intervals at rest. Present results provide new insight into mechanical and neural mechanisms underlying synchronized action potentials in these sensitive afferents, with clinical relevance for understanding the activation and tuning of neurons responsible for driving rapid compensatory reflex responses.

A UAV Wind Field Perception System Inspired by Biological Perception

People have raised their expectations for UAV performance due to the widespread use of UAVs in both military and non-military settings. One of the most significant fields of research right now is how to enhance UAVs’ endurance capabilities. Many birds in the wild have the ability to fly for extended periods of time or great distances using the wind, which is called energy harvesting. A seabird called an albatross can use the wind’s horizontal gradient on the water’s surface to generate energy. By gliding, they may fly for a very long time without flapping their wings, thus lowering their own energy consumption. Due to the albatrosses’ nostrils sensitive sensory nerves and sensitivity to environmental information, such as airflow, the albatrosses can modify its flight attitude. Similar to this, real-time dynamic planning of the trajectory can only be done for UAVs in order to realize energy-capturing flying if correct and real-time wind field information is obtained. As a result, developing wind field sensing technology is crucial to the realization of energy-capturing gliding. In this study, we built a 3D wind field sensing system with wind vane sensor and pitot tube. Wind tunnel tests were used to calibrate and alter it. The system’s operation is initially validated by real flight, which may give environmental information, enabling UAVs to utilize the wind field as a reference for planning their flight paths.

Chronic Pelvic Pain Develops in Sensory Neuron Conditional Asic3 Null Mice Subjected to Chemical Injury

Sensitization of primary afferents is an important underlying mechanism for visceral hypersensitivity and pain. We investigated the contribution of acid-sensing ion channels (ASICs) in sensory neurons to the development of pain in a model of chemical-induced cystitis. ASICs are assembled as heterotrimers in bladder sensory neurons; however, the deletion of the ASIC3 subunit results in a loss-of-function phenotype with sensory neurons unable to discharge action potentials in response to acidification. In this study, conditional sensory neuron Asic3 knockout (KO) mice ( Asic3 fl/fl ;Avil-Cre +/- ) and control littermates ( Asic3 fl/fl ;Avil-Cre -/- ) received cyclophosphamide (CYP) (IP 80 mg/kg), or saline, every other day for five days. Experimental observations were made after one day (acute) or 14 days (chronic) after the last dose of CYP. In the acute setting, both control and conditional Asic3 KO mice treated with CYP exhibited an irritated bladder phenotype with a high number of voiding events of small volume. However, voiding activity normalized in both groups within two weeks of receiving CYP. In contrast, conditional Asic3 KO mice treated with CYP developed pelvic allodynia that persisted for at least two weeks, whereas control mice had no pain phenotype. In the chronic setting, no apparent edema or inflammatory cells were observed in bladders of control or conditional Asic3 KO mice, indicating that the pelvic allodynia seen in conditional Asic3 KO mice treated with CYP is likely driven by abnormal functioning of the nervous system and not by inflammation. To assess whether, in the chronic setting, the referred pelvic allodynia seen in conditional Asic3 KO mice treated with CYP is caused by sensitized primary afferents, we examined the firing evoked by sustained suprathreshold electrical stimulation of acutely isolated bladder sensory neurons. Sensory neurons were classified based of the sensitivity of the action potential to tetrodotoxin (TTX), as TTX-resistant (TTX-R) or TTX-sensitive (TTX-S). Strikingly, ~ 40% (11/17) of the bladder sensory neurons with TTX-R action potentials from conditional Asic3 KO mice treated with CYP exhibited aberrant firing (i.e., sensitization) in response to suprathreshold stimulation, compared to 3% (1/33) in control mice. These findings indicate that the pelvic allodynia seen in conditional Asic3 KO mice is driven in part by sensitized bladder afferents. Taken together, our studies support the notion that ASICs operate at the nerve terminals to modulate nociceptor excitability and sensitization. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dietary monosodium glutamate increases visceral hypersensitivity in a mouse model of visceral pain.

