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American Journal of Physiology.... Sep 2019The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral...
The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill defined. The use of dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labeling with phosphorylated MAPK ERK 1/2 (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input. In the thoracolumbar dorsal horn, central projections of colonic afferents were primarily labeled from the wall of the colon and localized in laminae I and V. In contrast, lumbosacral projections were identified from both lumen and wall tracing, present within various dorsal horn laminae, collateral tracts, and the dorsal gray commissure. Nonnoxious in vivo colorectal distension evoked significant neuronal activation (pERK-immunoreactivity) within the lumbosacral dorsal horn but not in thoracolumbar regions. However, noxious in vivo colorectal distension evoked significant neuronal activation in both the thoracolumbar and lumbosacral dorsal horn, with the distribution of activated neurons correlating to the pattern of traced projections. Dorsal horn neurons activated by colorectal distension were identified as possible populations of projection neurons or excitatory and inhibitory interneurons based on their neurochemistry. Our findings demonstrate how colonic afferents in splanchnic and pelvic pathways differentially relay mechanosensory information into the spinal cord and contribute to the recruitment of spinal cord pathways processing non-noxious and noxious stimuli. In mice, retrograde tracing from the colon wall and lumen was used to identify unique populations of afferent neurons and central projections within the spinal cord dorsal horn. We show that there are pronounced differences between the spinal cord regions in the distribution pattern of colonic afferent central projections and the pattern of dorsal horn neuron activation evoked by colorectal distension. These findings demonstrate how colonic afferent input influences spinal processing of colonic mechanosensation.
Topics: Afferent Pathways; Animals; Colon; Male; Mice, Inbred C57BL; Neurons, Afferent; Posterior Horn Cells; Spinal Cord
PubMed: 31188624
DOI: 10.1152/ajpgi.00013.2019 -
Journal of Leukocyte Biology Sep 2022Understanding the innate immune system and how aberrant activation or impaired inhibition leads to the development of hyperinflammatory conditions, including...
Understanding the innate immune system and how aberrant activation or impaired inhibition leads to the development of hyperinflammatory conditions, including inflammatory bowel disease, is crucial for patient management and treatment. An emerging area of interest surrounding dysregulated inflammation focuses on membrane bound transient receptor potential (TRP) ion channels. These channels are permeable to calcium and other cations involved in the balance of leukocyte membrane potential and function, as well as afferent neuron signaling within the myenteric plexus of the GI tract, bladder, and skin. A particular channel, TRPM8, is an important cell surface marker for prostate cancer and participates in the function of cold sensing neurons. Specifically, this ion-gated receptor is shown to be activated by agonists such as menthol and eucalyptus, which aid in the soothing, cooling effects of these agents. Furthermore, the TRPM8 channel is also identified on the surface of resident tissue Mϕs and is also linked to the protective role and release of calcitonin gene-related peptide (CGRP) by sensory neurons.
Topics: Calcium Signaling; Cold Temperature; Humans; Menthol; Monocytes; TRPM Cation Channels
PubMed: 35570407
DOI: 10.1002/JLB.3CE0222-099R -
Neuroscience Bulletin Nov 2020Purinergic P2 receptors, activated by endogenous ATP, are prominently expressed on neuronal and non-neuronal cells during development of the auditory periphery and... (Review)
Review
Purinergic P2 receptors, activated by endogenous ATP, are prominently expressed on neuronal and non-neuronal cells during development of the auditory periphery and central auditory neurons. In the mature cochlea, extracellular ATP contributes to ion homeostasis, and has a protective function against noise exposure. Here, we focus on the modulation of activity by extracellular ATP during early postnatal development of the lower auditory pathway. In mammals, spontaneous patterned activity is conveyed along afferent auditory pathways before the onset of acoustically evoked signal processing. During this critical developmental period, inner hair cells fire bursts of action potentials that are believed to provide a developmental code for synaptic maturation and refinement of auditory circuits, thereby establishing a precise tonotopic organization. Endogenous ATP-release triggers such patterned activity by raising the extracellular K concentration and contributes to firing by increasing the excitability of auditory nerve fibers, spiral ganglion neurons, and specific neuron types within the auditory brainstem, through the activation of diverse P2 receptors. We review recent studies that provide new models on the contribution of purinergic signaling to early development of the afferent auditory pathway. Further, we discuss potential future directions of purinergic research in the auditory system.
