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Osteoarthritis and Cartilage Oct 2023There have been significant developments in understanding artemin/GFRα3 signaling in recent years, and there is now accumulating evidence that artemin has important...
OBJECTIVE
There have been significant developments in understanding artemin/GFRα3 signaling in recent years, and there is now accumulating evidence that artemin has important roles to play in pain signaling, including that derived from joint and bone, and that associated with osteorthritis (OA).
METHODS
A total of 163 Sprague-Dawley rats were used in this study. We used an animal model of mono-iodoacetate (MIA)-induced OA, in combination with electrophysiology, behavioral testing, Western blot analysis, and retrograde tracing and immunohistochemistry, to identify roles for artemin/GFRα3 signaling in the pathogenesis of OA pain.
RESULTS
We have found that: 1) GFRα3 is expressed in a substantial proportion of knee joint afferent neurons; 2) exogenous artemin sensitizes knee joint afferent neurons in naïve rats; 3) artemin is expressed in articular tissues of the joint, but not surrounding bone, early in MIA-induced OA; 4) artemin expression increases in bone later in MIA-induced OA when pathology involves subchondral bone; and 5) sequestration of artemin reverses MIA-induced sensitization of both knee joint and bone afferent neurons late in disease when there is inflammation of knee joint tissues and damage to the subchondral bone.
CONCLUSIONS
Our findings show that artemin/GFRα3 signaling has a role to play in the pathogenesis of OA pain, through effects on both knee joint and bone afferent neurons, and suggest that targeted manipulation of artemin/GFRα3 signaling may provide therapeutic benefit for the management of OA pain.
DATA AVAILABILITY
Data are available on request of the corresponding author.
Topics: Rats; Animals; Nociceptors; Rats, Sprague-Dawley; Pain; Neurons, Afferent; Inflammation; Disease Models, Animal
PubMed: 37353141
DOI: 10.1016/j.joca.2023.06.003 -
Physiology & Behavior Sep 2014The vagus nerve is a major pathway by which information is communicated between the brain and peripheral organs. Sensory neurons of the vagus are located in the nodose... (Review)
Review
The vagus nerve is a major pathway by which information is communicated between the brain and peripheral organs. Sensory neurons of the vagus are located in the nodose ganglia. These vagal afferent neurons innervate the heart, the lung and the gastrointestinal tract, and convey information about peripheral signals to the brain important in the control of cardiovascular tone, respiratory tone, and satiation, respectively. Glutamate is thought to be the primary neurotransmitter involved in conveying all of this information to the brain. It remains unclear how a single neurotransmitter can regulate such an extensive list of physiological functions from a wide range of visceral sites. Many neurotransmitters have been identified in vagal afferent neurons and have been suggested to modulate the physiological functions of glutamate. Specifically, the anorectic peptide transmitters, cocaine and amphetamine regulated transcript (CART) and the orexigenic peptide transmitters, melanin concentrating hormone (MCH) are differentially regulated in vagal afferent neurons and have opposing effects on food intake. Using these two peptides as a model, this review will discuss the potential role of peptide transmitters in providing a more precise and refined modulatory control of the broad physiological functions of glutamate, especially in relation to the control of feeding.
Topics: Animals; Eating; Humans; Neurons, Afferent; Neuropeptides; Signal Transduction; Vagus Nerve
PubMed: 24650553
DOI: 10.1016/j.physbeh.2014.03.011 -
Seminars in Immunopathology May 2018Neurogenic inflammation results from the release of biologically active agents from the peripheral primary afferent terminal. This release reflects the presence of... (Review)
Review
Neurogenic inflammation results from the release of biologically active agents from the peripheral primary afferent terminal. This release reflects the presence of releasable pools of active product and depolarization-exocytotic coupling mechanisms in the distal afferent terminal and serves to alter the physiologic function of innervated organ systems ranging from the skin and meninges to muscle, bone, and viscera. Aside from direct stimulation, this biologically important release from the peripheral afferent terminal can be initiated by antidromic activity arising from five anatomically distinct points of origin: (i) afferent collaterals at the peripheral-target organ level, (ii) afferent collaterals arising proximal to the target organ, (iii) from mid-axon where afferents lacking myelin sheaths (C fibers and others following demyelinating injuries) may display crosstalk and respond to local irritation, (iv) the dorsal root ganglion itself, and (v) the central terminals of the afferent in the dorsal horn where local circuits and bulbospinal projections can initiate the so-called dorsal root reflexes, i.e., antidromic traffic in the sensory afferent.
