The 5‐HT2A receptor is widely distributed in the rat spinal cord and mainly localized at the plasma membrane of postsynaptic neurons

Doly, Stéphane; Madeira, Alexandra; Fischer, Jacqueline; Brisorgueil, Marie‐Jeanne; Daval, G.; Bernard, Rozenn; Vergé, Daniel; Conrath, M.

doi:10.1002/cne.20082

Cited by 97 publications

(69 citation statements)

References 69 publications

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“…The absence of extracellular plasma membrane staining for 5-HT5AR is in complete contrast with observations made for 5-HT2AR in the rat dorsal horn using an antibody also recognizing an N-terminal sequence of the receptor (Doly et al, 2004). In the latter case, we observed dense staining localized in the extracellular space and outlining a large surface of the plasma membrane.…”

Section: Discussioncontrasting

confidence: 84%

5‐HT5A receptor localization in the rat spinal cord suggests a role in nociception and control of pelvic floor musculature

Doly

Fischer

Brisorgueil

et al. 2004

J of Comparative Neurology

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The 5-HT5A receptor is a seven-transmembrane receptor negatively coupled to adenylate cyclase, whose activation opens K+ channels. The 5-HT5A receptor may thus exert an inhibitory effect on neuronal activity. However, the function of this receptor is still largely unknown, in particular at the spinal level, and this is partly due to lack of specific ligands. Immunocytochemistry using specific anti-5-HT5A antibodies reveals a particularly dense labeling in the two superficial layers of the dorsal horn, suggesting that the 5-HT5A receptor may be involved in the spinal modulation of pain. In addition, a very intense staining in the lumbar dorsolateral nucleus (Onuf nucleus) in both males and females suggests that the 5-HT5A receptor is also involved in micturition through the control of urethral sphincter muscles. Colchicine pretreatment allows the staining of numerous cell bodies in lamina II. Fewer labeled cell bodies are seen in laminae I and III-VI, in the lateral spinal nucleus, and in lamina X. Electron microscope examination of 5-HT5A receptor immunoreactivity in spinal cords from untreated animals confirmed the postsynaptic labeling in all regions studied (dorsal horn, dorsolateral nucleus, and lamina X). The morphological heterogeneity of labeled dorsal horn cell bodies suggests that they belong to functionally distinct neurons (projection neurons and interneurons). In the lumbar dorsolateral nucleus, the labeling is preferentially localized on dendrites, suggesting that in this nucleus 5-HT preferentially acts at the dendritic level. Finally, the dense labeling of postsynaptic specializations suggests that the receptor may be in stock before being addressed to the synaptic differentiation.

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Section: Discussioncontrasting

confidence: 84%

5‐HT5A receptor localization in the rat spinal cord suggests a role in nociception and control of pelvic floor musculature

Doly

Fischer

Brisorgueil

et al. 2004

J of Comparative Neurology

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“…Interestingly, both ␣ 1 and 5-HT 2 agonists inhibited the amplitude of polysynaptic reflexes recorded from both L2 and L5 neurograms. Other reports have showed inhibition of spinal reflexes by 5-HT 2 in neonatal rats (Yomono et al 1992), and high expression of 5-HT 2 receptors have been reported in lamina II of rats (Doly et al 2004). The inhibition of afferent transmission may be due to potentiation of glycine conductances in first-order dorsal horn neurons by activation of inhibitory interneurons (Li et al 2002).…”

Section: Monoaminergic Modulation Of Rhythmic Activitymentioning

confidence: 82%

Monoaminergic Control of Cauda-Equina-Evoked Locomotion in the Neonatal Mouse Spinal Cord

