Publications by authors named "Rita Bardoni"

22 Publications

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Presynaptic Inhibition of Pain and Touch in the Spinal Cord: From Receptors to Circuits.

Int J Mol Sci 2021 Jan 2;22(1). Epub 2021 Jan 2.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Sensory primary afferent fibers, conveying touch, pain, itch, and proprioception, synapse onto spinal cord dorsal horn neurons. Primary afferent central terminals express a wide variety of receptors that modulate glutamate and peptide release. Regulation of the amount and timing of neurotransmitter release critically affects the integration of postsynaptic responses and the coding of sensory information. The role of GABA (γ-aminobutyric acid) receptors expressed on afferent central terminals is particularly important in sensory processing, both in physiological conditions and in sensitized states induced by chronic pain. During the last decade, techniques of opto- and chemogenetic stimulation and neuronal selective labeling have provided interesting insights on this topic. This review focused on the recent advances about the modulatory effects of presynaptic GABAergic receptors in spinal cord dorsal horn and the neural circuits involved in these mechanisms.
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http://dx.doi.org/10.3390/ijms22010414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795800PMC
January 2021

Identification of a Potent and Selective 5-HT Receptor Agonist with and Antinociceptive Activity.

ACS Chem Neurosci 2020 12 2;11(24):4111-4127. Epub 2020 Dec 2.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy.

Opioids are the gold standard drugs for the treatment of acute and chronic severe pain, although their serious side effects constitute a big limitation. In the search for new and safer drugs, 5-HTR agonists are emerging as potential candidates in pain relief therapy. In this work, we evaluated the affinity and activity of enantiomers of the two newly synthesized, potent 5-HTR agonists -[(2,2-diphenyl-1,3-dioxolan-4-yl)methyl]-2-[2-(pyridin-4-yl)phenoxy]ethan-1-ammonium hydrogenoxalate () and -((2,2-diphenyl-1,3-dioxolan-4-yl)methyl)-2-(2-(1-methyl-1-imidazol-5-yl)phenoxy)ethan-1-ammonium hydrogenoxalate () and . The role of chirality in the interaction with 5-HTR was evaluated by molecular docking. The activity of the was tested in mouse models of acute pain (hot plate) and severe tonic nociceptive stimulation (intraplantar formalin test). was active in the formalin test with a reduction in paw licking in both phases at 10 mg/kg, and its effect was abolished by the selective 5-HTR antagonist, WAY-100635. The eutomer ()-, but not the racemate, was active during the hot plate test at 10 and 20 mg/kg, and this effect was abolished by 30 min treatment with WAY-100635 at 30 min. Similarly to 8-OH-DPAT, ()- evoked a slow outward current and depressed spontaneous glutamatergic transmission in superficial dorsal horn neurons, more effectively than -. The eutomer ()- showed promising developability properties, such as high selectivity over 5-HT subtypes, no interaction with the μ receptors, and low hepato- and cardiotoxicity. Therefore, ()- may represent a potential candidate for the treatment of acute and chronic pain without having the adverse effects that are commonly associated with the classic opioid drugs.
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http://dx.doi.org/10.1021/acschemneuro.0c00289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016166PMC
December 2020

A spinal neural circuitry for converting touch to itch sensation.

Nat Commun 2020 10 8;11(1):5074. Epub 2020 Oct 8.

Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2) receive direct Aβ low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2 neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.
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http://dx.doi.org/10.1038/s41467-020-18895-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545208PMC
October 2020

Pain Inhibits GRPR Neurons via GABAergic Signaling in the Spinal Cord.

Sci Rep 2019 11 1;9(1):15804. Epub 2019 Nov 1.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, 63110, USA.

It has been known that algogens and cooling could inhibit itch sensation; however, the underlying molecular and neural mechanisms remain poorly understood. Here, we show that the spinal neurons expressing gastrin releasing peptide receptor (GRPR) primarily comprise excitatory interneurons that receive direct and indirect inputs from C and Aδ fibers and form contacts with projection neurons expressing the neurokinin 1 receptor (NK1R). Importantly, we show that noxious or cooling agents inhibit the activity of GRPR neurons via GABAergic signaling. By contrast, capsaicin, which evokes a mix of itch and pain sensations, enhances both excitatory and inhibitory spontaneous synaptic transmission onto GRPR neurons. These data strengthen the role of GRPR neurons as a key circuit for itch transmission and illustrate a spinal mechanism whereby pain inhibits itch by suppressing the function of GRPR neurons.
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http://dx.doi.org/10.1038/s41598-019-52316-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825123PMC
November 2019

Serotonergic Modulation of Nociceptive Circuits in Spinal Cord Dorsal Horn.

