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Overall incidence of spontaneous activity ("Total SA") and of each subtype vs. time after spinal nerve ligation. *, significantly different from control (POD 0), Fishers exact test. N = 149 to 255 cells per group, with a minimum of 3 different animals per group, for this and Figures 4 and 5. Bottom: examples of tonic (top), irregular (second) and bursting (third) activity. The bursting activity has been expanded to show the subthreshold oscillations observed between bursts (bottom trace).
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Sprouting of sympathetic fibers into sensory ganglia occurs in many preclinical pain models, providing a possible anatomical substrate for sympathetically enhanced pain. However, the functional consequences of this sprouting have been controversial. We used a transgenic mouse in which sympathetic fibers expressed green fluorescent protein, observab...
Contexts in source publication
Context 1
... form of spontaneous activity changed with time after SNL. Tonic firing prevailed on the first day, but by day 3 bursting was the form most commonly seen ( Figure 3). Bursting cells had subthreshold oscillations between bursts ( Figure 3). ...Context 2
... firing prevailed on the first day, but by day 3 bursting was the form most commonly seen ( Figure 3). Bursting cells had subthreshold oscillations between bursts ( Figure 3). ...Context 3
... the dorsal ramus was cut along with the ventral ramus, which as shown above greatly decreased sympa- thetic sprouting as observed on POD 3, the incidence of spontaneous activity on POD 3 was only 1.9%. This was significantly lower (p = 0.0002, Fisher's exact test) than the value observed in the usual SNL procedure in which only the ventral ramus was cut, which was 15% (as shown in Figure 3). In fact, this level of spontaneous activity was not significantly different (p = 1.0, ...Context 4
... fact, this level of spontaneous activity was not significantly different (p = 1.0, Fisher's exact test) from the level seen in uninjured cells (which was 3.1%, as shown in Figure 3). The 2 of 104 cells that showed spontaneous activity when the dorsal ramus was also cut were both of the bursting type. ...Context 5
... were not enough SA cells from normal DRG (n = 4) to include in the analysis. Equivalent diameters are based on a sphere with membrane capacitance of 1 μF/cm 2 examined without examination of GFP fluorescence (data presented in Figure 3) or to cells without basket formations from DRG in which EGFP fluorescence was observed during recording ( Figure 6). The majority of this spontaneous activity was of the bursting pattern. ...Context 6
... incidence of all types of spontaneous activity in bas- ket cells was 71%, and the incidence of bursting was 48%. This compares to values of 15% incidence of spon- taneous activity and 9% incidence of bursting on POD3 in the total population of DRG cells without examining GFP fluorescence (Figure 3). ...Context 7
... the data from DRG sections stained for TH, the average incidence of basket formations was 6.8% (Table 1). For comparison, the incidence of spontaneous activity in all DRG cells at this time point was 10% (Figure 3, after allowing for the fact that small cells were excluded from the electrophysiolo- gical data). This suggests that over half of the overall spontaneous activity may be attributed to basket cells, despite their overall rarity. ...Citations
... 50,63 Simultaneously, lesioned sensory neurons release NGF, which can bind to TrkA channels expressed on sensory neurons, resulting in hyperexcitation and exacerbating spontaneous firing of these neurons. 64 Increased NGF concentrations induce the sprouting of sympathetic postganglionic fibers, especially in neurons with ectopic firing, 48 which then interact with these injured neurons or fibers to form coupling structures in DRG or the skin. Simultaneously, the structure of sprouted sympathetic terminals is dilated and extracellularly releases ATP and norepinephrine (NE), 65,66 which can bind with P2 receptors and adrenergic α2 receptors expressed on neurons, 65 respectively, with the diffusion of satellite glia. ...
A series of studies have demonstrated acupoint sensitization, in which acupoints can be activated in combination with sensory hypersensitivity and functional plasticity during visceral disorders. However, the mechanisms of acupoint sensitization remain unclear. Neuroanatomy evidence showed nociceptors innervated in acupoints contribute to the mechanism of acupoint sensitization. Increasing studies suggested sympathetic nerve plays a key role in modulating sensory transmission by sprouting or coupling with sensory neuron/nociceptor in the peripheral, forming the functional structure of the sympathetic-sensory coupling. Notably, the sensory inputs of the disease-induced sensitized acupoint contribute to the homeostatic regulation and also involve in delivering therapeutic information under acupuncture, hence, the role of sprouted sympathetic in acupoint function should be given attention. We herein reviewed the current knowledge of sympathetic and its sprouting in pain modulation, then discussed and highlighted the potential value of sympathetic-sensory coupling in acupoint functional plasticity.