Monosodium glutamate (MSG) has been identified as a trigger of abdominal pain in irritable bowel syndrome (IBS), but the mechanism is unknown. This study examined whether MSG causes visceral hypersensitivity using a water-avoidance stress (WAS) mouse model of visceral pain. Mice were divided into four groups receiving treatment for 6 days: WAS + MSG gavage, WAS + saline gavage, sham-WAS + MSG gavage, and sham-WAS + saline gavage. The acute effects of intraluminal administration of 10 μM MSG on jejunal extrinsic afferent nerve sensitivity to distension (0-60 mmHg) were examined using ex vivo extracellular recordings. MSG was also applied directly to jejunal afferents from untreated mice. Glutamate concentration was measured in serum, and in the serosal compartment of Ussing chambers following apical administration. Acute intraluminal MSG application increased distension responses of jejunal afferent nerves from mice exposed to WAS + MSG. This effect was mediated by wide dynamic range and high-threshold units at both physiologic and noxious pressures (10-60 mmHg, p < 0.05). No effect of MSG was observed in the other groups, or when applied directly to the jejunal afferent nerves. Serum glutamate was increased in mice exposed to WAS + MSG compared to sham-WAS + saline, and serosal glutamate increased using WAS tissue (p = 0.0433). These findings demonstrate that repeated exposure to MSG in mice leads to sensitization of jejunal afferent nerves to acute ex vivo exposure to MSG. This may contribute to visceral hypersensitivity reported in response to MSG in patients with IBS.

Effects of Nitric Oxide on the Activity of P2X and TRPV1 Receptors in Rat Meningeal Afferents of the Trigeminal Nerve.

Nitric oxide is one of the endogenous molecules that play a key role in migraine. However, the interaction between NO and the main players in the nociceptive activity of the meningeal trigeminal afferents-TRPV1 and P2X3 receptors-remains unstudied. In the current project, the effects of acute and chronic NO administration on the activity of TRPV1 and P2X3 receptors in the peripheral afferents were studied using electrophysiological recording of action potentials of the trigeminal nerve in the rat hemiskull preparations. The data obtained indicate that exogenous and endogenous NO increased the activity of the trigeminal nerve independent on the inhibition of the TRPV1 and P2X3 receptors. The activity of the trigeminal nerve triggered by ATP changed neither in acute incubation in the NO donor-sodium nitroprusside (SNP) nor in the chronic nitroglycerine (NG)-induced migraine model. Moreover, the chronic NG administration did not increase in the number of degranulated mast cells in the rat meninges. At the same time, the capsaicin-induced activity of the trigeminal nerve was higher with chronic NO administration or after acute NO application, and these effects were prevented by N-ethylmaleimide. In conclusion, we suggested that NO positively modulates the activity of TRPV1 receptors by S-nitrosylation, which may contribute to the pro-nociceptive action of NO and underlie the sensitization of meningeal afferents in chronic migraine.

The voltage-gated sodium channel NaV1.7 underlies endometriosis-associated chronic pelvic pain.

Chronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera has shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar approaches for endometriosis-associated CPP remain underdeveloped. Here, we examined the role of the voltage-gated sodium (NaV) channel NaV1.7 in (i) the sensitivity of vagina-innervating sensory afferents and investigated whether (ii) NaV1.7 inhibition reduces nociceptive signals from the vagina and (iii) ameliorates endometriosis-associated CPP. The mechanical responsiveness of vagina-innervating sensory afferents was assessed with ex vivo single-unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of NaV1.7 with OD1 sensitised vagina-innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitised vagina-innervating pelvic afferents to mechanical stimuli. The highly selective NaV1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a NaV1.7-dependent manner. Moreover, in vivo intra-vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD which is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechanosensitivity nor in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that NaV1.7 plays a crucial role in endometriosis-induced vaginal hyperalgesia. Importantly, NaV1.7 inhibition selectively alleviated endometriosis-associated CPP without the loss of normal sensation, suggesting that selective targeting of NaV1.7 could improve the quality of life of women with endometriosis.

TRP Channels: Recent Development in Translational Research and Potential Therapeutic Targets in Migraine.

