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The schematic diagram of three types of neurons observed in the A11 region. Green, red, and blue dots represent Calb-, TH-, and Calb-/TH- double immunoreactive cell bodies, respectively. The average numbers of Calb-IR cell bodies observed at three levels are shown at the left column, and those of TH- and TH-/Calb- double immunoreactive cell bodies are shown at the right column. 3V third ventricle, fr fornix retroflexus. rostral A11 region, −3.16 mm; middle, −4.16 mm; caudal, −4.52 mm from bregma
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The A11 dopaminergic cell group is the only group among the A8–A16 dopaminergic cell groups that includes neurons innervating the spinal cord, and a decrease in dopaminergic transmission at the spinal cord is thought to contribute to the pathogenesis of restless legs syndrome. However, the mechanisms regulating the neuronal activity of A11 dopamine...
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... It is well known that several spinal cord regions receive dopaminergic input from the hypothalamic dopaminergic A11 nucleus [11][12][13][14][15], which appears to be responsible for activating DA receptors (DR) [13,16]. Moreover, the D1-and D2-like receptor families are expressed in the dorsal spinal cord [13,17,18]. Additionally, hypothalamic A11 has been related to the regulation of pain [11,19], measured through tactile hypersensitivity [20,21]. ...
Several types of sensory perception have circadian rhythms. The spinal cord can be considered a center for controlling circadian rhythms by changing clock gene expression. However, to date, it is not known if mechanonociception itself has a circadian rhythm. The hypothalamic A11 area represents the primary source of dopamine (DA) in the spinal cord and has been found to be involved in clock gene expression and circadian rhythmicity. Here, we investigate if the paw withdrawal threshold (PWT) has a circadian rhythm, as well as the role of the dopaminergic A11 nucleus, DA, and DA receptors (DR) in the PWT circadian rhythm and if they modify clock gene expression in the lumbar spinal cord. Naïve rats showed a circadian rhythm of the PWT of almost 24 h, beginning during the night–day interphase and peaking at 14.63 h. Similarly, DA and DOPAC’s spinal contents increased at dusk and reached their maximum contents at noon. The injection of 6-hydroxydopamine (6-OHDA) into the A11 nucleus completely abolished the circadian rhythm of the PWT, reduced DA tissue content in the lumbar spinal cord, and induced tactile allodynia. Likewise, the repeated intrathecal administration of D1-like and D2-like DA receptor antagonists blunted the circadian rhythm of PWT. 6-OHDA reduced the expression of Clock and Per1 and increased Per2 gene expression during the day. In contrast, 6-OHDA diminished Clock, Bmal, Per1, Per2, Per3, Cry1, and Cry2 at night. The repeated intrathecal administration of the D1-like antagonist (SCH-23390) reduced clock genes throughout the day (Clock and Per2) and throughout the night (Clock, Per2 and Cry1), whereas it increased Bmal and Per1 throughout the day. In contrast, the intrathecal injection of the D2 receptor antagonists (L-741,626) increased the clock genes Bmal, Per2, and Per3 and decreased Per1 throughout the day. This study provides evidence that the circadian rhythm of the PWT results from the descending dopaminergic modulation of spinal clock genes induced by the differential activation of spinal DR.
... However, after mapping these conventional cell groups within the prosomeric model (implying a different forebrain axis and the hypothalamus held to lie rostral to the diencephalon, plus two neuromeric hypothalamic parts -THy, Phy-and floor, basal, alar, and roof plates according to His, 1893His, , 1904, and a new acroterminal area; Puelles et al., 2012a;Díaz and Puelles, 2020), we excluded group A11 from the hypothalamic region because it relates to diencephalic prosomeres 1, 2 and 3 (Skagerberg and Lindvall, 1985;Marín et al., 2005;Puelles et al., 2012aPuelles et al., , 2021Ozawa et al., 2017). The dopaminergic group A15 is clearly preoptic, and thus belongs to the non-evaginated telencephalon within the prosomeric model ( Figure 15B; Shimogori et al., 2010;Puelles et al., 2012a). ...