Topics: Adenosine Triphosphate; Animals; Auditory Pathways; Cochlea; Hair Cells, Auditory, Inner; Receptors, Purinergic P2X; Spiral Ganglion
PubMed: 33040238
DOI: 10.1007/s12264-020-00586-4 -
The Journal of Neuroscience : the... Dec 2022Treatment with opioids not only inhibits nociceptive transmission but also elicits a rebound and persistent increase in primary afferent input to the spinal cord....
Treatment with opioids not only inhibits nociceptive transmission but also elicits a rebound and persistent increase in primary afferent input to the spinal cord. Opioid-elicited long-term potentiation (LTP) from TRPV1-expressing primary afferents plays a major role in opioid-induced hyperalgesia and analgesic tolerance. Here, we determined whether opioid-elicited LTP involves vesicular glutamate transporter-2 (VGluT2) or vesicular GABA transporter (VGAT) neurons in the spinal dorsal horn of male and female mice and identified underlying signaling mechanisms. Spinal cord slice recordings revealed that µ-opioid receptor (MOR) stimulation with DAMGO initially inhibited dorsal root-evoked EPSCs in 87% VGluT2 neurons and subsequently induced LTP in 49% of these neurons. Repeated morphine treatment increased the prevalence of VGluT2 neurons displaying LTP with a short onset latency. In contrast, DAMGO inhibited EPSCs in 46% VGAT neurons but did not elicit LTP in any VGAT neurons even in morphine-treated mice. Spinal superficial laminae were densely innervated by MOR-containing nerve terminals and were occupied by mostly VGluT2 neurons and few VGAT neurons. Furthermore, conditional knockout in dorsal root ganglion neurons diminished DAMGO-elicited LTP in lamina II neurons and attenuated hyperalgesia and analgesic tolerance induced by repeated treatment with morphine. In addition, DAMGO-elicited LTP in VGluT2 neurons was abolished by protein kinase C inhibition, gabapentin, knockout, or disrupting the α2δ-1-NMDA receptor interaction with an α2δ-1 C terminus peptide. Thus, brief MOR stimulation distinctively potentiates nociceptive primary afferent input to excitatory dorsal horn neurons via α2δ-1-coupled presynaptic NMDA receptors, thereby causing hyperalgesia and reducing analgesic actions of opioids. Opioid drugs are potent analgesics for treating severe pain and are commonly used during general anesthesia. However, opioid use often induces pain hypersensitivity, rapid loss of analgesic efficacy, and dose escalation, which can cause dependence, addiction, and even overdose fatality. This study demonstrates for the first time that brief opioid exposure preferentially augments primary sensory input to genetically identified glutamatergic excitatory, but not GABAergic/glycinergic inhibitory, neurons in nociceptive dorsal horn circuits. This opioid-elicited synaptic plasticity is cell type specific and mediated by protein kinase C-dependent and α2δ-1-dependent activation of NMDA receptors at primary sensory nerve terminals. These findings elucidate how intraoperative use of opioids for preemptive analgesia paradoxically aggravates postoperative pain and increases opioid consumption and suggest new strategies to improve opioid analgesic efficacy.