Migraine is a chronic neurological disorder that affects approximately 12% of the population. The cause of migraine headaches is not yet known, however, when the trigeminal system is activated, neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) are released, which cause neurogenic inflammation and sensitization. Advances in the understanding of migraine pathophysiology have identified new potential pharmacological targets. In recent years, transient receptor potential (TRP) channels have been the focus of attention in the pathophysiology of various pain disorders, including primary headaches. Genetic and pharmacological data suggest the role of TRP channels in pain sensation and the activation and sensitization of dural afferents. In addition, TRP channels are widely expressed in the trigeminal system and brain regions which are associated with the pathophysiology of migraine and furthermore, co-localize several neuropeptides that are implicated in the development of migraine attacks. Moreover, there are several migraine trigger agents known to activate TRP channels. Based on these, TRP channels have an essential role in migraine pain and associated symptoms, such as hyperalgesia and allodynia. In this review, we discuss the role of the certain TRP channels in migraine pathophysiology and their therapeutic applicability.

Enhanced Respiratory Frequency Response to Lower Limb Mechanoreceptors Activation in Patients with Chronic Obstructive Pulmonary Disease.

To investigate the mechanoreflex control of respiration and circulation in patients with chronic obstructive pulmonary disease (COPD). Twenty-eight patients with moderate-to-severe COPD (mean ± SD: 67.0 ± 7.9 yr, 10 women) and 14 age- and sex-matched controls (67.9 ± 2.6 yr, 7 women) participated in the study. Their dominant knee was passively moved to stimulate mechanoreceptors, whereas vastus lateralis surface electrical activity checked active contractions. A differential pressure flowmeter, an electrocardiogram, and a servo-controlled finger photoplethysmograph acquired cardiorespiratory data. To gain insight into the mechanoreflex arc, we further analyzed reduced/oxidized glutathione ratio and mechanoreceptor-related gene expression in a vastus lateralis biopsy of additional nine patients (63.9 ± 8.1 yr, 33% women) and eight controls (62.9 ± 9.1 yr, 38% women). Patients with COPD had a greater peak respiratory frequency response (COPD: Δ = 3.2 ± 2.3 vs Controls: 1.8 ± 1.2 cycles per minute, P = 0.036) and a smaller peak tidal volume response to passive knee movement than controls. Ventilation, heart rate, stroke volume, and cardiac output peak responses, and total peripheral resistance nadir response, were unaltered by COPD. In addition, patients had a diminished glutathione ratio (COPD: 13.3 ± 3.8 vs controls: 20.0 ± 5.5 a.u., P = 0.015) and an augmented brain-derived neurotrophic factor expression (COPD: 2.0 ± 0.7 vs controls: 1.1 ± 0.4 a.u., P = 0.002) than controls. Prostaglandin E receptor 4, cyclooxygenase 2, and Piezo1 expression were similar between groups. Respiratory frequency response to mechanoreceptors activation is increased in patients with COPD. This abnormality is possibly linked to glutathione redox imbalance and augmented brain-derived neurotrophic factor expression within locomotor muscles, which could increase mechanically sensitive afferents' stimulation and sensitivity.

O014 / #637 MACROPHAGE ACTIVATION IN CARDIOTHORACIC DORSAL ROOT GANGLIA SENSITIZES CARDIAC SPINAL AFFERENTS ASSOCIATED WITH A SUPPRESSION OF VOLTAGE-GATED POTASSIUM CHANNELS IN HEART FAILURE: TRACK 4: CARDIOVASCULAR DISORDERS / NEURAL ENGINEERING

The enhanced cardiac sympathetic afferent reflex (CSAR), a sympatho-excitatory reflex originating in the heart, contributes to elevated sympathetic tone as well as cardiac remodeling in chronic heart failure (CHF). The molecular and cellular mechanisms underlying cardiac spinal afferent sensitization are not fully understood. We hypothesized that chronic macrophage activation in the thoracic dorsal root ganglia (DRG) sensitizes cardiac spinal afferents via suppression of voltage-gated potassium (Kv) channels in CHF.

Activation of uroepithelial 5-HT4R inhibits mechanosensory activity of murine bladder afferent nerves.

