5-HT3 receptors in the rat central nervous system are mainly located on nerve fibres and terminals

Kidd, Emma Jane; Laporte, Anne-Marie; Langlois, Xavier; Fattaccini, C. M.; Doyen, Cécile Marie; Lombard, Marie-Christine; Gozlan, H.; Hamon, Michel

doi:10.1016/0006-8993(93)91674-h

Cited by 152 publications

(84 citation statements)

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“…The number of 5-HT 3 receptors in the dorsal horn can be greatly reduced by neonatal capsaicin treatment or dorsal rhizotomy, 55,56 which suggests that these receptors are expressed predominantly on peripheral nerve fibers and terminals, but that those remaining may represent 5-HT 3 receptors on inhibitory interneurons in the spinal cord. 57 Given the predominantly pronociceptive effect of 5-HT acting at 5-HT 3 receptors, however, and the clinical analgesic potential of the selective 5-HT 3 receptor antagonist ondansetron, 58 these presumptive GABA-dependent inhibitory effects may be masked by upregulated descending serotonergic facilitatory effects in the pathophysiological setting.…”

Section: -Ht Function In Different Pain Statesmentioning

confidence: 99%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

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Summary:The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent ␣ 2 -adrenoceptor-mediated inhibitory system and 5-HT 3 (and likely also 5-HT 2 ) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control. Key Words: 5-HT receptors, 5-HT, serotonin, noradrenaline, RVM, rostral ventromedial medulla, opioidinduced hyperalgesia, neuropathy, fibromyalgia. PAIN, COMORBIDITIES, AND MONOAMINESPain and mood share certain neurological pathways in the CNS and have overlapping neurochemical bases, in particular their modulation by monoamine systems. This provides the substrate through which pain can influence mood, giving rise to comorbidities or secondary symptoms such as anxiety and depression, 1,2 and by the same continuum allows mood to exacerbate pain; indeed, patients with depression often present with symptoms that include medically unexplained pain, with the mean prevalence of such occurrence cited as 65%.1,3 Emotional facets of nociception play a significant role in the pain experience, with fear largely driving adaptive behaviors that enable avoidance of actual or impending harm. This therefore subserves the key function of pain, to protect the integrity and survival of an organism. Moreover, the role of emotions and state of mind in pain partly underlie the variable relationship between the intensity of damaging stimuli and perceived pain, such that at any given time and for any given nociceptive stimulus, painful response can be influenced by emotional state (the psychological context in which the stimulus is received), emotional trait (the psychological characteristics of the recipient), and cognitive set (attention and vigilance, for example).Depression is associated with abnormalities in the monoaminergic ...

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Section: -Ht Function In Different Pain Statesmentioning

confidence: 99%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

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“…This however opposes the attenuation of aerent-evoked neurotransmission observed by Khasabov et al (1999) in similarly aged animals when CPBG was applied at much higher concentrations (10 ± 50 mM). Since the vast majority of 5-HT 3 receptors present in the spinal cord dorsal horn are found on primary aerent terminals (Hamon et al, 1989;Kidd et al, 1993;Laporte et al, 1995) where they can mediate a primary aerent depolarization (Khasabov et al, 1999), synaptic depression via presynaptic inhibitory mechanisms is expected. Even though 5-HT 3 receptors are also present on some dorsal horn neurons including GABAergic (Morales et al, 1998) and enkephalinergic interneurons (Tsuchiya et al, 1999), we found no evidence to suggest that CPBG mediated direct excitatory actions on the DDH neurons.…”

Section: Synaptic Facilitationmentioning

confidence: 99%

“…Several receptors, which include the 5-HT 1 , 5-HT 2 and 5-HT 3 receptors, have been identi®ed in the spinal cord dorsal horn (e.g. Huang & Peroutka, 1987;Marlier et al, 1991;Kidd et al, 1993;Pompeiano et al, 1994). With the exception of the ionotropic 5-HT 3 receptor, all serotonergic receptors are G protein-coupled receptors and hence capable of exerting a broad modulatory in¯uence on network and cell behaviour, as most, if not all, ligand-and voltage-gated channels can be modulated by 5-HT (e.g.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat

Garraway

Hochman

2001

British J Pharmacology

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1 Spinal cord slices and whole-cell patch clamp recordings were used to investigate the eects of serotonergic receptor ligands on dorsal root-evoked synaptic responses in deep dorsal horn (DDH) neurons of the neonatal rat at postnatal days (P) 3 ± 6 and P10 ± 14. 2 Bath applied 5-hydroxytryptamine (5-HT) potently depressed synaptic responses in most neurons. Similarly, the 5-HT 1/7 receptor agonist, 5-carboxamidotryptamine (5-CT) depressed synaptic responses. This action was probably mediated by 5-HT 1A receptor activation, since it occurred in the presence of the 5-HT 7 receptor antagonist clozapine and was not observed in the presence of NAN-190, a 5-HT 1A receptor antagonist. In the absence of any agonist, 5-HT 1A receptor antagonists often facilitated synaptic responses, suggesting that there is sucient endogenous 5-HT to tonically activate 5-HT 1A receptors. 3 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the 5-HT 1A/7 receptor agonist, facilitated synaptic responses, an action probably mediated by 5-HT 7 receptors, since the facilitation could be reversed by subsequent application of the 5-HT 7 receptor antagonist clozapine. 4 Agonists for the 5-HT 1B , 5-HT 2 and 5-HT 3 receptors exerted only modest modulatory actions. 5 A pharmacological analysis of the depression evoked by 5-HT suggested an action partly mediated by 5-HT 1A receptor activation, since antagonism of the 5-HT 1A receptor with NAN-190 or WAY-100635 partly reversed 5-HT-evoked depression. In comparison, 5-HT 7 receptor activation could account for much of the 5-HT-evoked facilitation. 6 We conclude that 5-HT is capable of modulating sensory input onto DDH neurons via several receptor subtypes, producing both facilitatory and depressant actions. Also, the actions of most receptor ligands on the evoked responses were similar within the ®rst 2 postnatal weeks.

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“…Specifically, a presynaptic locus has been implicated in the 5-HT3 receptor agonist-induced release of dopamine in the corpus striatum (Blandina et al, 1989) and in the olfactory tubercie (Zazpe et al, 1994), the release of cholecystokinin in the cerebral cortex and nucleus accumbens (Paudice and Raiteri, 1990), and the release of glutamate and GABA in the solitary tract nucleus (Glaum et al, 1992), although, curiously, 5-HT5 receptors appear to inhibit the evoked release of ACh in human cerebral cortical terminals (Maura et al, 1992). Indeed, in quantitative autoradiographic studies a substantial portion of the 5-HT3 receptors expressed in the CNS appears to be localized to presynaptic nerve terminals or fibers (Kidd et al, 1993). Furthermore, we have recently demonstrated the presence of physiologically functional 5-HT3 receptors on individual isohtted nerve terminals (synaptosomes) using laser-scanning confocal microscopy (Nichols and Mollard, 1996), wherein 5-HT3 receptor agonist-induced changes in Ca 2~level were observed in a small subset of individual striatal synaptosomes.…”

Section: -Htmentioning

confidence: 99%

High Calcium Permeability of Serotonin 5‐HT₃ Receptors on Presynaptic Nerve Terminals from Rat Striatum

Rondé

Nichols

1998

Journal of Neurochemistry

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Abstract:The serotonin 5-HT3 receptor, a ligand-gated ion channel, has previously been shown to be present on a subpopulation of brain nerve terminals, where, on activation, the 5-HT3 receptors induce Ca 2~influx. Whereas postsynaptic 5-HT 3 receptors induce depolarization, being permeant to Naãnd K~, the basis of presynaptic 5-HT3 receptor-induced calcium influx is unknown. Because the small size of isolated brain nerve terminals (synaptosomes) precludes electrophysiological measurements, confocal microscopic imaging has been used to detect calcium influx into them. Application of 100 n M 1-(m-chlorophenyl) biguanide (mCPBG), a highly specific 5-HT3 receptor agonist, induced increases in internal free Ca 2~concentration ([Ca2~]) and exocytosis in a subset of corpus striatal synaptosomes. mCPBG-induced increases in [Ca2~]ranged from 1.3 to 1 .6 times over basal values and were inhibited by 10 nM tropisetron, a potent and highly specific 5-HT 3 receptor antagonist, but were insensitive to the removal of external free Na~(substituted with N-methyl-o-glucamine), to prior depolarization induced on addition of 20 mM K~, or to voltage-gated Ca 2~channel blockade by 10 p~M Co2~/Cd2õrbyl ,uMw-conotoxin MVIIC/1~tMw-conotoxin GVIA/200 nM agatoxin TK. In contrast, the Ca2ĩ nflux induced by 5-HT 3 receptor activation in NG1 08-15 cells by 1 ,tiM mCPBG was substantially reduced by 10.tMCo 2~/Cd2ãnd was completely blocked by 1 ,uM nitrendipine, an L-type Ca2~channel blocker. We conclude that in contrast to the perikaryal 5-HT 3 receptors, presynaptic 5-HT3 receptors appear to be uniquely calcium-permeant. Key Words: Serotonin 5-HT3 receptorPresynaptic regulation-Synaptosomes-Confocal microscopy-Internal free Ca 2~concentration measurements-NG1O8-15 cells.

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5-HT3 receptors in the rat central nervous system are mainly located on nerve fibres and terminals

Cited by 152 publications

References 47 publications

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat

High Calcium Permeability of Serotonin 5‐HT₃ Receptors on Presynaptic Nerve Terminals from Rat Striatum

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5-HT3 receptors in the rat central nervous system are mainly located on nerve fibres and terminals

Cited by 152 publications

References 47 publications

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat

High Calcium Permeability of Serotonin 5‐HT3 Receptors on Presynaptic Nerve Terminals from Rat Striatum

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High Calcium Permeability of Serotonin 5‐HT₃ Receptors on Presynaptic Nerve Terminals from Rat Striatum