... DRGs, being a key component in the transmission of nociceptive sensory inputs and the signaling of proprioception to the central nervous system, play a vital role in pain and its management [69]. Previous studies have reported the sprouting of sympathetic terminals into DRGs [20,70], skin [22], cornea [68], and periosteum [66] under neuropathic and inflammatory pain, with a tendency to sprout towards large and medium-sized sensory neurons (Ab and Ad) with ectopic discharging [71], and the formation of a basket-like structure that contributes to sensory sensitization [22,40,41]. Recent studies have reported that sympathetic post-ganglionic fibers also sprout into the heart and sympathetic ganglia such as the stellate and superior cervical ganglia under chronic MI [18,72,73], and this is responsible for lethal arrhythmias [72]. ...
Myocardial ischemia (MI) causes somatic referred pain and sympathetic hyperactivity, and the role of sensory inputs from referred areas in cardiac function and sympathetic hyperactivity remain unclear. Here, in a rat model, we showed that MI not only led to referred mechanical hypersensitivity on the forelimbs and upper back, but also elicited sympathetic sprouting in the skin of the referred area and C8-T6 dorsal root ganglia, and increased cardiac sympathetic tone, indicating sympathetic sensory coupling. Moreover, intensifying referred hyperalgesic inputs with noxious mechanical, thermal, and electro-stimulation (ES) of the forearm augmented sympathetic hyperactivity and regulated cardiac function, whereas deafferentation of the left brachial plexus diminished sympathoexcitation. Intradermal injection of the a 2 adrenoceptor (a 2 AR) antagonist yohimbine and agonist dexmedetomidine in the forearm attenuated the cardiac adjustment by ES. Overall, these findings suggest that sensory inputs from the referred pain area contribute to cardiac functional adjustment via peripheral a 2 AR-mediated sympathetic-sensory coupling.
... In a different mouse model, in which excess fibers and basket formations are observed, we observed that both were associated with increased excitability of nearby neurons (Xie et al., 2011). ...
Spontaneous pain refers to pain occurring without external stimuli. It is a primary complaint in chronic pain conditions and remains difficult to treat. Moreover, the mechanisms underlying spontaneous pain remain poorly understood. Here we employed in vivo imaging of dorsal root ganglion (DRG) neurons and discovered a distinct form of abnormal spontaneous activity following peripheral nerve injury: clusters of adjacent DRG neurons firing synchronously and sporadically. The level of cluster firing correlated directly with nerve injury-induced spontaneous pain behaviors. Furthermore, we demonstrated that cluster firing is triggered by activity of sympathetic nerves, which sprout into DRGs after injury, and identified norepinephrine as a key neurotransmitter mediating this unique firing. Chemogenetic and pharmacological manipulations of sympathetic activity and norepinephrine receptors suggest that they are necessary and sufficient for DRG cluster firing and spontaneous pain behavior. Therefore, blocking sympathetically mediated cluster firing may be a new paradigm for treating spontaneous pain.
... Sympathetic axons, driven by satellite cell-derived growth factors, extend from DRG vasculature and preferentially surround neurons that project to the gracile nucleus (Ma and Bisby, 1999;Zhou et al., 1999), i.e., Aβ LTMRs. They also tend to surround spontaneously active neurons (Xie et al., 2011), though other studies show comparable targeting of injured and uninjured neurons (Ma and Bisby, 1999). It remains unclear whether there is selective localization of IB4 neuronal processes or microglia/macrophages around injured or uninjured subpopulations. ...
Despite the widespread study of how injured nerves contribute to chronic pain, there are still major gaps in our understanding of pain mechanisms. This is particularly true of pain resulting from nerve injury, or neuropathic pain, wherein tactile or thermal stimuli cause painful responses that are particularly difficult to treat with existing therapies. Curiously, this stimulus-driven pain relies upon intact, uninjured sensory neurons that transmit the signals that are ultimately sensed as painful. Studies that interrogate uninjured neurons in search of cell-specific mechanisms have shown that nerve injury alters intact, uninjured neurons resulting in an activity that drives stimulus-evoked pain. This review of neuropathic pain mechanisms summarizes cell-type-specific pathology of uninjured sensory neurons and the sensory ganglia that house their cell bodies. Uninjured neurons have demonstrated a wide range of molecular and neurophysiologic changes, many of which are distinct from those detected in injured neurons. These intriguing findings include expression of pain-associated molecules, neurophysiological changes that underlie increased excitability, and evidence that intercellular signaling within sensory ganglia alters uninjured neurons. In addition to well-supported findings, this review also discusses potential mechanisms that remain poorly understood in the context of nerve injury. This review highlights key questions that will advance our understanding of the plasticity of sensory neuron subpopulations and clarify the role of uninjured neurons in developing anti-pain therapies.
... The sympathetic sprouting fiber in DRG has been described as a significant event involving in the development of neuropathic pain following L5 SNL following adult nerve lesion [16,19,20]. The sprouting fibers preferentially formed nests with synapse-like structures around the spontaneously active neurons or tangled with efferent fibers [18,42]. The number of sprouting fibers had been proved statistically correlated with neuropathic behaviors [16,43]. ...