Serotonin (5-HT) is known to act via multiple 5-HT receptors at spinal and supraspinal levels to regulate micturition. However, the contribution of peripheral 5-HT and its receptors in bladder physiology and pathology is not very well understood, despite evidence showing expression of multiple 5-HT receptors in the bladder wall and 5-HT may activate bladder afferent nerves. The current study was designed to investigate the possible role of 5-HT4R in modulation of the sensitivity of bladder afferents to bladder filling. Immunofluorescent staining showed abundant 5-HT4R immunoreactivity largely confined to the uroepithelium in wild type (WT) but not 5-HT4R−/− mice. In the ex vivo bladder-pelvic nerve preparation, intravesical application of the 5-HT4R agonist RS67333 (1–30 μm) caused concentration-dependent decreases of the pelvic nerve response to bladder filling. Such effect was not observed in the presence of 5-HT4R antagonist GR125487 or in 5-HT4R−/− preparations. A cohort of 5-HT4R−/− and WT control mice were treated with intraperitoneal injections of cyclophosphamide (CYP) (75 mg/kg, three times at 2 days interval) to induce chronic cystitis. Void spot analysis showed that CYP-treated 5-HT4R−/− mice urinated more frequently than their CYP-treated WT counterparts. Concomitantly, bladder afferents of CYP-treated 5-HT4R−/− mice displayed exaggerated sensitivity to bladder filling in comparison with the CYP-treated WT controls. These data suggest that 5-HT4R expressed on uroepithelial cells plays an inhibitory role in mechanosensory transduction in the bladder. Loss of 5-HT4R-mediated inhibition may enhance bladder afferent sensitivity and exacerbate bladder overactivity in pathological conditions. We propose that 5-HT4R agonists might be exploited for the treatment of overactive and painful bladder symptoms.

Sensitization of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity.

Visceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut‐related side‐effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro‐inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNFα‐triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesized that TNFR1‐evoked p38 MAPK activity may also be responsible for TNFα sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNFα‐mediated increases in intracellular [Ca2+] and sensitization of capsaicin responses. The sensitizing effects of TNFα were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre‐treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα‐induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease. Key points The pro‐inflammatory cytokine TNFα is elevated in gastrointestinal disease and sensitizes colonic afferents via modulation of TRPA1 and NaV1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα‐mediated colonic afferent sensitization. Specifically, we show that:TNFα sensitizes sensory neurons and colonic afferents to the TRPV1 agonist capsaicin.TNFα‐mediated sensitization of sensory neurons and colonic nociceptors is dependent on TNFR1 expression.TNFα sensitization of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK.Collectively these data support the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in gastrointestinal disease.

Continuous administration of mirabegron has advantages in inhibition of central sensitization compared with short-term treatment cessation in a mouse model of overactive bladder.

There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model. Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, β-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization. OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51vs. 5.76 ± 0.95 min in sham mice), increased non-voiding contractions (0.39 ± 0.11vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, β2, β3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG indicate bladder efferent and afferent hyperexcitability. In addition, CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in OAB mice. However, theCON group exhibited reduced β2, β3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder, reduced CCL2 and CCR2 in DRG, which are markers of afferent hyperexcitability, and reduced immunoreactivities of CX3CR1, GFAP, and CCR2 in the L6 spinal cord, which are markers of the central sensitization. Moreover, theCON group showed better improvements in nonvoiding contractions (0.16 ± 0.09vs. 0.44 ± 0.17/min) and voiding efficiency (93.9 ± 7.4% vs. 76.5 ± 13.1%) and reductions in bladder β3 receptors and CCL2 of L6-S1 DRG, and immunoreactivities of CX3CR1 and GFAP in the L6 spinal cord compared to theCES group. Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

Effect of Sympathetic Neurotransmitters on Muscle Spindle Afferent Sensitivity to Muscle Stretch in Adult Mice