Topics: Animals; Humans; Neurogenic Inflammation; Neurons, Afferent; Spinal Nerve Roots
PubMed: 29423889
DOI: 10.1007/s00281-017-0669-2 -
Journal of Anatomy Nov 2022Primary sensory neurons are a heterogeneous population of cells able to respond to both innocuous and noxious stimuli. Like most neurons they are highly... (Review)
Review
Primary sensory neurons are a heterogeneous population of cells able to respond to both innocuous and noxious stimuli. Like most neurons they are highly compartmentalised, allowing them to detect, convey and transfer sensory information. These compartments include specialised sensory endings in the skin, the nodes of Ranvier in myelinated axons, the cell soma and their central terminals in the spinal cord. In this review, we will highlight the importance of these compartments to primary afferent function, describe how these structures are compromised following nerve damage and how this relates to neuropathic pain.
Topics: Axons; Ganglia, Spinal; Neurons; Neurons, Afferent; Spinal Cord
PubMed: 34528255
DOI: 10.1111/joa.13544 -
International Journal of Molecular... May 2019The tooth has an unusual sensory system that converts external stimuli predominantly into pain, yet its sensory afferents in teeth demonstrate cytochemical properties of... (Review)
Review
The tooth has an unusual sensory system that converts external stimuli predominantly into pain, yet its sensory afferents in teeth demonstrate cytochemical properties of non-nociceptive neurons. This review summarizes the recent knowledge underlying this paradoxical nociception, with a focus on the ion channels involved in tooth pain. The expression of temperature-sensitive ion channels has been extensively investigated because thermal stimulation often evokes tooth pain. However, temperature-sensitive ion channels cannot explain the sudden intense tooth pain evoked by innocuous temperatures or light air puffs, leading to the hydrodynamic theory emphasizing the microfluidic movement within the dentinal tubules for detection by mechanosensitive ion channels. Several mechanosensitive ion channels expressed in dental sensory systems have been suggested as key players in the hydrodynamic theory, and TRPM7, which is abundant in the odontoblasts, and recently discovered PIEZO receptors are promising candidates. Several ligand-gated ion channels and voltage-gated ion channels expressed in dental primary afferent neurons have been discussed in relation to their potential contribution to tooth pain. In addition, in recent years, there has been growing interest in the potential sensory role of odontoblasts; thus, the expression of ion channels in odontoblasts and their potential relation to tooth pain is also reviewed.
Topics: Dental Pulp; Dentin; Gene Expression Regulation; Humans; Ion Channels; Neurons, Afferent; Odontoblasts; Pain; Protein Serine-Threonine Kinases; TRPM Cation Channels; Tooth; Trigeminal Ganglion
PubMed: 31071917
DOI: 10.3390/ijms20092266 -
Cell Reports Nov 2022The trigeminal sensory innervation of the cranial meninges is thought to serve a nociceptive function and mediate headache pain. However, the activity of meningeal...
The trigeminal sensory innervation of the cranial meninges is thought to serve a nociceptive function and mediate headache pain. However, the activity of meningeal afferents under natural conditions in awake animals remains unexplored. Here, we used two- and three-dimensional two-photon calcium imaging to track the activity of meningeal afferent fibers in awake mice. Surprisingly, a large subset of afferents was activated during non-noxious conditions such as locomotion. We estimated locomotion-related meningeal deformations and found afferents with distinct dynamics and tuning to various levels of meningeal expansion, compression, shearing, and Z-axis motion. Further, these mechanosensitive afferents were often tuned to distinct directions of meningeal expansion or compression. Thus, in addition to their role in headache-related pain, meningeal sensory neurons track the dynamic mechanical state of the meninges under natural conditions.
Topics: Animals; Mice; Meninges; Neurons, Afferent; Headache; Locomotion
PubMed: 36384109
DOI: 10.1016/j.celrep.2022.111648 -
The Journal of Pharmacology and... Sep 2017The nonselective cation channel transient receptor potential ankryn subtype family 1 (TRPA1) is expressed in neurons of dorsal root ganglia and trigeminal ganglia and...