Most of the studies on neurochemical mapping, connectivity, and physiology in the hypothalamic region were carried out in rats and under the columnar morphologic paradigm. According to the columnar model, the entire hypothalamic region lies ventrally within the diencephalon, which includes preoptic, anterior, tuberal, and mamillary anteroposterior regions, and sometimes identifying dorsal, intermediate, and ventral hypothalamic partitions. This model is weak in providing little or no experimentally corroborated causal explanation of such subdivisions. In contrast, the modern prosomeric model uses different axial assumptions based on the parallel courses of the brain floor, alar-basal boundary, and brain roof (all causally explained). This model also postulates that the hypothalamus and telencephalon jointly form the secondary prosencephalon, separately from and rostral to the diencephalon proper. The hypothalamus is divided into two neuromeric (transverse) parts called peduncular and terminal hypothalamus (PHy and THy). The classic anteroposterior (AP) divisions of the columnar hypothalamus are rather seen as dorsoventral subdivisions of the hypothalamic alar and basal plates. In this study, we offered a prosomeric immunohistochemical mapping in the rat of hypothalamic cells expressing tyrosine hydroxylase (TH), which is the enzyme that catalyzes the conversion of L-tyrosine to levodopa (L-DOPA) and a precursor of dopamine. This mapping was also combined with markers for diverse hypothalamic nuclei [agouti-related peptide ( Agrp ), arginine vasopressin ( Avp ), cocaine and amphetamine-regulated transcript ( Cart ), corticotropin releasing Hormone ( Crh ), melanin concentrating hormone ( Mch ), neuropeptide Y ( Npy ), oxytocin/neurophysin I ( Oxt ), proopiomelanocortin ( Pomc ), somatostatin ( Sst ), tyrosine hidroxilase ( Th ), and thyrotropin releasing hormone ( Trh )]. TH-positive cells are particularly abundant within the periventricular stratum of the paraventricular and subparaventricular alar domains. In the tuberal region, most labeled cells are found in the acroterminal arcuate nucleus and in the terminal periventricular stratum. The dorsal retrotuberal region (PHy) contains the A13 cell group of TH-positive cells. In addition, some TH cells appear in the perimamillary and retromamillary regions. The prosomeric model proved useful for determining the precise location of TH-positive cells relative to possible origins of morphogenetic signals, thus aiding potential causal explanation of position-related specification of this hypothalamic cell type.
... In the A10 region, approximately one-third of Calb + neurons co-express vesicular glutamate transporter 2 (vGluT2), and some of them innervate the nucleus accumbens, indicating that Calb + neurons appear to regulate DA neurons within the A10 region locally, as well as target areas of A10 DA neurons, such as the nucleus accumbens [18]. We previously reported that Calb + neurons are present in the A11 region with a heterogeneous distribution pattern, and that some of these Calb + neurons also project to the spinal cord [21]. However, the neurochemical nature and functional roles of these A11 Calb + neurons are still largely unknown. ...
... We did not perform fluorescent IHC with triple-labeling for TH, Calb, and CGRP. However, our previous study demonstrated that cellular co-localization of Calb with TH is rarely found [21], indicating that many Calb + /CGRP + neurons appear to be TH − neurons. With regard to the function of CGRP + neurons in the A11 region, Charbit et al. [2,3] suggested that these TH + /CGRP + neurons are associated with migraine. ...