The primary sensory input for proprioception, or the sense of body position in space, comes from muscle spindle afferents, which are mechanoreceptors that relay information about changes in muscle length. The muscle spindle is also innervated by sympathetic neurons, but the role of this sympathetic innervation on muscle spindle function is not well understood. Here we test the hypothesis that muscle spindle afferents will exhibit decreased firing in response to muscle stretch following exposure to the sympathetic neurotransmitters norepinephrine and epinephrine. To test this hypothesis we used an ex vivo mouse muscle‐nerve preparation. We recorded muscle spindle afferent firing activity during ramp‐and‐hold stretch and sinusoidal vibration before and after the addition of norepinephrine, epinephrine, or adrenergic receptor agonists. We observed significantly decreased firing during the end of stretch after both norepinephrine (100 µm, n=6) and epinephrine (30 µm, n=6). To identify the adrenergic receptor(s) involved, we also tested two ɑ2 adrenergic receptor agonists, Clonidine and Dexmedetomidine, and the ɑ1 receptor agonist phenylephrine. Both ɑ2 receptor agonists caused a decrease in muscle spindle afferent firing (1 mM clonidine, n=8 decreased firing; 100 µm dexmedetomidine, n=3). Phenylephrine had no significant effect on muscle spindle afferent firing (100 µm n=2; 30 µm n=6). These results show direct effects of sympathetic neurotransmitters on muscle spindle afferent stretch sensitivity and further support the hypothesis that sympathetic innervation of the muscle spindle plays an important role in modulating muscle spindle afferent activity and therefore motor control. Future studies will investigate the location of the adrenergic receptor(s) mediating this effect as well as the mechanism of action.

SPARC: Sex difference in colorectal afferent sensitization in zymosan‐induced visceral hypersensitivity as revealed by high‐throughput GCaMP recordings in thoracolumbar and lumbosacral DRG

Female patients with irritable bowel syndrome (IBS) report more intense visceral pain sensation than male patients. Female rats show more sensitive and cycle‐dependent visceromotor responses (VMR) to graded colorectal distension (CRD). Both clinical psychophysical evidence and preclinical behavioral data support an apparent sex difference in visceral nociception. However, very little is known regarding the potential differences in sensory neural encoding of distal colon and rectum (colorectum) between males and females. In this study, we systematically assessed the sex difference in colorectal neural encoding by conducting high‐throughput optical recordings in intact dorsal root ganglia (DRG) from control and visceral hypersensitive mice. We crossbred GCaMP6f mice with VGLUT2‐Cre mice to express GCamP6f gene in most colorectal sensory neurons. Mice receiving intracolonic treatment of zymosan (30mg/mL, 0.2mL) for three consecutive days developed behavioral visceral hypersensitivity as validated by enhanced VMR to CRD. We then harvested the colorectum with pelvic nerve, lumbar splanchnic nerve and T12 to S1 DRG in continuity in an ex vivo preparation for GCaMP6f recordings. A total of 2275 colorectal afferents were characterized from both sexes in control and zymosan‐treated groups. DRG neurons responding to either colorectal distension (15, 30, 45 and 60 mmHg) and/or mucosal shearing (20‐30 mL/min) were functionally categorized into four classes: mucosal, muscular‐mucosal and high‐ and low‐threshold muscular afferents. In control group, the number of colorectal afferents recorded per mouse were slightly lower in male mice than in female ones (38.7 vs. 45.2) with no significant difference in their distributions across thoracolumbar (TL) and lumbosacral (LS) DRG. In zymosan group, more afferents were recorded from each male mice than female ones (53.8 vs. 44.1) showing significantly higher TL innervation (T12, L1, and L2 DRG) in male group. Within the male groups, zymosan treatment resulted in a significant increase in the proportion of TL innervation as compared with saline treatment. In contrast, female mice showed no difference in the proportion of colorectal neurons between saline‐ and zymosan‐treated groups. Our results have revealed a significant sex difference in colorectal afferent innervation and sensitization in the context of behavioral visceral hypersensitivity. The current outcomes draw further focused research on the neurophysiological differences between sexes that could drive the differential gastrointestinal symptoms in male and female IBS patients.

Differential Activation of Canal and Otolith Afferents by Acoustic Tone Bursts in Rats.

