The distribution of the common acupoints of acupuncture-moxibustion for gastrointestinal diseases conforms to the rule of the segmental homology of somatic afferent nerve-visceral nerve circuit at the spinal cord level. Acupuncture-moxibustion regulates the gastrointestinal function through the nerve-endocrine-immune system, and especially depending on the integrity of the structure and function of nervous system. The somatic afferent nerve-visceral nerve circuit plays an important role in the process of acupuncture and moxibustion for regulating the gastrointestinal function. There are three dimensions. ① The somatic afferent nerve-visceral nerve circuit at the peripheral level, including the somatic afferent nerve-visceral afferent nerve circuit centered on the dorsal root ganglion, and the somatic afferent nerve-visceral efferent nerve circuit centered on the sympathetic ganglia; ② that at the spinal cord level; ③ that at the supra-spinal cord level, focusing on the various reflex circuits with the solitary nucleus involved. The somatic afferent nerve-visceral nerve circuit at the spinal level and inferior to it determines the segmental regulation of acupuncture-moxibustion in the gastrointestinal system, while that at the level superior to the spinal cord determines the supersegmental action of acupuncture-moxibustion in regulating the gastrointestinal system. The neurophysiological mechanism of acupuncture-moxibustion is multi-circuits and multi-targets in regulating gastrointestinal function.
Humans ; Moxibustion ; Acupuncture Therapy ; Acupuncture Points ; Gastrointestinal Tract/physiology* ; Animals ; Neurons, Afferent/physiology* ; Afferent Pathways/physiology*

Piezo2, a mechanosensitive ion channel, serves as a crucial mechanotransducer in dental primary afferent (DPA) neurons and is potentially involved in hypersensitivity to mild mechanical irritations observed in dental patients. Given Piezo2's widespread expression across diverse subpopulations of DPA neurons, this study aimed to characterize the mechanosensory properties of Piezo2-expressing DPA neurons with a focus on distinct features of voltage-gated sodium channels (VGSCs) and neuropeptide profiles. Using whole-cell patch-clamp recordings, we observed mechanically activated action potentials (APs) and classified AP waveforms based on the presence or absence of a hump during the repolarization phase. Single-cell reverse transcription polymerase chain reaction combined with patch-clamp recordings revealed specific associations between AP waveforms and molecular properties, including tetrodotoxin-resistant VGSCs (Na_V1.8 and Na_V1.9) and TRPV1 expression. Reanalysis of the transcriptomic dataset of DPA neurons identified correlations between neuropeptides-including two CGRP isoforms (α-CGRP and β-CGRP), Substance P, and Galanin-and the expression of Na_V1.8 and Na_V1.9, which were linked to defined AP subtypes. These molecular associations were further validated in Piezo2⁺ DPA neurons using fluorescence in situ hybridization. Together, these findings highlight the electrophysiological and neurochemical heterogeneity of Piezo2-expressing DPA neurons and their specialized roles in distinct mechanosensory signal transmission.
Ion Channels/physiology* ; Mechanotransduction, Cellular/physiology* ; Animals ; Neurons, Afferent/metabolism* ; Patch-Clamp Techniques ; Mice ; TRPV Cation Channels/metabolism* ; Action Potentials ; Rats

Obesity is a prevalent disease with significant morbidity and mortality. It is a state of chronic low-grade inflammation due to excess body fat. Weight homeostasis is maintained through changes in various gastrointestinal hormones caused by dietary intake. However, being overweight or obese breaks the balance of these appetite-related gastrointestinal hormones and creates resistance to the actions of these hormones. The sensitivity of vagal afferent neurons to peripheral signals becomes blunted. Cytokines produced by excessive fat tissue damage our normal immune system, making us vulnerable to infection. In addition, various changes in gastrointestinal motility occur. Therefore, this review focuses on the various changes in gastrointestinal hormones, the immune state, the vagus nerve, and gastrointestinal movement in obese patients.
Adipose Tissue ; Cytokines ; Gastrointestinal Hormones ; Gastrointestinal Motility ; Homeostasis ; Humans ; Immune System ; Inflammation ; Mortality ; Neurons, Afferent ; Obesity ; Overweight ; Physiology ; Vagus Nerve