The A11 region plays a role in numerous physiological functions, including pain and locomotor activity, and consists of a variety of neurons including GABAergic, calbindin positive (Calb+), and dopaminergic (DA) neurons. However, the neurochemical nature of Calb+ neurons and their regulatory role in the A11 region remain largely unknown. In this study, we examined the kind of functional markers co-expressed in the Calb+ neurons using sections from 8-week-old rats. To examine a marker related to classical neurotransmitters, we performed in situ hybridization for vesicular glutamate transporter 2 (vGluT2) or glutamate decarboxylase (GAD) 65 and 67, in conjunction with Calb immunohistochemistry. We found cellular co-expression of Calb with vGluT2 or GAD65/67 throughout the A11 region. Nearly all Calb+/GAD65/67+ neurons were found in the rostral-middle aspect of the A11 region. In contrast, Calb+/vGluT2+ neurons were found predominantly in the middle-caudal aspect of the A11 region. For receptors and neuropeptides, we performed immunohistochemistry for androgen receptor (AR), estrogen receptors (ERα and ERβ), and calcitonin gene-related peptide (CGRP). We found that Calb+ neurons co-expressed AR in the rostral aspect of the A11 region in both male and female rats. However, we rarely find cellular co-expression of Calb with ERα or ERβ in this region. For CGRP, we found both Calb+ neurons with or without CGRP expression. These results demonstrate that Calb+ neurons co-express many functional markers. Calb+ neurons have a distinct distribution pattern and may play a variety of regulatory roles, depending on their location within the A11 region.
... This is in contrast to responses in male rats, in which both serotonergic and dopaminergic pathways are activated (Naitou et al. 2018). It is well known that dopamine in the lumbar spinal cord is mainly released by descending neurons projecting from the A11 region of the diencephalon (Skagerberg et al. 1982;Koblinger et al. 2014;Ozawa et al. 2017). Taking into account that the density of descending dopaminergic fibres is lower in females than in males (Pappas et al. 2010), the lack of involvement of dopaminergic pathways in female rats would be due to insufficient release of dopamine from the descending fibres. ...
Key points
This study showed a remarkable sex difference in responses of colorectal motility to noxious stimuli in the colorectum in rats: colorectal motility was enhanced in response to intracolonic administration of a noxious stimulant, capsaicin, in male rats but not in female rats.
The difference in descending neurons from the brain to spinal cord operating after noxious stimulation could be responsible for the sex difference.
In male rats, serotoninergic and dopaminergic neurons are dominantly activated, both of which activate the spinal defaecation centre.
In female rats, GABAergic neurons in addition to serotoninergic neurons are activated. GABA may compete for facilitative action of 5‐HT in the spinal defaecation centre, and thereby colorectal motility is not enhanced in response to intracolonic administration of capsaicin.
The findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome.
Abstract
We previously demonstrated that noxious stimuli in the colorectum enhance colorectal motility through activation of descending pain inhibitory pathways in male rats. It can be expected that the regulatory mechanisms of colorectal motility differ in males and females owing to remarkable sex differences in descending pain inhibitory pathways. Thus, we aimed to clarify sex differences in responses of colorectal motility to noxious stimuli in rats. Colorectal motility was measured in vivo in anaesthetized rats. Administration of a noxious stimulant, capsaicin, into the colorectal lumen enhanced colorectal motility in male rats but not in female rats. Quantitative PCR and immunohistochemistry showed that TRPV1 expression levels in the dorsal root ganglia and in the colorectal mucosa were comparable in male and female rats. When a GABAA receptor inhibitor was intrathecally administered to the L6–S1 level of the spinal cord, colorectal motility was facilitated in response to intracolonic capsaicin even in female rats. The capsaicin‐induced response in the presence of the GABA blocker in female rats was inhibited by intrathecal administration of 5‐HT2 and ‐3 receptor antagonists but not by a D2‐like dopamine receptor antagonist. Our findings demonstrate that intracolonic noxious stimulation activates GABAergic and serotoninergic descending neurons in female rats, whereas serotoninergic and dopaminergic neurons are dominantly activated in male rats. Thus, the difference in the descending neurons operating after noxious stimulation would be responsible for the sexually dimorphic responses of colorectal motility. Our findings provide a novel insight into pathophysiological mechanisms of sex differences in functional defaecation disorders such as irritable bowel syndrome.