Vestibular evoked myogenic potentials (VEMPs) are routinely used to test otolith function, but which specific vestibular afferent neurons and central circuits are activated by auditory frequency VEMP stimuli remains unclear. To examine this question, we analyzed the sensitivity of individual vestibular afferents in adult Sprague-Dawley rats to tone bursts delivered at 9 frequencies (125-4000Hz) and 3 intensity levels (60, 70, 80dB SL re: acoustic brainstem response (ABR) threshold). Afferent neuron tone sensitivity was quantified by the cumulative probability of evoking a spike (CPE). Based on a threshold CPE of 0.1, acoustic stimuli in the present study evoked responses in 78.2 % (390/499) of otolith afferent neurons vs. 48.4 % (431/891) of canal afferent neurons. Organ-specific vestibular inputs to the central nervous system in response to tone bursts differ based on intensity and frequency content of the stimulus. At frequencies below 500Hz, tone bursts primarily activated both otolith afferents, even at the highest intensity tested (80dB SL re ABR threshold). At 1500Hz, however, tone bursts activated the canal and otolith afferents at the moderate and high intensities tested (70, 80dB SL), but activated only otolith afferents at the low intensity tested (60dB SL). Within an end organ, diversity of sensitivity between individual afferent neurons correlated with spontaneous discharge rate and regularity. Examination of inner ear fluid mechanics in silico suggests that the frequency response and preferential activation of the otolith organs likely arise from inner ear fluid motion trapped near the oval and round windows. These results provide insight into understanding the mechanisms of sound activation of the vestibular system and developing novel discriminative VEMP testing protocols and interpretative guidelines in humans.

Cardiorespiratory responses to muscle metaboreflex activation in fibrosing interstitial lung disease.

New Findings What is the central question of this study? We determined whether sensory feedback from metabolically sensitive skeletal muscle afferents (metaboreflex) causes a greater ventilatory response and higher dyspnoea ratings in fibrosing interstitial lung disease (FILD). What is the main finding and its importance? Ventilatory responses and dyspnoea ratings during handgrip exercise and metaboreflex isolation were not different in FILD and control groups. Blood pressure and heart rate responses to handgrip were attenuated in FILD but not different to controls during metaboreflex isolation. These findings suggest that the muscle metaboreflex contribution to the respiratory response to exercise is not altered in FILD. Exercise limitation and dyspnoea are hallmarks of fibrosing interstitial lung disease (FILD); however, the physiological mechanisms are poorly understood. In other respiratory diseases, there is evidence that an augmented muscle metaboreflex may be implicated. We hypothesized that metaboreflex activation in FILD would result in elevated ventilation and dyspnoea ratings compared to healthy controls, due to augmented muscle metaboreflex. Sixteen FILD patients (three women, 69±14 years; mean±SD) and 16 age‐matched controls (four women, 67±7 years) were recruited. In a randomized cross‐over design, participants completed two min of rhythmic handgrip followed by either (i) two min of post‐exercise circulatory occlusion (PECO trial) to isolate muscle metaboreflex activation, or (ii) rested for four min (Control trial). Minute ventilation (V˙E; pneumotachometer), dyspnoea ratings (0–10 Borg scale), mean arterial pressure (MAP; finger photoplethysmography) and heart rate (HR; electrocardiogram) were measured. V˙E was higher in the FILD group at baseline and exercise increased V˙E similarly in both groups. V˙E remained elevated during PECO, but there was no between‐group difference in the magnitude of this response (ΔV˙E FILD 4.2 ± 2.5 L·min–1 vs. controls 3.6 ± 2.4 L·min–1, P = 0.596). At the end of PECO, dyspnoea ratings in FILD were similar to controls (1.0 ± 1.3 units vs. 0.5 ± 1.1 units). Exercise increased MAP and HR (P < 0.05) in both groups; however, responses were lower in FILD. Collectively, these findings suggest that there is not an augmented effect of the muscle metaboreflex on breathing and dyspnoea in FILD, but haemodynamic responses to handgrip are reduced relative to controls.

Дистанционная психологическая помощь при хронической висцеральной боли на фоне синдрома раздраженного кишечника.