Authors:
Rita Bardoni

Curr Neuropharmacol 2019 ;17(12):1133-1145

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, 41125, Italy.

Background: Despite the extensive number of studies performed in the last 50 years, aimed at describing the role of serotonin and its receptors in pain modulation at the spinal cord level, several aspects are still not entirely understood. The interpretation of these results is often complicated by the use of different pain models and animal species, together with the lack of highly selective agonists and antagonists binding to serotonin receptors.

Method: In this review, a search has been conducted on studies investigating the modulatory action exerted by serotonin on specific neurons and circuits in the spinal cord dorsal horn. Particular attention has been paid to studies employing electrophysiological techniques, both in vivo and in vitro.

Conclusion: The effects of serotonin on pain transmission in dorsal horn depend on several factors, including the type of receptors activated and the populations of neurons involved. Recently, studies performed by activating and/or recording from identified neurons have importantly contributed to the understanding of serotonergic modulation on dorsal horn circuits.
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http://dx.doi.org/10.2174/1570159X17666191001123900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057206PMC
April 2020

Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice.

Cell Rep 2018 Apr;23(3):866-877

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Chronic itch or pruritus is a debilitating disorder that is refractory to conventional anti-histamine treatment. Kappa opioid receptor (KOR) agonists have been used to treat chronic itch, but the underlying mechanism remains elusive. Here, we find that KOR and gastrin-releasing peptide receptor (GRPR) overlap in the spinal cord, and KOR activation attenuated GRPR-mediated histamine-independent acute and chronic itch in mice. Notably, canonical KOR-mediated G signaling is not required for desensitizing GRPR function. In vivo and in vitro studies suggest that KOR activation results in the translocation of Ca-independent protein kinase C (PKC)δ from the cytosol to the plasma membrane, which in turn phosphorylates and inhibits GRPR activity. A blockade of phospholipase C (PLC) in HEK293 cells prevented KOR-agonist-induced PKCδ translocation and GRPR phosphorylation, suggesting a role of PLC signaling in KOR-mediated GRPR desensitization. These data suggest that a KOR-PLC-PKCδ-GRPR signaling pathway in the spinal cord may underlie KOR-agonists-induced anti-pruritus therapies.
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http://dx.doi.org/10.1016/j.celrep.2018.03.087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937707PMC
April 2018

Distinct roles of NMB and GRP in itch transmission.

Sci Rep 2017 11 13;7(1):15466. Epub 2017 Nov 13.

Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, 63110, USA.

A key question in our understanding of itch coding mechanisms is whether itch is relayed by dedicated molecular and neuronal pathways. Previous studies suggested that gastrin-releasing peptide (GRP) is an itch-specific neurotransmitter. Neuromedin B (NMB) is a mammalian member of the bombesin family of peptides closely related to GRP, but its role in itch is unclear. Here, we show that itch deficits in mice lacking NMB or GRP are non-redundant and Nmb/Grp double KO (DKO) mice displayed additive deficits. Furthermore, both Nmb/Grp and Nmbr/Grpr DKO mice responded normally to a wide array of noxious stimuli. Ablation of NMBR neurons partially attenuated peripherally induced itch without compromising nociceptive processing. Importantly, electrophysiological studies suggested that GRPR neurons receive glutamatergic input from NMBR neurons. Thus, we propose that NMB and GRP may transmit discrete itch information and NMBR neurons are an integral part of neural circuits for itch in the spinal cord.
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http://dx.doi.org/10.1038/s41598-017-15756-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684337PMC
November 2017

GABA receptors-mediated tonic inhibition of glutamate release from Aβ fibers in rat laminae III/IV of the spinal cord dorsal horn.