Topics: Rats; Male; Female; Mice; Animals; Receptors, N-Methyl-D-Aspartate; Analgesics, Opioid; Hyperalgesia; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Rats, Sprague-Dawley; Morphine; Spinal Cord; Neurons; Protein Kinase C; Pain; Neurons, Afferent
PubMed: 36379705
DOI: 10.1523/JNEUROSCI.1704-22.2022 -
Neuroscience Letters Feb 2021Cancer neurobiology is an emerging discipline that inevitably unfurls new perspectives in oncology. The role that nerves play in cancer progression resonates with the... (Review)
Review
Cancer neurobiology is an emerging discipline that inevitably unfurls new perspectives in oncology. The role that nerves play in cancer progression resonates with the long-reported dependency of tumors on neuro-molecular mechanisms that remain insufficiently elucidated. Whereas interactions between neurotrophic growth factors and receptors have been heavily studied in the nervous system, their expression in cancers and their impact on tumor cell growth and metastasis through their corresponding signaling pathways has been undervalued. Accumulating evidence suggests that trophic factors released by nerves strongly influence tumor development and that this neural contribution appears to not only play a stimulatory role but also function as an essential part of the tumor's microenvironment. This bidirectional communication between proliferating cells and tumor-infiltrating nerves drives axonogenesis and tumor growth and migration. Acquiring a better understanding of the trophic interactions between primary afferent neurons and invading tumors will guide clinically actionable strategies to prevent tumor-associated axonogenesis, disrupting the chemical crosstalk between neurons and tumors and ultimately decreasing tumor growth and spread.
Topics: Animals; Humans; Intercellular Signaling Peptides and Proteins; Neoplasm Metastasis; Neoplasms; Neurons, Afferent; Tumor Microenvironment
PubMed: 33482305
DOI: 10.1016/j.neulet.2021.135658 -
American Journal of Physiology.... Nov 2019The pancreas consists of both the exocrine (acini and ducts) and endocrine (islets) compartments to participate in and regulate the body's digestive and metabolic...
The pancreas consists of both the exocrine (acini and ducts) and endocrine (islets) compartments to participate in and regulate the body's digestive and metabolic activities. These activities are subjected to neural modulation, but characterization of the human pancreatic afferent and efferent nerves remains difficult because of the lack of three-dimensional (3-D) image data. Here we prepare transparent human donor pancreases for 3-D histology to reveal the pancreatic microstructure, vasculature, and innervation in a global and integrated fashion. The pancreatic neural network consists of the substance P (SP)-positive sensory (afferent) nerves, the vesicular acetylcholine transporter (VAChT)-positive parasympathetic (efferent) nerves, and the tyrosine hydroxylase (TH)-positive sympathetic (efferent) nerves. The SP afferent nerves were found residing along the basal domain of the interlobular ducts. The VAChT and TH efferent nerves were identified at the peri-acinar and perivascular spaces, which follow the blood vessels to the islets. In the intrapancreatic ganglia, the SP (scattered minority, ~7%) and VAChT neurons co-localize, suggesting a local afferent-efferent interaction. Compared with the mouse pancreas, the human pancreas differs in ) the lack of SP afferent nerves in the islet, ) the lower ganglionic density, and ) the obvious presence of VAChT and TH nerves around the intralobular adipocytes. The latter implicates the neural influence on the pancreatic steatosis. Overall, our 3-D image data reveal the human pancreatic afferent and efferent innervation patterns and provide the anatomical foundation for future high-definition analyses of neural remodeling in human pancreatic diseases. Modern three-dimensional (3-D) histology with multiplex optical signals identifies the afferent and efferent innervation patterns of human pancreas, which otherwise cannot be defined with standard histology. Our 3-D image data reveal the unexpected association of sensory and parasympathetic nerves/neurons in the intrapancreatic ganglia and identify the sympathetic and parasympathetic nerve contacts with the infiltrated adipocytes. The multiplex approach offers a new way to characterize the human pancreas in remodeling (e.g., fatty infiltration and duct lesion progression).
Topics: Acinar Cells; Adipose Tissue; Adult; Animals; Female; Humans; Imaging, Three-Dimensional; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Neuroanatomical Tract-Tracing Techniques; Neurons, Afferent; Neurons, Efferent; Pancreas, Exocrine; Substance P; Tyrosine 3-Monooxygenase; Vesicular Acetylcholine Transport Proteins
PubMed: 31509431
DOI: 10.1152/ajpgi.00116.2019 -
The Journal of Physiology Feb 2023Tactile sensitivity is affected by age, as shown by the deterioration of spatial acuity assessed with the two-point discrimination task. This is assumed to be partly a...
