Capsaicin-Sensitive Vagal Afferent Nerve-Mediated Interoceptive Signals in the Esophagus

Heartburn and non-cardiac chest pain are the predominant symptoms in many esophageal disorders, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), functional heartburn and chest pain, and eosinophilic esophagitis (EoE). At present, neuronal mechanisms underlying the process of interoceptive signals in the esophagus are still less clear. Noxious stimuli can activate a subpopulation of primary afferent neurons at their nerve terminals in the esophagus. The evoked action potentials are transmitted through both the spinal and vagal pathways to their central terminals, which synapse with the neurons in the central nervous system to induce esophageal nociception. Over the last few decades, progress has been made in our understanding on the peripheral and central neuronal mechanisms of esophageal nociception. In this review, we focus on the roles of capsaicin-sensitive vagal primary afferent nodose and jugular C-fiber neurons in processing nociceptive signals in the esophagus. We briefly compare their distinctive phenotypic features and functional responses to mechanical and chemical stimulations in the esophagus. Then, we summarize activation and/or sensitization effects of acid, inflammatory cells (eosinophils and mast cells), and mediators (ATP, 5-HT, bradykinin, adenosine, S1P) on these two nociceptive C-fiber subtypes. Lastly, we discuss the potential roles of capsaicin-sensitive esophageal afferent nerves in processing esophageal sensation and nociception. A better knowledge of the mechanism of nociceptive signal processes in primary afferent nerves in the esophagus will help to develop novel treatment approaches to relieve esophageal nociceptive symptoms, especially those that are refractory to proton pump inhibitors.

TRP Channel Agonists Activate Different Afferent Neuromodulatory Mechanisms in Guinea Pig Urinary Bladder

Activation of TRP channels expressed in urinary bladder afferent nerves and urothelium releases neurotransmitters that influence bladder function. Experiments were undertaken to examine the mechanisms underlying effects of TRPA1 (allyl isothiocyanate, AITC), TRPV1 (capsaicin, CAPS), and TRPC (oleoyl-2-acetyl-sn-glycerol, OAG) agonists on guinea pig bladder activity. Effects of these agonists were compared with effects of nitro-oleic acid (OA-NO2), an electrophilic nitro-fatty acid, known to activate TRPV1, TRPA1 or TRPC channels in sensory neurons. AITC (100 μM) increased (231%) area of spontaneous bladder contractions (SBCs) an effect reduced by a TRPA1 antagonist (HC3-03001, HC3, 10 μM) and reversed to inhibition by indomethacin (INDO, 500 nM) a cyclooxygenase inhibitor. The post-INDO inhibitory effect of AITC was mimicked (39% depression) by calcitonin gene-related peptide (CGRP, 100 nM) and blocked by a CGRP antagonist (BIBN, 25 μM). CAPS (1 μM) suppressed SBCs by 30% in 81% of strips, an effect blocked by a TRPV1 antagonist (diarylpiperazine, 1 μM) or BIBN. SBCs were suppressed by OA-NO2 (30 μM, 21% in 77% of strips) or by OAG (50 μM, 30%) an effect blocked by BIBN. OA-NO2 effects were not altered by HC3 or diarylpiperazine. OA-NO2 also induced excitation in 23% of bladder strips. These observations raise the possibility that guinea pig bladder is innervated by at least two types of afferent nerves: [1] Type A express TRPA1 receptors that induce the release of prostaglandins and excite the detrusor, [2] Type B express TRPV1, TRPA1 and TRPC receptors and release CGRP that inhibits the detrusor.