Mol Pain 2017 Jan-Dec;13:1744806917710041

2 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Presynaptic GABA receptors (GABARs) are highly expressed in dorsal root ganglion neurons and spinal cord dorsal horn. GABARs located in superficial dorsal horn play an important antinociceptive role, by acting at both pre- and postsynaptic sites. GABARs expressed in deep dorsal horn could be involved in the processing of touch sensation and possibly in the generation of tactile allodynia in chronic pain. The objective of this study was to characterize the morphological and functional properties of GABARs expressed on Aβ fibers projecting to lamina III/IV and to understand their role in modulating excitatory synaptic transmission. We performed high-resolution electron microscopic analysis, showing that GABA subunit is expressed on 71.9% of terminals in rat lamina III-IV. These terminals were engaged in axodendritic synapses and, for the 46%, also expressed glutamate immunoreactivity. Monosynaptic excitatory postsynaptic currents, evoked by Aβ fiber stimulation and recorded from lamina III/IV neurons in spinal cord slices, were strongly depressed by application of baclofen (0.1-2.5 µM), acting as a presynaptic modulator. Application of the GABAR antagonist CGP 55845 caused, in a subpopulation of neurons, the potentiation of the first of two excitatory postsynaptic currents recorded with the paired-pulse protocol, showing that GABARs are endogenously activated. A decrease in the paired-pulse ratio accompanied the effect of CGP 55845, implying the involvement of presynaptic GABARs. CGP 55845 facilitated only the first excitatory postsynaptic current also during a train of four consecutive stimuli applied to Aβ fibers. These results suggest that GABARs tonically inhibit glutamate release from Aβ fibers at a subset of synapses in deep dorsal horn. This modulation specifically affects only the early phase of synaptic excitation in lamina III-IV neurons.
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http://dx.doi.org/10.1177/1744806917710041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456036PMC
April 2018

Transient, activity dependent inhibition of transmitter release from low threshold afferents mediated by GABAA receptors in spinal cord lamina III/IV.

Mol Pain 2015 Oct 13;11:64. Epub 2015 Oct 13.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Campi, 287, 41125, Modena, Italy.

Background: Presynaptic GABAA receptors (GABAARs) located on central terminals of low threshold afferent fibers are thought to be involved in the processing of touch and possibly in the generation of tactile allodynia in chronic pain. These GABAARs mediate primary afferent depolarization (PAD) and modulate transmitter release. The objective of this study was to expand our understanding of the presynaptic inhibitory action of GABA released onto primary afferent central terminals following afferent stimulation.

Results: We recorded evoked postsynaptic excitatory responses (eEPSCs and eEPSPs) from lamina III/IV neurons in spinal cord slices from juvenile rats (P17-P23, either sex), while stimulating dorsal roots. We investigated time and activity dependent changes in glutamate release from low threshold A fibers and the impact of these changes on excitatory drive. Blockade of GABAARs by gabazine potentiated the second eEPSC during a train of four afferent stimuli in a large subset of synapses. This resulted in a corresponding increase of action potential firing after the second stimulus. The potentiating effect of gabazine was due to inhibition of endogenously activated presynaptic GABAARs, because it was not prevented by the blockade of postsynaptic GABAARs through intracellular perfusion of CsF. Exogenous activation of presynaptic GABAARs by muscimol depressed evoked glutamate release at all synapses and increased paired pulse ratio (PPR).

Conclusions: These observations suggest that afferent driven release of GABA onto low threshold afferent terminals is most effective following the first action potential in a train and serves to suppress the initial strong excitatory drive onto dorsal horn circuitry.
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http://dx.doi.org/10.1186/s12990-015-0067-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605127PMC
October 2015

Delta opioid receptors presynaptically regulate cutaneous mechanosensory neuron input to the spinal cord dorsal horn.

Neuron 2014 Mar 27;81(6):1312-1327. Epub 2014 Feb 27.