Tactile sensitivity is affected by age, as shown by the deterioration of spatial acuity assessed with the two-point discrimination task. This is assumed to be partly a result of age-related changes of the peripheral somatosensory system. In particular, in the elderly, the density of mechanoreceptive afferents decreases with age and the skin tends to become drier, less elastic and less stiff. To assess to what degree mechanoreceptor density, skin hydration, elasticity and stiffness can account for the deterioration of tactile spatial sensitivity observed in the elderly, several approaches were combined, including psychophysics, measurements of finger properties, modelling and simulation of the response of first-order tactile neurons. Psychophysics confirmed that the Elderly group has lower tactile acuity than the Young group. Correlation and commonality analysis showed that age was the most important factor in explaining decreases in behavioural performance. Biological elasticity, hydration and finger pad area were also involved. These results were consistent with the outcome of simulations showing that lower afferent density and lower Young's modulus (i.e. lower stiffness) negatively affected the tactile encoding of stimulus information. Simulations revealed that these changes resulted in a lower build-up of task-relevant stimulus information. Importantly, the reduction in discrimination performance with age in the simulation was less than that observed in the psychophysical testing, indicating that there are additional peripheral as well as central factors responsible for age-related changes in tactile discrimination. KEY POINTS: Ageing effects on tactile perception involve the deterioration of spatial sensitivity, although the contribution of central and peripheral factors is not clear. We combined psychophysics, measurements of finger properties, modelling and simulation of the response of first-order tactile neurons to investigate to what extent skin elasticity, stiffness, hydration, finger pad area and afferent density can account for the lower spatial sensitivity observed in the elderly. Correlation and commonality analysis revealed that age was the most important factor to predict behavioural performance. Skin biological elasticity, hydration and finger pad area contributed to a lesser extent. The simulation of first-order tactile neuron responses indicated that reduction in afferent density plays a major role in the deterioration of tactile spatial acuity. Simulations also showed that lower skin stiffness and lower afferent density affect the build-up of stimulus information and the response of SA1 (i.e. type 1 slowly adapting fibres) and RA1 (i.e. type 1 rapidly adapting fibres) afferent fibres.
Topics: Humans; Aged; Skin; Touch; Touch Perception; Mechanoreceptors; Aging; Neurons, Afferent
PubMed: 36533658
DOI: 10.1113/JP283174 -
Molecular Pain 2023The role of Aβ-afferents in somatosensory function is often oversimplified as low threshold mechanoreceptors (LTMRs) with large omission of Aβ-afferent involvement in...
The role of Aβ-afferents in somatosensory function is often oversimplified as low threshold mechanoreceptors (LTMRs) with large omission of Aβ-afferent involvement in nociception. Recently, we have characterized Aβ-afferent neurons which have large diameter somas in the trigeminal ganglion (TG) and classified them into non-nociceptive and nociceptive-like TG afferent neurons based on their electrophysiological properties. Here, we extend our previous observations to further characterize electrophysiological properties of trigeminal Aβ-afferent neurons and investigate their mechanical and chemical sensitivity by patch-clamp recordings from large-diameter TG neurons in ex vivo TG preparations of adult male and female rats. Based on cluster analysis of electrophysiological properties, trigeminal Aβ-afferent neurons can be classified into five discrete types (type I, IIa, IIb, IIIa, and IIIb), which responded differentially to mechanical stimulation and sensory mediators including serotonin (5-HT), acetylcholine (ACh) and adenosine triphosphate (ATP). Notably, type I neuron action potential (AP) was small in amplitude, width was narrow in duration, and peak dV/dt repolarization was great with no deflection observed, whereas discretely graded differences were observed for type IIa, IIb, IIIa, and IIIb, as AP increased in amplitude, width broadened in duration, and peak dV/dt repolarization reduced with the emergence of increasing deflection. Type I, IIa, and IIb neurons were mostly mechanically sensitive, displaying robust and rapidly adapting mechanically activated current (I) in response to membrane displacement, while IIIa and IIIb, conversely, were almost all mechanically insensitive. Interestingly, mechanical insensitivity coincided with increased sensitivity to 5-HT and ACh. Together, type I, IIa and IIb display features of LTMR Aβ-afferent neurons while type IIIa and type IIIb show properties of nociceptive Aβ-afferent neurons.