The nonselective cation channel transient receptor potential ankryn subtype family 1 (TRPA1) is expressed in neurons of dorsal root ganglia and trigeminal ganglia and also in vagal afferent neurons that innervate the lungs and gastrointestinal tract. Many TRPA1 agonists are reactive electrophilic compounds that form covalent adducts with TRPA1. Allyl isothiocyanate (AITC), the common agonist used to identify TRPA1, contains an electrophilic group that covalently binds with cysteine residues of TRPA1 and confers a structural change on the channel. There is scientific motivation to identify additional compounds that can activate TRPA1 with different mechanisms of channel gating. We provide evidence that ethyl vanillin (EVA) is a TRPA1 agonist. Using fluorescent calcium imaging and whole-cell patch-clamp electrophysiology on dissociated rat vagal afferent neurons and TRPA1-transfected COS-7 cells, we discovered that EVA activates cells also activated by AITC. Both agonists display similar current profiles and conductances. Pretreatment with A967079, a selective TRPA1 antagonist, blocks the EVA response as well as the AITC response. Furthermore, EVA does not activate vagal afferent neurons from TRPA1 knockout mice, showing selectivity for TRPA1 in this tissue. Interestingly, EVA appears to be pharmacologically different from AITC as a TRPA1 agonist. When AITC is applied before EVA, the EVA response is occluded. However, they both require intracellular oxidation to activate TRPA1. These findings suggest that EVA activates TRPA1 but via a distinct mechanism that may provide greater ease for study in native systems compared with AITC and may shed light on differential modes of TRPA1 gating by ligand types.
Topics: Animals; Benzaldehydes; COS Cells; Chlorocebus aethiops; HEK293 Cells; Humans; Isothiocyanates; Male; Mice; Neurons, Afferent; Nodose Ganglion; Oximes; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; TRPA1 Cation Channel; TRPC Cation Channels
PubMed: 28620120
DOI: 10.1124/jpet.116.239384 -
Current Opinion in Pharmacology Jun 2015Cough is a reflex that serves to protect the airways. Excessive or chronic coughing is a major health issue that is poorly controlled by current therapeutics.... (Review)
Review
Cough is a reflex that serves to protect the airways. Excessive or chronic coughing is a major health issue that is poorly controlled by current therapeutics. Significant effort has been made to understand the mechanisms underlying the cough reflex. The focus of this review is the evidence supporting the role of specific airway sensory nerve (afferent) populations in the initiation and modulation of the cough reflex in health and disease.
Topics: Animals; Chronic Disease; Cough; Humans; Neurons, Afferent; Reflex
PubMed: 25704498
DOI: 10.1016/j.coph.2015.02.001 -
Journal of Internal Medicine Jul 2017Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The... (Review)
Review
Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.
Topics: Bacterial Physiological Phenomena; Gastroenteritis; Gastrointestinal Tract; Humans; Ion Channels; Neuropeptides; Sensory Receptor Cells
PubMed: 28155242
DOI: 10.1111/joim.12591 -
Neurotoxicology Jul 2014Ototoxicity is a major cause of the loss of hearing and balance in humans. Ototoxic compounds include pharmaceuticals such as aminoglycoside antibiotics, anti-malarial... (Review)
Review
Ototoxicity is a major cause of the loss of hearing and balance in humans. Ototoxic compounds include pharmaceuticals such as aminoglycoside antibiotics, anti-malarial drugs, loop diuretics and chemotherapeutic platinum agents, and industrial chemicals including several solvents and nitriles. Human and rodent data indicate that the main target of toxicity is hair cells (HCs), which are the mechanosensory cells responsible for sensory transduction in both the auditory and the vestibular system. Nevertheless, the compounds may also affect the auditory and vestibular ganglion neurons. Exposure to ototoxic compounds has been found to cause HC apoptosis, HC necrosis, and damage to the afferent terminals, of differing severity depending on the ototoxicity model. One major pathway frequently involved in HC apoptosis is the c-jun N-terminal kinase (JNK) signaling pathway activated by reactive oxygen species, but other apoptotic pathways can also play a role in ototoxicity. Moreover, little is known about the effects of chronic low-dose exposure. In rodent vestibular epithelia, extrusion of live HCs from the sensory epithelium may be the predominant form of cell demise during chronic ototoxicity. In addition, greater involvement of the afferent terminals may occur, particularly the calyx units contacting type I vestibular HCs. As glutamate is the neurotransmitter in this synapse, excitotoxic phenomena may participate in afferent and ganglion neuron damage. Better knowledge of the events that take place in chronic ototoxicity is of great interest, as it will increase understanding of the sensory loss associated with chronic exposure and aging.
Topics: Animals; Anti-Infective Agents; Hair Cells, Auditory; Hair Cells, Vestibular; Humans; Neurodegenerative Diseases; Vestibular Diseases
PubMed: 24333467
DOI: 10.1016/j.neuro.2013.11.009