Why are ganglia absent in ventral roots

Studies using multiple labeling immunohistochemistry Coward et al. In contrast to animal studies, in humans the Na V 1. Immunoreactivities for Na V 1. Nevertheless, the strongest immunoreactivity was detected in small neurons Coward et al. A recent study investigating the presence of Na V 1.

The Na V 1. Interestingly, the study directly compared proportions of positive cells in human and mouse DRG and showed significant differences between mouse and humans for Na V 1. The expression of the Na V 1. In contrast, the expression of the Na V 1. These findings are supported by an RNAseq study Ray et al. In addition to transcriptional and translational data, electrophysiological studies confirm the functional presence of Na V 1.

Sensitivity to the puffer fish toxin tetrodotoxin TTX selectively differentiates between channel subtypes, where Na V 1. Human DRG neurons possess TTX-sensitive and TTX-resistant channels, but in contrast to rodents, where TTX-resistant currents are mainly restricted to small diameter neurons, in humans they are present in small and large diameter neurons Han et al.

Nevertheless, the Na V 1. However, in humans, Na V 1. Voltage-gated calcium channels Ca V are essential components of sensory neuron function Park and Luo, as activation of these channels contributes to exocytosis of transmitter-filled vesicles at synaptic endings.

Interestingly, the Ca V 2. Calcium-activated potassium channels K Ca are important contributors to the after hyper-polarization of neurons which can be modulated by NMDA-type glutamate receptor activation and nerve ligation, and therefore contribute to nociceptive signaling Li et al. Immunoreactivities for voltage-independent human K Ca 2. The channels are part of a variety of neuronal signaling pathways including nociception.

Using a carefully tested antiserum, Pan et al. Pan et al. Transient receptor potential cation channel subfamily V member 1 TRPV1 is a channel protein that is activated by the vanilloid capsaicin, an ingredient of hot chili peppers, by low pH and noxious heat.

Endogenous agonists are endocannabinoids such as anandamide and N -arachidonoyl-dopamine Suh and Oh, TRPV1 is a non-selective cation channel that has been shown to be an important component of nociceptive signaling Suh and Oh, Capsaicin induces pain in humans Simone et al.

Consequently, topical capsaicin is currently being successfully used in treatment of pain conditions such as postherpetic neuralgia Anand and Bley, Interestingly, most studies describe the presence of immunoreactivity not only in small-sized neurons but also in medium and some studies in large-sized somata Lauria et al.

Transient receptor potential cation channel ankyrin 1 TRPA1 is a channel protein activated by mustard oil and cinnamaldehyde, and plays an important role as an irritant sensor of a vast amount of compounds in nociceptive signaling, with its expression confirmed in animal DRG neurons Chen and Hackos, Neuropeptides such as CGRP, SP and galanin are neuromodulators that are co-released with transmitters at the central and peripheral terminals of sensory neurons.

In addition to being important cellular markers used in identifying subpopulations of sensory neurons, they are also fundamental contributors to nociceptor function. Calcitonin-gene-related-peptide CGRP is a neuropeptide composed of 37 amino acids. Although the peptide is a strong arterial vasodilator, it also plays a major role in nociception Marti et al. Substance P SP is a neuropeptide composed of 11 amino acids.

It selectively binds to the neurokinin 1 receptor present on nociceptive projection neurons in the rat spinal cord dorsal horn and causes enhanced synaptic activity Gautam et al. Animal studies demonstrate a clear involvement of SP in nociceptive signaling, however, in humans, the evidence to date is not as convincing Babenko et al.

Similarly, SP immunoreactivity is present early in development in neuronal cell bodies of fetal DRG but reports vary. Marti et al. Despite the apparent similarities between humans and rodents, with both having a subpopulation of nociceptive DRG neurons containing SP, blockade of the action of SP via inhibition of neurokinin 1 receptors is effective in relieving pain in mice Laird et al.

Galanin modulates the excitability of dorsal horn neurons and the presynaptic release of glutamate from primary afferents see review, Lang et al. Somatostatin is a neuropeptide of either 14 or 28 amino acids in length, generated from a precursor peptide and is involved in pain processing via interaction with its cognate receptors producing inhibitory, analgesic effects Mollenholt et al. More recent studies suggest that somatostatin is also involved in the signaling of itch Huang et al.