Topics: Rats; Male; Female; Animals; Serotonin; Neurons, Afferent; Nociceptors; Mechanoreceptors; Neurons; Action Potentials; Trigeminal Ganglion
PubMed: 36526445
DOI: 10.1177/17448069221148958 -
European Journal of Immunology Nov 2019The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have... (Review)
Review
The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have been studied extensively in the context of their primary function of initiation of voluntary and involuntary movement, transmission of sensations and induction of appropriate behavioral response such as withdrawal to avoid tissue injury or scratching to remove irritating molecules. More recently, breakthrough articles have shown that, on top of their primary function of signal transmission to the spinal cord and brain, peripheral neurons (including afferent neurons) could directly sense environmental alarms and consequently regulate the development of various type of immune responses through the release of neuropeptides or growth factors. In this review, we discuss recent advances in the neural regulation of the immune response, both in physiological and pathological contexts by taking into account the type of organs (lungs, skin and gut), subtypes of peripheral neurons (sympathetic, nociceptive and intrinsic gut neurons) or immune cells and strains of pathogens studied. We also highlight future challenges in the field and potential therapeutic innovations targeting neuro-immune interactions.
Topics: Animals; Bacterial Infections; Brain; Cytokines; Gastrointestinal Tract; Humans; Immunity, Innate; Immunity, Mucosal; Intercellular Signaling Peptides and Proteins; Lung; Neuropeptides; Nociception; Peripheral Nervous System; Sensory Receptor Cells; Skin; Spinal Cord; Synaptic Transmission
PubMed: 31327163
DOI: 10.1002/eji.201848027 -
Journal of Neurophysiology Jan 2021Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous,...
Vagal afferent fibers contact neurons in the nucleus of the solitary tract (NTS) and release glutamate via three distinct release pathways: synchronous, asynchronous, and spontaneous. The presence of TRPV1 in vagal afferents is predictive of activity-dependent asynchronous glutamate release along with temperature-sensitive spontaneous vesicle fusion. However, pharmacological blockade or genetic deletion of TRPV1 does not eliminate the asynchronous profile and only attenuates the temperature-dependent spontaneous release at high temperatures (>40°C), indicating additional temperature-sensitive calcium conductance(s) contributing to these release pathways. The transient receptor potential cation channel melastatin subtype 3 (TRPM3) is a calcium-selective channel that functions as a thermosensor (30-37°C) in somatic primary afferent neurons. We predict that TRPM3 is expressed in vagal afferent neurons and contributes to asynchronous and spontaneous glutamate release pathways. We investigated these hypotheses via measurements on cultured nodose neurons and in brainstem slice preparations containing vagal afferent to NTS synaptic contacts. We found histological and genetic evidence that TRPM3 is highly expressed in vagal afferent neurons. The TRPM3-selective agonist, pregnenolone sulfate, rapidly and reversibly activated the majority (∼70%) of nodose neurons; most of which also contained TRPV1. We confirmed the role of TRPM3 with pharmacological blockade and genetic deletion. In the brain, TRPM3 signaling strongly controlled both basal and temperature-driven spontaneous glutamate release. Surprisingly, genetic deletion of TRPM3 did not alter synchronous or asynchronous glutamate release. These results provide convergent evidence that vagal afferents express functional TRPM3 that serves as an additional temperature-sensitive calcium conductance involved in controlling spontaneous glutamate release onto neurons in the NTS. Vagal afferent signaling coordinates autonomic reflex function and informs associated behaviors. Thermosensitive transient receptor potential (TRP) channels detect temperature and nociceptive stimuli in somatosensory afferent neurons, however their role in vagal signaling remains less well understood. We report that the TRPM3 ion channel provides a major thermosensitive point of control over vagal signaling and synaptic transmission. We conclude that TRPM3 translates physiological changes in temperature to neurophysiological outputs and can serve as a cellular integrator in vagal afferent signaling.
Topics: Action Potentials; Animals; Excitatory Postsynaptic Potentials; Exocytosis; Glutamic Acid; Hot Temperature; Male; Neurons, Afferent; Pregnenolone; Rats; Rats, Sprague-Dawley; TRPM Cation Channels; Vagus Nerve
PubMed: 33296617
DOI: 10.1152/jn.00229.2020