Visceral versus somatic pain: an educational review of anatomy and clinical implications

Somatic and visceral nociceptive signals travel via different pathways to reach the spinal cord. Additionally, signals regulating visceral blood flow and gastrointestinal tract (GIT) motility travel via efferent sympathetic nerves. To offer optimal pain relief and increase GIT motility and blood flow, we should interfere with all these pathways. These include the afferent nerves that travel with the sympathetic trunks, the somatic fibers that innervate the abdominal wall and part of the parietal peritoneum, and the sympathetic efferent fibers. All somatic and visceral afferent neural and sympathetic efferent pathways are effectively blocked by appropriately placed segmental thoracic epidural blocks (TEBs), whereas well-placed truncal fascial plane blocks evidently do not consistently block the afferent visceral neural pathways nor the sympathetic efferent nerves. It is generally accepted that it would be beneficial to counter the effects of the stress response on the GIT, therefore most enhanced recovery after surgery protocols involve TEB. The TEB failure rate, however, can be high, enticing practitioners to resort to truncal fascial plane blocks. In this educational article, we discuss the differences between visceral and somatic pain, their management and the clinical implications of these differences.

Function of Renal Nerves in Kidney Physiology and Pathophysiology

Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater understanding of how renal nerves control the kidney under physiological and pathophysiological conditions is needed. In this review, we provide an overview of the current knowledge of the anatomy of efferent and afferent renal nerves and their functions in normal and pathophysiological conditions. We also suggest further avenues of research for development of novel therapies targeting the renal nerves.

A Literature Review of the Effects of Self-Myofascial Release with a Foam Roller on Human Fascial System and Cardiovascular Function

PURPOSE: Self-myofascial release (SMR) using a foam roller is a popular intervention used to improve flexibility and restore skeletal muscles, fascia, tendons, ligaments and soft-tissue extensibility. However, the mechanism about the effects of SMR on flexibility, delayed onset of muscle soreness and arterial stiffness has not been elucidated. The purpose of this review is to provide basic knowledge for the mechanism about the effects of SMR from a functional and anatomical perspective.METHODS: In this review, we summarized previous studies investigating the effects of SMR which were associated with the human fascial system on flexibility, delayed onset of muscle soreness, arterial stiffness and autonomic nervous system (ANS).RESULTS: SMR with a foam roller can improve flexibility by increasing blood flow and circulation to the soft tissues. Foam rollingrelated mechanisms to increase range of motion or reduce pain include the activation of cutaneous and fascial mechanoreceptors and interstitial afferent nerves that modulate sympathetic/parasympathetic activation as well as the activation of global pain modulatory systems and reflex-induced reductions in muscle and myofascial tone. In addition, SMR with a foam roller may improve arterial stiffness, which was associated with increased circulating level of nitric oxide induced by elevated shear stress on the walls of the blood vessel.CONCLUSIONS: SMR using a foam roller improves flexibility by relaxing tension in skeletal muscles or fascia and may help to improve arterial stiffness and the function of the ANS. We suggest that SMR using a foam roller may help to reduce the risks of cardiovascular disease as a new alternative method.

Multi-target Treatment for Irritable Bowel Syndrome with STW 5: Pharmacological Modes of Action

Irritable bowel syndrome (IBS) is a heterogeneous and complex functional gastrointestinal disorder with aglobal prevalence of approximately 11% and high geographic variation. IBS encompasses various symptomclusters considered to reflect complex patho-etiological mechanisms, and effective treatment options arelimited, with most medications targeting individual mechanisms and symptoms. Therefore, multi-targetedtreatment is required. IBS is currently viewed as a disorder of disturbed gut–brain interactions withabnormalities at different sites along the gut–brain axis, including altered gastrointestinal motility, visceralhypersensitivity, increased intestinal permeability, and altered gut microbiota. All of these abnormalitiesrepresent individual targets for STW 5, a herbal preparation with nine different extracts indicated for thetreatment of functional dyspepsia and IBS. As a multi-targeted medicinal drug, STW 5 possesses multiplepharmacodynamic effects. Several in vitro and in vivo studies have demonstrated STW 5 efficacy on numerousIBS patho-mechanisms targeting gastrointestinal smooth muscles, visceral afferent nerves, inflammation, gutpermeability, and the gut microbiome.