... It is well known that several spinal cord regions receive dopaminergic input from the hypothalamic dopaminergic A11 nucleus [11][12][13][14][15], which appears to be responsible for activating DA receptors (DR) [13,16]. Moreover, the D1-and D2-like receptor families are expressed in the dorsal spinal cord [13,17,18]. Additionally, hypothalamic A11 has been related to the regulation of pain [11,19], measured through tactile hypersensitivity [20,21]. ...
Patients with degenerative diseases refer to feeling more pain during the night. However, it is unknown whether spinal nociception can be circadian and how is it controlled. We investigated whether the paw withdrawal threshold (PWT) could exhibit physiological circadian behavior as well as the contribution of the dopaminergic A11 nucleus and the spinal dopamine (DA) receptors (DRs) on the circadian PWT and the spinal clock gene transcription. Results revealed that control rats present a circadian PWT. Injecting 6-hydroxidopamine (6-OHDA) into the dopaminergic A11 nucleus reduced DA tissue content in the lumbar spinal cord, abolished the circadian PWT, induced allodynia, and reduced Period 1 and 2 (Per1 and 2), retinoid-related orphan receptor α (Rorα), Cryptochrome 1 (Cry1), and brain and muscle aryl-hydrocarbon receptor nuclear translocator-like protein (Bmal) mRNA. Likewise, administration of D1-like and D2-like DR antagonists blunted circadian PWT, producing allodynia, and altered the clock genes mRNA. In contrast, administration of D1-like or D2-like DR agonists blocked 6-OHDA-induced allodynia. This study shows that the spinal cord has physiological circadian PWT, which is modulated by the descending dopaminergic A11 through differential activation of the spinal DRs. Also, A11 nuclei and spinal DRs can regulate the clock gene transcription, which can likely modulate the circadian PWT.
... Both D1-like and D2-like receptors exist in the rat spinal cord at a high density [184]. There are descending dopaminergic pathways to the spinal dorsal horn from the periventricular posterior region (A11) of the hypothalamus in rats [185][186][187][188]. Intrathecally-administrated apomorphine (a D2 receptor agonist) inhibited thermally and chemically evoked noxious responses in rats ( [189]; see [190] for review). ...
Much evidence indicates that hypothalamus-derived neuropeptides, oxytocin, orexins A and B, inhibit nociceptive transmission in the rat spinal dorsal horn. In order to unveil cellular mechanisms for this antinociception, the effects of the neuropeptides on synaptic transmission were examined in spinal lamina II neurons that play a crucial role in antinociception produced by various analgesics by using the whole-cell patch-clamp technique and adult rat spinal cord slices. Oxytocin had no effect on glutamatergic excitatory transmission while producing a membrane depolarization, γ-aminobutyric acid (GABA)-ergic and glycinergic spontaneous inhibitory transmission enhancement. On the other hand, orexins A and B produced a membrane depolarization and/or a presynaptic spontaneous excitatory transmission enhancement. Like oxytocin, orexin A enhanced both GABAergic and glycinergic transmission, whereas orexin B facilitated glycinergic but not GABAergic transmission. These inhibitory transmission enhancements were due to action potential production. Oxytocin, orexins A and B activities were mediated by oxytocin, orexin-1 and orexin-2 receptors, respectively. This review article will mention cellular mechanisms for antinociception produced by oxytocin, orexins A and B, and discuss similarity and difference in antinociceptive mechanisms among the hypothalamic neuropeptides and other endogenous pain modulators (opioids, nociceptin, adenosine, adenosine 5’-triphosphate (ATP), noradrenaline, serotonin, dopamine, somatostatin, cannabinoids, galanin, substance P, bradykinin, neuropeptide Y and acetylcholine) exhibiting a change in membrane potential, excitatory or inhibitory transmission in the spinal lamina II neurons.