Dentin hypersensitivity is an abrupt intense pain caused by innocuous stimuli to exposed dentinal tubules. Mechanosensitive ion channels have been assessed in dental primary afferent neurons and odontoblasts to explain dentin hypersensitivity. Dentinal fluid dynamics evoked by various stimuli to exposed dentin cause mechanical stress to the structures underlying dentin. This review briefly discusses three hypotheses regarding dentin hypersensitivity and introduces recent findings on mechanosensitive ion channels expressed in the dental sensory system and discusses how the activation of these ion channels is involved in dentin hypersensitivity.
Dental Physiological Phenomena ; Dentin Sensitivity ; Dentin ; Dentinal Fluid ; Hydrodynamics ; Ion Channels ; Mechanoreceptors ; Neurons, Afferent ; Odontoblasts ; Stress, Mechanical

PURPOSE: The neurological molecular mechanisms underlying the voiding dysfunction associated with nonbacterial chronic prostatitis/chronic pelvic pain syndrome remain poorly understood. In this study, we assessed whether prostate inflammation activated bladder afferent neurons, leading to bladder dysfunction, and sought to elucidate the underlying mechanisms. METHODS: Thirty male Sprague-Dawley rats were divided into 3 groups: sham-saline, formalin-injected, and capsaicin-pretreated and formalin-injected. Chemical prostatitis was induced by 0.1 mL of 10% buffered formalin injected into the ventral prostate. Capsaicin was injected subcutaneously to desensitize capsaicin-sensitive nerves. In each group, conscious cystometry was performed, and c-fos expression within the spinal cord was determined immunocytochemically. Double immunofluorescent staining with c-fos and choline acetyltransferase (ChAT) was performed. On the third day after pseudorabies virus (PRV) infection, c-fos and PRV double-staining was performed. RESULTS: Intraprostatic formalin significantly increased the maximal voiding pressure and decreased the intercontraction interval, compared with controls. Pretreatment with capsaicin significantly reversed these effects. More c-fos-positive cells were observed in the sacral parasympathetic nucleus (SPN) and dorsal gray commissure (DCM) in the prostatitis group than in the sham group. c-fos-positive cells decreased in the capsaicin-pretreated group. Preganglionic neurons labeled by c-fos and ChAT were observed in the SPN in rats with prostatitis. Interneurons labeled by c-fos and PRV were identified in the DCM after PRV infection. CONCLUSIONS: Our results suggest that prostate inflammation activates afferent nerve fibers projecting to the lumbosacral spinal cord, producing reflex activation of spinal neurons innervating the bladder and bladder hyperreflexia. This is mediated by capsaicin-sensitive prostate afferent neurons.
Animals ; Capsaicin ; Choline O-Acetyltransferase ; Formaldehyde ; Herpesvirus 1, Suid ; Humans ; Inflammation* ; Interneurons ; Male ; Models, Animal* ; Nerve Fibers ; Neurons ; Neurons, Afferent ; Pelvic Pain ; Prostate ; Prostatitis* ; Rats* ; Rats, Sprague-Dawley ; Reflex ; Reflex, Abnormal ; Spinal Cord ; Urinary Bladder

Migraine is a neurological disorder characterized by recurrent and disabling severe headaches. Although several anticonvulsant drugs that block voltage-dependent Na⁺ channels are widely used for migraine, far less is known about the therapeutic actions of carbamazepine on migraine. In the present study, therefore, we characterized the effects of carbamazepine on tetrodotoxin-resistant (TTX-R) Na⁺ channels in acutely isolated rat dural afferent neurons, which were identified by the fluorescent dye DiI. The TTX-R Na⁺ currents were measured in medium-sized DiIpositive neurons using the whole-cell patch clamp technique in the voltage-clamp mode. While carbamazepine had little effect on the peak amplitude of transient Na⁺ currents, it strongly inhibited steady-state currents of transient as well as persistent Na⁺ currents in a concentration-dependent manner. Carbamazepine had only minor effects on the voltage-activation relationship, the voltage-inactivation relationship, and the use-dependent inhibition of TTX-R Na⁺ channels. However, carbamazepine changed the inactivation kinetics of TTX-R Na⁺ channels, significantly accelerating the development of inactivation and delaying the recovery from inactivation. In the current-clamp mode, carbamazepine decreased the number of action potentials without changing the action potential threshold. Given that the sensitization of dural afferent neurons by inflammatory mediators triggers acute migraine headaches and that inflammatory mediators potentiate TTX-R Na⁺ currents, the present results suggest that carbamazepine may be useful for the treatment of migraine headaches.
Action Potentials ; Animals ; Anticonvulsants ; Carbamazepine* ; Headache ; Kinetics ; Migraine Disorders ; Nervous System Diseases ; Neurons* ; Neurons, Afferent ; Rats ; Sodium Channels ; Trigeminal Ganglion*

Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5-HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch-clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons.
Antiemetics ; Drug Therapy ; Ginger* ; Herbal Medicine ; Humans ; Nausea ; Neurons* ; Neurons, Afferent ; Ondansetron ; Receptors, Serotonin, 5-HT3 ; Serotonin* ; Visceral Afferents* ; Vomiting ; Water

The rostral ventromedial medulla (RVM) is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus (NRM) and nucleus gigantocellularis pars α (NGCα)]. Fluorescence immunohistochemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryptophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.
Animals ; Female ; Male ; Medulla Oblongata ; cytology ; metabolism ; Mice ; Mice, Transgenic ; Neural Pathways ; cytology ; metabolism ; Neurons, Afferent ; cytology ; metabolism ; Nociception ; physiology ; Receptor, Melanocortin, Type 4 ; genetics ; metabolism ; Serotonergic Neurons ; metabolism ; Tyrosine 3-Monooxygenase ; metabolism

The long belief that dental primary afferent (DPA) neurons are entirely composed of nociceptive neurons has been challenged by several anatomical and functional investigations. In order to characterize non-nociceptivepopulation among DPA neurons, retrograde transport fluorescent dye was placed in upper molars of rats and immunohistochemical detection of peripherin and neurofilament 200 in the labeled trigeminal ganglia was performed. As the results, majority ofDPA neurons were peripherin-expressing small-sized neurons, showing characteristic ofnociceptive C-fibers. However, 25.7% of DPA were stained with antibody against neurofilament 200, indicating significant portion of DPA neurons are related to large myelinated Abeta fibers. There were a small number of neurons thatexpressed both peripherin and neurofilament 200, suggestive of Adelta fibers. The possible transition of neurochemical properties by neuronal injury induced by retrograde labeling technique was ruled out by detection of minimal expression of neuronal injury marker, ATF-3. These results suggest that in addition to the large population of C-fiber-related nociceptive neurons, a subset of DPA neurons is myelinated large neurons, which is related to low-threshold mechanosensitive Abeta fibers. We suggest that these Abeta fiber-related neurons might play a role as mechanotransducers of fluid movement within dentinal tubules.
Animals ; Dentin ; Intermediate Filament Proteins ; Membrane Glycoproteins ; Molar ; Myelin Sheath ; Nerve Tissue Proteins ; Neurofilament Proteins ; Neurons ; Neurons, Afferent ; Nociceptors ; Rats ; Trigeminal Ganglion

Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. This review article discussed the mechanism of gastrointestinal MMC. Luminal administration of 5-hydroxytryptamine (5-HT) initiates duodenal phase II followed by gastrointestinal phase III with a concomitant increase of plasma motilin release in conscious dogs. Duodenal 5-HT concentration is increased during gastric phase II and phase III. Intravenous infusion of motilin increases luminal 5-HT content and induces gastrointestinal phase III. 5-HT4 antagonists significantly inhibits both of gastric and intestinal phase III, while 5-HT3 antagonists inhibited only gastric phase III. These suggest that gastrointestinal MMC cycle is mediated via the interaction between motilin and 5-HT by the positive feedback mechanism. Gastric MMC is regulated via vagus, 5-HT3/4 receptors and motilin, while intestinal MMC is regulated via intrinsic primary afferent neurons and 5-HT4 receptors. Stress is highly associated with the pathogenesis of functional dyspepsia. Acoustic stress attenuates gastric phase III without affecting intestinal phase III in conscious dogs, via reduced vagal activity and increased sympathetic activity. It has been shown that subset of functional dyspepsia patients show reduced vagal activity and impaired gastric phase III. The physiological importance of gastric MMC is a mechanical and chemical cleansing of the empty stomach in preparation for the next meal. The impaired gastric MMC may aggravate dyspeptic symptoms following a food ingestion. Thus, maintaining gastric MMC in the interdigestive state is an important factor to prevent the postprandial dyspeptic symptoms.
Acoustics ; Animals ; Autonomic Pathways ; Contracts ; Dogs ; Dyspepsia ; Eating ; Enterochromaffin Cells ; Humans ; Infusions, Intravenous ; Meals ; Motilin ; Myoelectric Complex, Migrating ; Neurons, Afferent ; Phenobarbital ; Plasma ; Receptors, Serotonin, 5-HT4 ; Serotonin ; Serotonin 5-HT3 Receptor Antagonists ; Serotonin 5-HT4 Receptor Antagonists ; Stomach