ContextVisceral pain is a leading symptom for patients with irritable bowel syndrome (IBS) that affects 10% - 20 % of the world population. Conventional pharmacological treatments to manage IBS-related visceral pain is unsatisfactory. Recently, medications have emerged to treat IBS patients by targeting the gastrointestinal (GI) tract and peripheral nerves to alleviate visceral pain while avoiding adverse effects on the central nervous system (CNS). Several investigational drugs for IBS also target the periphery with minimal CNS effects.Evidence of AcquisitionIn this paper, reputable internet databases from 1960 - 2016 were searched including Pubmed and ClinicalTrials.org, and 97 original articles analyzed. Search was performed based on the following keywords and combinations: irritable bowel syndrome, clinical trial, pain, visceral pain, narcotics, opioid, chloride channel, neuropathy, primary afferent, intestine, microbiota, gut barrier, inflammation, diarrhea, constipation, serotonin, visceral hypersensitivity, nociceptor, sensitization, hyperalgesia.ResultsCertain conventional pain managing drugs do not effectively improve IBS symptoms, including NSAIDs, acetaminophen, aspirin, and various narcotics. Anxiolytic and antidepressant drugs (Benzodiazepines, TCAs, SSRI and SNRI) can attenuate pain in IBS patients with relevant comorbidities. Clonidine, gabapentin and pregabalin can moderately improve IBS symptoms. Lubiprostone relieves constipation predominant IBS (IBS-C) while loperamide improves diarrhea predominant IBS (IBS-D). Alosetron, granisetron and ondansetron can generally treat pain in IBS-D patients, of which alosetron needs to be used with caution due to cardiovascular toxicity. The optimal drugs for managing pain in IBS-D and IBS-C appear to be eluxadoline and linaclotide, respectively, both of which target peripheral GI tract.ConclusionsConventional pain managing drugs are in general not suitable for treating IBS pain. Medications that target the GI tract and peripheral nerves have better therapeutic profiles by limiting adverse CNS effects.

Electrode arrays interfacing with peripheral nerves are essential for neuromodulation devices targeting peripheral organs to relieve symptoms. To modulate (i.e., single-unit recording and stimulating) individual peripheral nerve axons remains a technical challenge. Here, we report an in vitro setup to allow simultaneous single-unit recordings from multiple mouse sciatic nerve axons. The sciatic nerve (~30 mm) was harvested and transferred to a tissue chamber, the ~5mm distal end pulled into an adjacent recording chamber filled with paraffin oil. A custom-built multi-wire electrode array was used to interface with split fine nerve filaments. Single-unit action potentials were evoked by electrical stimulation and recorded from 186 axons, of which 49.5% were classed A-type with conduction velocities (CV) greater than 1 m/s and 50.5% were C-type (CV < 1 m/s). The single-unit recordings had no apparent bias towards A- or C-type axons, were robust and repeatable for over 60 minutes, and thus an ideal opportunity to assess different neuromodulation strategies targeting peripheral nerves. For instance, ultrasonic modulation of action potential transmission was assessed using the setup, indicating increased nerve conduction velocity following ultrasound stimulus. This setup can also be used to objectively assess the design of next-generation electrode arrays interfacing with peripheral nerves.

Visceral pain is one of the principal complaints of patients with irritable bowel syndrome, and this pain is reliably evoked by mechanical distension and stretch of distal colon and rectum (colorectum). This study focuses on the biomechanics of the colorectum that could play critical roles in mechanical neural encoding. We harvested the distal 30 mm of the colorectum from mice, divided evenly into three 10-mm-long segments (colonic, intermediate and rectal), and conducted biaxial mechanical stretch tests and opening-angle measurements for each tissue segment. In addition, we determined the collagen fiber orientations and contents across the thickness of the colorectal wall by nonlinear imaging via second harmonic generation (SHG). Our results reveal a progressive increase in tissue compliance and prestress from colonic to rectal segments, which supports prior electrophysiological findings of distinct mechanical neural encodings by afferents in the lumbar splanchnic nerves (LSN) and pelvic nerves (PN) that dominate colonic and rectal innervations, respectively. The colorectum is significantly more viscoelastic in the circumferential direction than in the axial direction. In addition, our SHG results reveal a rich collagen network in the submucosa and orients approximately ±30° to the axial direction, consistent with the biaxial test results presenting almost twice the stiffness in axial direction versus the circumferential direction. Results from current biomechanical study strongly indicate the prominent roles of local tissue biomechanics in determining the differential mechanical neural encoding functions in different regions of the colorectum. NEW & NOTEWORTHY Mechanical distension and stretch—not heat, cutting, or pinching—reliably evoke pain from distal colon and rectum. We report different local mechanics along the longitudinal length of the colorectum, which is consistent with the existing literature on distinct mechanotransduction of afferents innervating proximal and distal regions of the colorectum. This study draws attention to local mechanics as a potential determinant factor for mechanical neural encoding of the colorectum, which is crucial in visceral nociception.