... Among these regions, we focused on the locus coeruleus (LC; the A6 region), because activation of the nucleus suppresses visceromotor reflex response to colorectal distension (35). Additionally, roles of the A11 region, the principle source of dopamine in the spinal cord (4,8,25), were examined. Our results revealed that the brainstem monoaminergic nuclei activate the spinal defecation center, resulting in enhancement of colorectal motility. ...
... with the role of dopamine because dopaminergic neurons in the A11 region lack dopamine reuptake transporters (14,15). It has been shown that dopaminergic neuronal cell bodies are not present in the lumbosacral spinal cord (8), suggesting that an endogenous source of dopamine in the spinal defecation center is descending neurons projecting from the A11 region (4,25). Taken together, the results suggest that the A11 region plays a role in regulation of colorectal motility as a supraspinal defecation center. ...
We previously demonstrated that administration of norepinephrine, dopamine and serotonin into the lumbosacral defecation center caused propulsive contractions of the colorectum. It is known that the monoamines in the spinal cord are mainly released from descending neurons in the brainstem. In fact, stimulation of the medullary raphe nuclei, the origin of descending serotonergic neurons, enhances colorectal motility via the lumbosacral defecation center. Therefore, the purpose of this study was to examine the roles ofthe noradrenergic nucleus locus coeruleus (LC) and dopaminergic nucleus A11 region in the defecation reflex. Colorectal motility was measured with a balloon in anesthetized rats. Electrical stimulation of the LC and A11 region increased colorectal pressure only when a GABA A receptor antagonist was injected into the lumbosacral spinal cord. The effects of the LC stimulation and A11 region stimulation on colorectal motility were inhibited by antagonists of α1-adrenoceptors and D2-like dopamine receptors injected into the lumbosacral spinal cord, respectively. Spinal injection of a norepinephrine-dopamine reuptake inhibitor augmented the colokinetic effect of LC stimulation. The effect of stimulation of each nucleus was abolished by surgical severing of the parasympathetic pelvic nerves. Our findings demonstrate that activation of descending noradrenergic neurons from the LC and descending dopaminergic neurons from the A11 region causes enhancement of colorectal motility via the lumbosacral defecation center. The present study provides a novel concept that the brainstem monoaminergic nuclei play a role as supraspinal defecation centers.
... Here I will focus on the contribution of the descending dopaminergic pathway to pain modulation in the DHSC. The A11 nucleus located in the periventricular, posterior region of the hypothalamus contains at least three neurochemical-distinct types of neurons: neurons expressing tyrosine hydroxylase (TH), the rate limiting enzyme in the synthesis of catecholamines, necessary to synthetize L-3,4-dihydroxyphenylalanine; neurons expressing calbindin; and neurons expressing both TH and calbindin (Ozawa et al., 2017). TH-expressing neurons in the A11 nucleus also express the aromatic L-amino acid decarboxylase, the enzyme that converts L-3,4-dihydroxyphenylalanine to dopamine, and the vesicular monoamine transporter 2 which is necessary for packaging dopamine into vesicles, strongly supporting the dopaminergic phenotype of the TH-expressing neurons in the A11 nucleus. ...
Nociceptive signals conveyed to the dorsal horn of the spinal cord by primary nociceptors are subject to extensive modulation by local neurons and by supraspinal descending pathways to the spinal cord before being relayed to higher brain centers. Descending modulatory pathways to the spinal cord comprise, among others, noradrenergic, serotonergic, γ-Aminobutyric acid (GABA)ergic, and dopaminergic fibers. The contributions of noradrenaline, serotonin, and GABA to pain modulation have been extensively investigated. In contrast, the contributions of dopamine to pain modulation remain poorly understood. The focus of this review is to summarize the current knowledge of the contributions of dopamine to pain modulation. Hypothalamic A11 dopaminergic neurons project to all levels of the spinal cord and provide the main source of spinal dopamine. Dopamine receptors are expressed in primary nociceptors as well as in spinal neurons located in different laminae in the dorsal horn of the spinal cord, suggesting that dopamine can modulate pain signals by acting at both presynaptic and postsynaptic targets. Here, I will review the literature on the effects of dopamine and dopamine receptor agonists/antagonists on the excitability of primary nociceptors, the effects of dopamine on the synaptic transmission between primary nociceptors and dorsal horn neurons, and the effects of dopamine on pain in rodents. Published data support both anti-nociceptive effects of dopamine mediated by D2-like receptors and pro-nociceptive effects mediated by D1-like receptors. © E-Flow Wolters Kluwer Medknow Publications 2019. All rights reserved.