Background:
Sympathetic sprouting in the dorsal root ganglion (DRG) following nerve injuries had been proved to induce adult neuropathic pain. However, it is unclear whether the abnormal sprouting occurs in infant nerve injury.
Methods:
L5 spinal nerve ligation (SNL) or sham surgery was performed on adult rats and 10-day-old pups, and mechanical thresholds and heat hyperalgesia were analyzed on 3, 7, 14, 28, and 56 postoperative days. Tyrosine hydroxylase-labeled sympathetic fibers were observed at each time point, and 2 neurotrophin receptors (p75NTR and TrkA) were identified to explore the mechanisms of sympathetic sprouting.
Results:
Adult rats rapidly developed mechanical and heat hyperalgesia from postoperative day 3, with concurrent sympathetic sprouting in DRG. In contrast, the pup rats did not show a significantly lower mechanical threshold until postoperative day 28, at which time the sympathetic sprouting became evident in the DRG. No heat hyperalgesia was presented in pup rats at any time point. There was a late expression of glial p75NTR in DRG of pups from postoperative day 28, which was parallel to the occurrence of sympathetic sprouting. The expression of TrkA did not show such a postoperative syncing change.
Conclusion:
The delayed-onset mechanical allodynia in the infant nerve lesion was accompanied with parallel sympathetic sprouting in DRG. The late parallel expression of glial p75NTR injury may play an essential role in this process, which provides novel insight into the treatment of delayed adolescent neuropathic pain.
... TH is a useful marker for CA synthesis and is the first enzyme in CA biosynthesis and catalyzes L-tyrosine to L-DOPA conversion. These neurons showed spontaneous activity, and there is evidence they were sprouting in the ventral roots or dorsal roots as evidenced by cutting the dorsal ramus and ventral ramus significantly reduced spontaneous activity of the sympathetic fibers [10]. ...
The sympathetic trunk ganglia contain the cell bodies of neurons. However, some patients who undergo sympathectomy can develop compensatory hyperhidrosis. To evaluate for ectopic pathways, the present anatomical study was performed. Ten adult cadavers underwent dissection of the spinal canal and removal of randomly selected ventral roots, which were submitted for histological analysis. Random ventral root samples were taken from cervical, thoracic, and lumbosacral regions in each specimen. Each histological section was then analyzed and the presence or absence of sympathetic cells documented for level and position within the ventral root. Of all samples, a sympathetic nerve cell was found in 80% of ventral roots. At least one sympathetic cell was found in these 80%. Most sympathetic cells were found in the proximal one-third of the ventral root. Such cells were found at all spinal levels and no specific level within a vertebral region was found to house a greater concentration of these cells. No statistical significance was found when comparing sides or sex. Our study confirmed that sympathetic cells exist in the majority of human ventral roots. Such data might better explain various clinical presentations and postoperative complications/findings.
... The fact that fiber composition remained unchanged thus would imply a perfectly proportionate reduction of the sympathetic fibers, which is highly unlikely. The observation that disbudding does not entail a shift in fiber composition, however, does not preclude cross-excitation between afferent and efferent fibers as has been suggested in reporter mice and in painful Morton's neuromas (Lindqvist et al., 2000;Xie et al., 2011). ...
Disbudding of calves is a standard husbandry procedure to reduce the risk of injuries to other cattle and to workers. Whereas acute pain resulting from disbudding has been studied extensively, little is known about chronic pain as a potential long-term consequence. The goal of the present study was to investigate possible morphological changes in the cornual nerve as a function of disbudding. Samples were collected from 17 randomly selected bulls and from 21 calves from a prospective clinical study. Among the calves, 13 were disbudded and 8 were sham-disbudded. Out of the disbudded calves, 4 showed signs of chronic pain. In all the animals, the infraorbital nerve was used as a methodological check. Morphological analysis included measuring minimal diameters of the axons present in both the cornual and infraorbital nerves. Sympathetic fibers were identified as based on the presence of Tyroxine hydroxylase (TH). TH-negative fibers were considered afferents. Trigeminal ganglia from the calves were immunostained for glial fibrillary acidic protein (GFAP) and Activating transcription factor 3 (ATF3). R. cornualis and N. infraorbitalis differed in terms of axon diameters and proportion of TH-positive fibers. Weak evidence (p > .091) of a difference in axon diameters between control and disbudded calves was found in R. cornualis, but the proportion of TH-positive fibers was alike in both groups. Average glial envelope and the percentages of ATF3-positive neurons revealed no difference between calves with and without signs of pain. Thus, available evidence is insufficient to support neuropathic changes as a result of disbudding in calves.