Abstract. Ultrasound that is widely used in medical diagnosis has drawn growing interests as a noninvasive means of neuromodulation. Focused pulsed ultrasound (FPUS) effectively modulates neural encoding and transmission in the peripheral nervous system (PNS) with unclear mechanism of action, which is further confounded by contradictory experimental outcomes from recordings of compound action potentials (CAP). To address that, we developed a novel in vitro set up to achieve simultaneous single-unit recordings from individual mouse sciatic nerve axon and systematically studied the neuromodulation effects of FPUS on individual axon. Unlike previous CAP recordings, our single-unit recordings afford superior spatial and temporal resolution to reveal the subtle but consistent effects of ultrasonic neuromodulation. Our results indicate that, 1) FPUS did not evoke action potentials directly in mouse sciatic nerve at all the tested intensities (spatial peak temporal average intensity, ISPTA of 0.91 to 28.2 W/cm 2 ); 2) FPUS increases the nerve conduction velocity (CV) in both fast-conducting A-and slow-conducting C-type axons with effects more pronounced at increased stimulus duration and intensity; and 3) effects of increased CV is reversible and cannot be attributed to the change of local temperature. Our results support existing theories of non-thermal mechanisms underlying ultrasonic neuromodulation with low-intensity FPUS, including NICE, flexoelectricity, and solition models. This work also provides a solid experimental basis to further advance our mechanistic understandings of ultrasonic neuromodulation in the PNS. IntroductionUltrasound (US) has prevailed the field of medical diagnosis for long but yet to be established as a therapeutic paradigm. Neuromodulatory effects of US were first reported in 1929 when Harvey showed that innervated skeletal muscles from frogs and turtles responded to US stimulation in vitro (1). More recent researches focus on the US effects at the central nervous system (CNS), including the disruption of blood brain barrier, motor and sensory responses, and suppressed or evoked action potentials e.g., (2-12), which culminated in the approval of the Food and Drug Administration (FDA) to treat refractory patients with essential tremor using MRI-guided focused ultrasound (13). In addition, ex vivo studies on hippocampal slice cultures have shown that, low-intensity FPUS can elicit electrical activities as indicated by calcium imaging from mouse (14) and simultaneously enhance (at fiber volley) and suppress (at dendritic layers) compound action potentials (CAP) from rat hippocampal dentate gyrus (15).In contrast, the effects of US on the peripheral nervous system (PNS) is comparatively understudied with inconsistent reports. US appears to evoke or enhance the peripheral neural activities in frog sciatic nerve in vitro (16), sensitize neuron in C. elegans (17), cause deqi sensations (i.e., tingling, numbness, heaviness, and fullness) by stimulation of an acupuncture point (LI4, He Gu) (18), an...

Neuromodulation as a non‐drug alternative for managing visceral pain in irritable bowel syndrome ( IBS ) may target sensitized afferents of distal colon and rectum (colorectum), especially their somata in the dorsal root ganglion ( DRG ). Developing selective DRG stimulation to manage visceral pain requires knowledge of the topological distribution of colorectal afferent somata which are sparsely distributed in the DRG . Here, we implemented GC a MP 6f to conduct high‐throughput optical recordings of colorectal afferent activities in lumbosacral DRG , that is, optical electrophysiology. Using a mouse ex vivo preparation with distal colorectum and L5‐S1 DRG in continuity, we recorded 791 colorectal afferents' responses to graded colorectal distension (15, 30, 40, and 60 mmHg) and/or luminal shear flow (20–30 mL /min), then functionally classified them into four mechanosensitive classes, and determined the topological distribution of their somata in the DRG . Of the 791 colorectal afferents, 90.8% were in the L6 DRG , 8.3% in the S1 DRG , and only 0.9% in the L5 DRG . L6 afferents had all four classes: 29% mucosal, 18.4% muscular‐mucosal, 34% low‐threshold ( LT ) muscular, and 18.2% high‐threshold ( HT ) muscular afferents. S1 afferents only had three classes: 19.7% mucosal, 34.8% LT muscular, and 45.5% HT muscular afferents. All seven L5 afferents were HT muscular. In L6 DRG , somata of HT muscular afferents were clustered in the caudal region whereas somata of the other classes did not cluster in specific regions. Outcomes of this study can directly inform the design and improvement of next‐generation neuromodulation devices that target the DRG to alleviate visceral pain in IBS patients.

Ultrasonic (US) neuromodulation has emerged as a promising therapeutic means by delivering focused energy deep into the nervous tissue. Low-intensity ultrasound (US) directly activates and/or inhibits neurons in the central nervous system (CNS). US neuromodulation of the peripheral nervous system (PNS) is less developed and rarely used clinically. The literature on the neuromodulatory effects of US on the PNS is controversial, with some studies documenting enhanced neural activities, some showing suppressed activities, and others reporting mixed effects. US, with different ranges of intensity and strength, is likely to generate distinct physical effects in the stimulated neuronal tissues, which underlies different experimental outcomes in the literature. In this review, we summarize all the major reports that document the effects of US on peripheral nerve endings, axons, and/or somata in the dorsal root ganglion. In particular, we thoroughly discuss the potential impacts of the following key parameters on the study outcomes of PNS neuromodulation by US: frequency, pulse repetition frequency, duty cycle, intensity, metrics for peripheral neural activities, and type of biological preparations used in the studies. Potential mechanisms of peripheral US neuromodulation are summarized to provide a plausible interpretation of the seemly contradictory effects of enhanced and suppressed neural activities of US neuromodulation.

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We have tested the feasibility of thermal grills, a harmless method to induce pain. The thermal grills consist of interlaced tubes that are set at cool or warm temperatures creating a painful "illusion" (no tissue injure is caused) in the brain when the cool and warm stimuli are presented collectively. Advance in objective pain assessment research is limited because the gold standard, the self-reporting pain scales, is highly subjective and only works for alert and cooperative patients. However, the main difficulty for pain studies is the potential harm caused to participants. We have recruited N=23 subjects in whom we induced electric pulses (EP) and thermal grill (TG) stimulation. The TG effectively induced three different levels of pain, as evidenced by the visual analogue scale (VAS) provided by the subjects after each stimulus. Furthermore, objective physiological measurements based on electrodermal activity (EDA) showed a significant increase in levels as stimulation level increases. We found that VAS was highly correlated with the TG stimulation level. The thermal grill stimulation safely elicited pain levels up to 9 out of 10. The TG stimulation allows extending studies of pain to ranges of pain in which other stimuli are harmful.