Gordon

Whelan²

2006

Journal of Neurophysiology

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. Monoaminergic projections are among the first supraspinal inputs to innervate spinal networks. Little is known regarding the role of monoamines in modulating ongoing locomotor patterns evoked by endogenous release of neurotransmitter. Here we activate a locomotor-like rhythm by electrical stimulation of afferents and then test the modulatory effects of monoamines on the frequency, pattern, and quality of the rhythm. Stimulation of the cauda equina induced a rhythm consisting of left-right and ipsilateral alternation indicative of locomotor-like activity. First, we examined the effects of noradrenaline (NA), serotonin (5-HT), or dopamine (DA) at dose levels that did not elicit locomotor activity. Bath application of NA and DA resulted in a depression of the cauda-equina-evoked rhythm. Conversely, bathapplied 5-HT increased both the amplitude and cycle period of the evoked rhythm, an effect that was mimicked by the addition of 5-HT 2 agonists to the bath. Application of 5-HT 7 agonists disrupted the evoked rhythmic behavior. Next, we examined the effects of NA ␣ 1 and ␣ 2 agonists and found that the suppressive effects of NA on the rhythm could be reproduced by adding the ␣ 2 agonist, clonidine, to the bath. In contrast, bath applying the ␣ 1 agonist, phenylephrine, increased the amplitude and duration of the cycle period. Finally, the suppressive effects of DA were not replicated by the administration of D 1 , D 2 , or D 3 agonists although application of NA ␣ 2 antagonists reversed the effects of DA. Application of D 1 agonists, increased the amplitude of the bursts but did not affect the cycle period. Our results indicate that monoamines can control the expression, pattern, and timing of cauda-equina-evoked locomotor patterns in developing mice.

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“…This effect was very likely due to the restoration of endogenous inhibition, because slight changes in E Cl were shown to have an important impact on the strength of inhibition (5-7, 10). 5-HT 2A Rs are strongly expressed in the ventral horn (45) and are mainly localized in the plasma membrane of neurons, covering a large surface of cell bodies and dendrites (46). These receptors are dramatically up-regulated in the motoneuron somata and dendrites following SCI (47), an effect that starts as early as 1 d after transection (48).…”

Section: Discussionmentioning

confidence: 99%

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

Bos

Sadlaoud

Boulenguez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

158

172

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In healthy adults, activation of γ-aminobutyric acid (GABA) A and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl -] i ), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E IPSP , in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT 2A receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT 2A R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2). ] i (depolarizing shift of the chloride equilibrium potential, E Cl ) dramatically compromises the inhibitory control of firing rate and excitatory inputs (5-7). Given the role of KCC2 in regulating the strength of inhibitory synaptic transmission, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance.Spasticity is a disabling complication affecting individuals with spinal cord injury (SCI) and is characterized by a velocity-dependent increase in muscle tone resulting from hyperexcitable stretch reflexes, spasms, and hypersensitivity to normally innocuous sensory stimulations (8, 9). Down-regulation of KCC2 after SCI in rats is implicated in the development of spasticity (10) and chronic pain (11,12). Notably, the expression of KCC2 in the motoneuron membrane is reduced, and, concomitantly, the density of cytoplasmic clusters is higher, suggesting that the surface stability of the transporter is reduced in these pathological conditions (10).Mounting evidence indicates that phosphorylation of KCC2 in the C-terminal intracellular domain dynamically regulates its activity and surface expression (1). In particular, phosphorylation by protein kinase (PK)C, enhances KCC2 activity and reduces endocytosis (13). Interestingly, activation of 5-hydroxytryptamine type 2 receptors (5-HT 2 Rs) to serotonin stimulates PKC and strengthens the left-right alternation of motor bursts observed during locomotion (14-16), which rely on reciprocal inhibition (17, 18). ...

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The 5‐HT2A receptor is widely distributed in the rat spinal cord and mainly localized at the plasma membrane of postsynaptic neurons

Cited by 97 publications

References 69 publications

5‐HT5A receptor localization in the rat spinal cord suggests a role in nociception and control of pelvic floor musculature

5‐HT5A receptor localization in the rat spinal cord suggests a role in nociception and control of pelvic floor musculature

Monoaminergic Control of Cauda-Equina-Evoked Locomotion in the Neonatal Mouse Spinal Cord

Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2

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