... Many reports support that sympathetic sprouting in the DRG is an important underlying mechanism for neuropathic pain, for instance after peripheral nerve injury (McLachlan et al., 1993) or in the chronically compressed DRG (Chien et al., 2005). According to this view, sympathetic fibers only form nests around DRG neurons in conditions of neuropathic pain (Cheng et al., 2015;Xie et al., 2011). Interestingly, after spinal nerve injury, DRG neurons surrounded by sympathetic axons are more likely to be spontaneously active, which is a hallmark of neuropathic pain (Xie et al., 2011). ...
... According to this view, sympathetic fibers only form nests around DRG neurons in conditions of neuropathic pain (Cheng et al., 2015;Xie et al., 2011). Interestingly, after spinal nerve injury, DRG neurons surrounded by sympathetic axons are more likely to be spontaneously active, which is a hallmark of neuropathic pain (Xie et al., 2011). Sympathetic fibers seem to enhance excitability and drive spontaneous activity in sensory neurons via the release of sympathetic neurotransmitters (Xie et al., 2010). ...
Dorsal root ganglion (DRG) neurons are the first neurons of the sensory pathway. They are activated by a variety of sensory stimuli that are then transmitted to the central nervous system. An important feature of DRG neurons is their unique morphology where a single process -the stem axon- bifurcates into a peripheral and a central axonal branch, with different functions and cellular properties. Distinctive structural aspects of the two DRG neuron branches may have important implications for their function in health and disease. However, the link between DRG axonal branch structure, polarity and function has been largely neglected in the field, and relevant information is rather scattered across the literature. In particular, ultrastructural differences between the two axonal branches are likely to account for the higher transport and regenerative ability of the peripheral DRG neuron axon when compared to the central one. Nevertheless, the cell intrinsic factors contributing to this central-peripheral asymmetry are still unknown. Here we critically review the factors that may underlie the functional asymmetry between the peripheral and central DRG axonal branches. Also, we discuss the hypothesis that DRG neurons may assemble a structure resembling the axon initial segment that may be responsible, at least in part, for their polarity and electrophysiological features. Ultimately, we suggest that the clarification of the axonal ultrastructure of DRG neurons using state-of-the-art techniques will be crucial to understand the physiology of this peculiar cell type.
... Furthermore, SGCs may mask or inhibit neuronal growth factor receptors in vivo, a condition lost in dissociated DRG cultures 29 . Interestingly, an axotomy associated sympatho-sensory sprouting is observed in sensory ganglia, which is discussed in the pathogenesis of sympathetically maintained chronic pain 65 . If the underlying neurotrophic signals originate from neurons and/or SGCs is a current focus in pain research. ...
Dogs can be used as a translational animal model to close the gap between basic discoveries in rodents and clinical trials in humans. The present study compared the species-specific properties of satellite glial cells (SGCs) of canine and murine dorsal root ganglia (DRG) in situ and in vitro using light microscopy, electron microscopy, and immunostainings. The in situ expression of CNPase, GFAP, and glutamine synthetase (GS) has also been investigated in simian SGCs. In situ, most canine SGCs (>80%) expressed the neural progenitor cell markers nestin and Sox2. CNPase and GFAP were found in most canine and simian but not murine SGCs. GS was detected in 94% of simian and 71% of murine SGCs, whereas only 44% of canine SGCs expressed GS. In vitro, most canine (>84%) and murine (>96%) SGCs expressed CNPase, whereas GFAP expression was differentially affected by culture conditions and varied between 10% and 40%. However, GFAP expression was induced by bone morphogenetic protein 4 in SGCs of both species. Interestingly, canine SGCs also stimulated neurite formation of DRG neurons. These findings indicate that SGCs represent an exceptional, intermediate glial cell population with phenotypical characteristics of oligodendrocytes and astrocytes and might possess intrinsic regenerative capabilities in vivo.
... Fukuda et al. (2013) were the first to demonstrate that sensory nerves play an important role in bone remodeling. Recently, some interactions between sensory neurons and sprouting sympathetic fibers have been observed (Xie et al., 2011). The sympathetic nervous system is known to inhibit bone mass accrual. ...
Bone remodeling occurs at the bone surface throughout adult life and associates bony quantity and quality. This process is a balance between the osteoblastic bone formation and osteoclastic bone resorption, which cross-talks together. Semaphorin 3A is a membrane-associated secreted protein and regarded as a diffusible axonal chemorepellent, which has been identified in the involvement of bone resorption and formation synchronously. However, the role of Semaphorin 3A in bone homeostasis and diseases remains elusive, in particular the association to osteoblasts and osteoclasts. In this review article, we summarize recent progress of Semaphorin 3A in the bone mass, homeostasis, and diseases and discuss the novel application of nerve-based bone regeneration. This will facilitate the understanding of Semaphorin 3A in skeletal biology and shed new light on the modulation and potential treatment in the bone disorders.