Dorsal root ganglia neurons with immunoreactivity for somatostatin are present by gestational weeks 9 and 10, and a small population of immunoreactive cells are detectable throughout all fetal stages, with enduring expression within cells present in DRG of 4-month-old infants Charnay et al. Endothelin-1 ET1 is one of three peptide isoforms, 21 amino acids in length, which act as vasoconstrictors but also induce pruritus and pain Smith et al.

The ET1 peptide is elevated in patients suffering from sickle cell disease, which is associated with episodes of severe pain and animal studies showed that absence of the ET A receptor subtype blocked sickle cells disease-related pain behavior Lutz et al. The eight amino acids long peptide angiotensin II is part of the renin—angiotensin—aldosterone system RAAS that controls water and electrolyte balance and therefore blood pressure.

This peptide also contributes to the regulation of nociception. Animal studies show intrathecally applied angiotensin II elicits nociceptive behavioral responses Cridland and Henry, ; Nemoto et al. Direct involvement of angiotensin II in pain signaling pathways, was supported by experiments where angiotensin II treatment of cultured human DRG neurons increased their response to capsaicin, whereas treatment with an AT 2 R antagonist reduced capsaicin responses Anand et al.

Whether this occurs via a direct action on neurons, or via effects on immune cell-neuron interactions remains to be determined. Despite the uncertainty surrounding their mechanism of action, AT 2 R antagonists are being used as effective analgesics in humans and laboratory animals Rice et al.

In mice, these neurons have been shown represent the group of GDNF-dependent, non-peptidergic nociceptors Bogen et al. Although Davidson et al. However, it is known that control for the specificity of lectin binding in human sections is difficult, and this is further highlighted in these studies reporting varying detection between membrane and cytosolic I-B4 staining identified by different research groups. Receptors for these factors include the tropomyosin receptor kinases Trk A, B, and C, and the low affinity receptor p75 Lewin and Nykjaer, NGF and the activation of its cognate receptor TrkA, is a key factor in the development of DRG neurons, but also critical for the induction of hyperalgesia and pain via modulation of signaling events in adult DRG neurons.

Neurotrophin receptors are present in DRG from early in development through to adulthood, however, the dynamics of receptor expression patterns from development to adulthood remain to be studied.

Glial-derived neurotrophic factor is another neurotrophic factor which, after interaction with its receptors RET proto-oncogene tyrosine kinase RET and co-receptor GFRalpha1, modulates a subpopulation of nociceptive, I-B4 binding neurons. The effect of GDNF is complex. Nerve growth factor and its receptors have been described in human DRG Vega et al. Therefore, it is of fundamental interest to determine factors that drive neurotrophin receptor mRNA expression in development.

Nitric oxide synthase NOS isoforms 1—3 are present in DRG and its product nitric oxide NO is involved in nociceptive signaling with evidence supporting analgesic and algesic actions. Gamma amino butyric acid GABA and its receptors are the main inhibitors in the nervous system. Both are expressed in DRG neurons. Additional evidence for the presence and involvement of GABA B receptors in the excitability of human DRG neurons has been provided from experiments investigating the inhibitory action of a cone-snail venom V C 1.

In summary, only a small population of molecules that have been described to be involved in the function of DRG neurons in laboratory animals have so far been investigated in humans. It is evident from existing studies that expression patterns and functions of molecules in DRG do not perfectly match between human and laboratory animal. Important differences exist between human DRG compared to laboratory animals and careful conducted future studies will be essential to reconcile and validate these to appropriately translate animal data into human context.

At the physiological level, the longer peripheral processes and associated soma size of human DRG is likely to account for some of these differences, such as immunoreactivity for neurofilament in all human DRG neurons including those classified as large.

Similarly, many molecules characteristic of nociceptors including TRPV1, CGRP and P 2 X 3 and voltage-gated sodium channels are restricted to small and medium sized neurons in mice but in not in humans where nociception-related proteins immunohistochemistry and mRNAs in situ hybridization are present in neurons of all sizes. By all means, these discrepancies do not completely invalidate results from animal studies in a human translational context.

Indeed, most human DRG neurons show remarkably similar patterns in respect to immunoreactivities for pain-related molecules being detected in smaller sized neurons characteristic for nociceptors. But the diversity across sizes combined with differences in electrophysiological properties Zhang et al. Regardless of species, DRG contain multiple types of neurons and multiple types of other cells including satellite cells and cells associated with immune and vascular function.