Chronic visceral pain, which increases with stress, is a hallmark of functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Modern pharmacological interventions, diets for patients with chronic visceral pain are usually insufficient, and many of them are fraught with undesirable side effects and short remission. Modern protocols of cognitive behavioral therapy of the third wave, which are available in a remote format, show efficiency, cost-effectiveness in relieving chronic visceral pain caused by stress. The article describes the specifics of the third wave of CBT in relation to the treatment of IBS. A cognitive-behavioral approach to the treatment of irritable bowel syndrome is detailed, which reverses increased stress reactivity and afferent sensitization in the central and peripheral nervous systems, respectively, which leads to a more complete and prolonged relief of IBS symptoms in the patient. The specificity and effectiveness of the protocol of remote cognitive behavioral therapy to enhance awareness in IBS J. is shown. Henrich and integration of cognitive behavioral therapy of the second and third waves to improve the lifestyle of patients with IBS.

Mechanisms of reduced leptin-mediated satiety signaling during obesity.

Disrupted leptin signaling in vagal afferent neurons contributes to hyperphagia and obesity. Thus, we tested the hypothesis that intrinsic negative regulators of leptin signaling, suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B) underlie dysfunctional leptin-mediated vagal afferent satiety signaling during obesity. Experiments were performed on standard chow-fed control mice, high-fat fed (HFF), or low-fat fed (LFF) mice. SOCS3 and PTP1B expression were quantified using western blot and quantitative PCR. Nodose ganglion neuronal excitability and jejunal afferent sensitivity were measured by patch clamp and extracellular afferent recordings, respectively. Increased expression of SOCS3 and PTP1B were observed in the jejunum of HFF mice. Prolonged incubation with leptin attenuated nodose ganglion neuronal excitability, and this effect was reversed by inhibition of SOCS3. Leptin potentiated jejunal afferent nerve responses to CCK in LFF mice but decreased them in HFF mice. Inhibition of SOCS3 restored impaired vagal afferent neuronal excitability and afferent nerve responses to satiety mediators during obesity. Two-pore domain K+ channel (K2P) conductance and nitric oxide (NO) production that we previously demonstrated were elevated during obesity were decreased by inhibitions of SOCS3 or PTP1B. This study suggests that obesity impairs vagal afferent sensitivity via SOCS3 and PTP1B, likely as a consequence of obesity-induced hyperleptinemia. The mechanisms underlying leptin resistance appear also to cause a more global impairment of satiety-related vagal afferent responsiveness.

Disruption of Hyaluronic Acid in Skeletal Muscle Induces Decreased Voluntary Activity via Chemosensitive Muscle Afferent Sensitization in Male Mice.

PEGPH20, a human recombinant hyaluronidase, has been proposed as a coadjutant to pancreatic cancer chemotherapy. In early trials, patients reported increased widespread muscle pain as the main adverse reaction to PEGPH20. To understand how PEGPH20 caused musculoskeletal pain, we systemically administered PEGPH20 to male mice and measured voluntary wheel activity and pain-related behaviors. These were paired with ex vivo electrophysiology of primary sensory neurons, whole DRG real-time PCR, and immunohistochemistry of hindpaw muscle. PEGPH20 induced significantly lower wheel running, compared with vehicle-treated animals, and decreased mechanical withdrawal thresholds 5 d after PEGPH20 injections. Chemo-sensory muscle afferents showed increased responses to noxious chemical stimulation of their receptive fields (RFs) in the PEGPH20-treated group. This was correlated with upregulation of the NGF receptor TrkA, the transient receptor potential vanilloid type 1 (TRPV1) channel and ATP-sensitive channel P2X3 in the DRG. Immunohistochemistry of hindpaw muscles revealed damage to the muscle architecture and extensive infiltration of the tissue by cells of the myelomonocytic lineage 3 d after PEGPH20 injection. Peripheral macrophage ablation in macrophage Fas-induced apoptosis (MaFIA) mice, however, did not prevent the decreased voluntary activity and instead caused even lower levels of running. These results suggest that disruption of hyaluronic acid (HA) within the muscle extracellular matrix (ECM) sensitizes chemo-nociceptive muscle afferents possibly leading to altered pain-like behaviors. Ablation experiments suggest macrophages are necessary for adequate recovery of voluntary activity after HA disruption. These data support a role for HA and macrophages in tissue integrity and muscle pain development in patients taking PEGPH20.