... Significant reduction of beta-endorphin and met-enkephalin cells and similar leu-enkephalin cells in the thalamus of iRLS patients compared with controls, while beta-endorphin, met-enkephalin, leuenkephalin, and TH cells were similar in the substantia nigra of both study groups both TH and calbindin, project to the spinal cord [5]. In non-human primates, the absence of expression of DRD 1 mRNA, and expression of DRD 2 and DRD 5 mRNAs in the dorsal horn, have been observed, while DRD 3 mRNA is expressed both in the dorsal and ventral horns [4]. ...
The most important traditional hypotheses of the pathogenesis of idiopathic restless legs syndrome (iRLS) involve dopaminergic dysfunction and iron deficiency. However, a possible role of other neurotransmitter or neuromodulators, mainly glutamate, gamma-hydroxybutyric acid (GABA), and adenosine have been suggested in recent reports. Moreover, iron deficiency in experimental models (which causes sensorimotor symptoms resembling those of RLS) is able to induce changes in dopaminergic, glutamatergic and adenosinergic neurotransmission, thus suggesting its crucial role in the pathogenesis of this disease. Relationship between iRLS and opiates, oxidative stress and nitric oxide, and with vitamin D deficiency has also been reported, although data regarding these variables should be considered as preliminary. In this review, we focus on studies relating to neurochemical findings in iRLS.
... Early or Primary RLS is very complicated and difficult to diagnose [9]. Primary RLS affects total quality of life progressively with no identified cause and mal diagnosed as growing pain in children that is why it is categorized as idiopathic more often [10]. The RLS is a complex neurological sleep disorder which involves many physiological symptoms which confuses with other pathophysiology like Parkinsonism more often hence misdiagnosed and mal treated more often [6]. ...
Restless legs syndrome is a chronic progressive sleep associated
sensory motor disorder which develops within the neurological disorders like
Parkinsonism, Neuropathy pain and possible dementia. The global prevalence
of restless legs syndrome is increasing day by day and research studies
have been reported the essential need for research in specific diagnosis and
treatment of restless legs syndrome. Prevalence of Restless legs syndrome
is more in Female and pregnant women than men in the almost whole world.
In India and many other countries of Asia and throughout the world the term
Restless legs syndrome (RLS) is still a questionnaire. It is reported many a
time by the Physicians, Neurologists and Gynecologists as a mal-diagnosis
of Restless legs syndrome in India and in others countries also. The exact
pathophysiology of the RLS is still not clear, but some superficial assumptions
regarding the progressions of disease and root of disease through the gene
molecular concepts. Few Traditional Chinese medicine and allopathic medicine
have been reported a successful treatment of RLS, but it is either symptomatic
or depends on time management. Dopamine Agonist and opioids are possible
symptomatic treatment for RLS, but no treatment is available if it has entered
in a severe stage of RLS. Relations to the lower cerebral ferric and Dopamine
levels are probably reported as the cause for Restlessness like, although
genetic biomarkers have been developed for the diagnosis of the disease. The
core treatment of the disease is still under discovery. Early diagnosis of the
disease can make difference in the first line treatment.
Keywords: Restless leg syndrome; Parkinsonism; Neuropathy;
Preeclampsia; Dopamine antagonist; Ferric ion; Pregnancy; Periodic limb
movement disorder (PLMD)