Dissociation of ganglia and culture of primary sensory neurons is useful to identify neuronal characteristics, but inferences from these studies must recognize that some types of neurons, specifically those with larger size, will likely not survive mechanical isolation and subsequent culture conditions. More importantly, critical issues related to antibody specificity highlight challenges relevant to data collections from both human and animal tissues, including the ability to compare neuronal subpopulations across species.

An emerging and clinically significant area for further investigation is the interaction of neuronal and non-neuronal cells within DRG, and certain neuron-immune cell interactions involved in pain sensitivity have been shown to be consistent in humans and in laboratory animals.

Sensory neuron-immune cell interactions are increasingly recognized as important mechanisms that contribute to chronic pain, yet there is surprisingly sparse investigative reporting of cells such as macrophages and satellite cells in human DRG. In the next few decades, researchers will hopefully find increasing opportunities to investigate and validate molecular and cellular characteristics of human DRG tissues.

The failure of swathes of clinical trials based on animal model data in the past few decades reinforces the importance of human studies in clinical translation and therapeutic development, especially in very complex conditions such as chronic pain. Early insights from a handful of comparative studies suggest fundamental differences in molecular characteristics of rodent and human DRG nociceptive neurons, as well as other cell types in the DRG, and may provide key pieces of information to select optimal targets and aid more effective drug design strategies.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We thank Assoc. Sonja Klebe for her expertise in the use of the CD antiserum and Patricia Vilimas for her support in the staining procedure. Alexandrou, A. Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.

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Try out PMC Labs and tell us what you think. Learn More. George's University, St. George's, Grenada, West Indies. 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. 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. The sympathetic nervous system SNS is part of the visceral nervous system, also known as the autonomic nervous system ANS. Anatomically, on each side of the spinal cord, a paravertebral sympathetic trunk exists and is attached to the ventral rami of the spinal nerves Fig. The sympathetic nerves leave the thoracolumbar T1—L2 parts of the spinal cord and are distributed to the periphery and the viscera [ 1 ].

The SNS will increase blood pressure, heart rate, and dilate the pupils and bronchi and is the part of the ANS that responds to acute stimuli [ 2 ]. The SNS does this by secreting epinephrine from the adrenal medulla, which will also slow down the motility of the gastrointestinal tract [ 3 ]. The SNS plays an important role in temperature regulation of the skin, blood pressure control when rising from a seated position, and in the control of reproductive functions.

Sympathetic output can be controlled on an organ system basis, which is crucial for maintaining homeostasis [ 4 ]. As we have identified occasional sympathetic neuronal cells bodies in ventral rootlets, the present study was performed to better elucidate this microanatomy in a large series of cadavers. As severe compensatory hyperhidrosis can complicate postoperative sympathectomy for hyperhidrosis, such anatomical findings might improve our understanding of such untoward outcomes.

Ten adult fresh frozen cadavers 20 sides underwent dissection of the spinal canal. Specifically, following laminectomy and opening of the dura mater, the ventral roots from their extension from the ventral horn of the spinal cord until their fusion with the dorsal roots at the intervertebral canal were harvested and submitted for histological analysis Fig. Five specimens were male and five were female with an average age at death of 85 years range, 50—98 years.

Additionally, for each harvested specimen, the adjacent sympathetic ganglion was also harvested so that its sympathetic cell bodies could be used for comparison. For hematoxylin and eosin staining, sections were brought to distilled water and stained with hematoxylin for 4 minutes and then rinsed with running tap water.

Next, differentiation was performed with 0. Slides were then stained with eosin for 2 minutes. Finally, slides were dehydrated, cleared, and mounted. Differentiation was performed with lithium carbonate solution for 30 seconds then rinsed with distilled water. Counterstaining with cresyl violet solution was performed and distilled water used to rinse. S Ab-2 antibody common marker for neural tissue Lab Vision, San Diego, CA, USA with rabbit polyclonal and a dilution of and an incubation time of 60 minutes at room temperature was used.

Sections were made through each harvested ventral root including longitudinal axial sections. Using a light microscope, each histological section was then analyzed and the presence or absence of sympathetic cells documented for level and position within the ventral root.

For ease of analysis, each ventral root was divided into thirds. Additionally, a literature search was conducted using PubMed and Google Scholar for relevant articles relating to evidence for the presence of sympathetic ganglion cells in the ventral roots. Literature was excluded if there was no discussion pertaining to sympathetic root ganglia anatomy.

Of all samples, a sympathetic cell Figs. Neurofilament and S Figs. The TH demonstrated granular cytoplasmic immunoreactivity. NeuN Fig. In general, the ectopic sympathetic cells were found in the proximal one-third i. However, occasionally, these cells were found more distally i. Such cells were found at all spinal levels and although not significant, were most often seen in cervical and lumbosacral levels.

No specific level within a vertebral region was found to house a greater concentration of these cells. Roughly one-half of all ectopic sympathetic were found within the periphery of the ventral root Fig. All ectopic sympathetic cells had a similar histology to the sympathetic cells sampled from the sympathetic ganglia of the sympathetic trunk of the adjacent spinal level. Our study confirmed the presence of sympathetic ganglion cells in the ventral roots of human cadaveric specimens.

Although the exact function cannot be elucidated from a postmortem study, the circuitry of such cells can be theorized based on clinical and experimental animal data. Bell and Magendie laid the foundation i. Since then, it has been generally accepted that the dorsal root contains sensory axons and that the ventral root consists of axons from motor neurons [ 6 ]. However, histological studies conducted by Matthews and colleagues [ 7 , 8 ] showed the evidence of presence of some motor fibers in the dorsal roots.

They were able to see that one month after a dorsal root section in cats, activity in the nerve fibers remained. Matthews and Barron suspected from their histological studies that certain fibers in the dorsal roots were motor in nature [ 5 ]. It is thought that the axons may take different routes and that some of the efferent fibers might come directly from cells within the spinal cord, while others could arise from neurons whose cell bodies are in spinal ganglia at differing spinal levels [ 5 ].

There is evidence from animal studies on catecholamine CA containing neurons that sympathetics, verified with positive TH staining, may leave through the ventral roots [ 9 ].

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 ]. Some patients have been reported non-somatic motor sensations when the ventral roots were stimulated [ 11 , 12 , 13 , 14 ]. These findings have been confirmed in several animal studies, specifically by the findings of receptive fields carried by fibers in the ventral root [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].

Coggeshall et al. These findings suggest that a large number of fibers of the ventral root may be sensory. After this discovery, Clifton et al. They found evidence of unmyelinated afferent fibers attached to receptive fields in the periphery, which means that much of the information enters the spinal cord via unmyelinated fibers through the ventral roots [ 6 ].

Therefore, our study identified sympathetic cell bodies in the ventral root is not surprising. Clinically we can apply these concepts of the presence of sympathetic ganglia cells in the ventral roots by looking at the effects of sympathectomies and hyperhidrosis. Sweating is thought to be mediated primarily by the SNS especially in times of stress.

However, there are times in which the SNS goes on overdrive leading to conditions such as essential hyperhidrosis. It may affect multiple parts of the body; however the most common areas are the hands, armpits, feet, head and inguinal area [ 26 , 27 , 28 ].

A treatment option for essential hyperhidrosis is to perform a sympathectomy. This surgery, for palmar hyperhidrosis, entails removing the sympathetic ganglia between T2—T4 or T5 and is often successful.

However, in a study done by Baumgartner and Toh, it was shown that in some patients compensatory hyperhidrosis occurred. This might be explained by the presence of sympathetic ganglia in the ventral roots remaining even after the sympathectomy. In their study, these authors reported patients with either palmar hyperhidrosis or axillary hyperhidrosis [ 29 ]. However, of the patients who underwent thoracoscopic sympathectomy, 1.

In sum, our findings elucidate ectopic sympathetic neurons in the ventral root of the human spinal cord. Such findings are important for better understanding of the variations of the human nervous system [ 30 , 31 , 32 , 33 ].

Our study confirmed that sympathetic ganglion cells exist in the majority of human ventral roots. While the function of these ectopic neurons needs further investigation, such a finding might contribute to poor outcomes following some sympathectomies where hyperhidrosis is recalcitrant or in patients who develop compensatory hyperhidrosis following such procedures.

Conflicts of Interest: No potential conflict of interest relevant to this article was reported. National Center for Biotechnology Information , U. Journal List Anat Cell Biol v. Anat Cell Biol. Published online Feb Chrissie Massrey , 4 Marwah M. Shane Tubbs 1.