Department of Anesthesiology, Perioperative and Pain Medicine, Department of Molecular and Cellular Physiology, Stanford Neurosciences Institute, Stanford University, Palo Alto, CA 94304, USA. Electronic address:

Cutaneous mechanosensory neurons detect mechanical stimuli that generate touch and pain sensation. Although opioids are generally associated only with the control of pain, here we report that the opioid system in fact broadly regulates cutaneous mechanosensation, including touch. This function is predominantly subserved by the delta opioid receptor (DOR), which is expressed by myelinated mechanoreceptors that form Meissner corpuscles, Merkel cell-neurite complexes, and circumferential hair follicle endings. These afferents also include a small population of CGRP-expressing myelinated nociceptors that we now identify as the somatosensory neurons that coexpress mu and delta opioid receptors. We further demonstrate that DOR activation at the central terminals of myelinated mechanoreceptors depresses synaptic input to the spinal dorsal horn, via the inhibition of voltage-gated calcium channels. Collectively our results uncover a molecular mechanism by which opioids modulate cutaneous mechanosensation and provide a rationale for targeting DOR to alleviate injury-induced mechanical hypersensitivity.
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http://dx.doi.org/10.1016/j.neuron.2014.01.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072501PMC
March 2014

Role of presynaptic glutamate receptors in pain transmission at the spinal cord level.

Authors:
Rita Bardoni

Curr Neuropharmacol 2013 Sep;11(5):477-83

Department of Biomedical, metabolic and neural sciences, University of Modena and Reggio Emilia, Italy.

Nociceptive primary afferents release glutamate, activating postsynaptic glutamate receptors on spinal cord dorsal horn neurons. Glutamate receptors, both ionotropic and metabotropic, are also expressed on presynaptic terminals, where they regulate neurotransmitter release. During the last two decades, a wide number of studies have characterized the properties of presynaptic glutamatergic receptors, particularly those expressed on primary afferent fibers. This review describes the subunit composition, distribution and function of presynaptic glutamate ionotropic (AMPA, NMDA, kainate) and metabotropic receptors expressed in rodent spinal cord dorsal horn. The role of presynaptic receptors in modulating nociceptive information in experimental models of acute and chronic pain will be also discussed.
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http://dx.doi.org/10.2174/1570159X11311050002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763755PMC
September 2013

Pre- and postsynaptic inhibitory control in the spinal cord dorsal horn.

Ann N Y Acad Sci 2013 Mar;1279:90-6

Department of Biomedical, Metabolic and Neural Science, University of Modena and Reggio Emilia, Modena, Italy.

Sensory information transmitted to the spinal cord dorsal horn is modulated by a complex network of excitatory and inhibitory interneurons. The two main inhibitory transmitters, GABA and glycine, control the flow of sensory information mainly by regulating the excitability of dorsal horn neurons. A presynaptic action of GABA has also been proposed as an important modulatory mechanism of transmitter release from sensory primary afferent terminals. By inhibiting the release of glutamate from primary afferent terminals, activation of presynaptic GABA receptors could play an important role in nociceptive and tactile sensory coding, while changes in their expression or function could be involved in pathological pain conditions, such as allodynia.
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http://dx.doi.org/10.1111/nyas.12056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359868PMC
March 2013

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice.

J Clin Invest 2011 Apr 7;121(4):1608-23. Epub 2011 Mar 7.

Institute for Pharmacology, Heidelberg University, Heidelberg, Germany.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA-type) glutamate receptors (AMPARs) play an important role in plasticity at central synapses. Although there is anatomical evidence for AMPAR expression in the peripheral nervous system, the functional role of such receptors in vivo is not clear. To address this issue, we generated mice specifically lacking either of the key AMPAR subunits, GluA1 or GluA2, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system. Nociceptor-specific deletion of GluA1 led to disruption of calcium permeability and reduced capsaicin-evoked activation of nociceptors. Deletion of GluA1, but not GluA2, led to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. Further analysis revealed that GluA1-containing AMPARs regulated the responses of nociceptors to painful stimuli in inflamed tissues and controlled the excitatory drive from the periphery into the spinal cord. Consequently, peripherally applied AMPAR antagonists alleviated inflammatory pain by specifically blocking calcium-permeable AMPARs, without affecting physiological pain or eliciting central side effects. These findings indicate an important pathophysiological role for calcium-permeable AMPARs in nociceptors and may have therapeutic implications for the treatment chronic inflammatory pain states.
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http://dx.doi.org/10.1172/JCI44911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069784PMC
April 2011

Glutamate-mediated astrocyte-to-neuron signalling in the rat dorsal horn.

J Physiol 2010 Mar 18;588(Pt 5):831-46. Epub 2010 Jan 18.

Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italy.

By releasing neuroactive agents, including proinflammatory cytokines, prostaglandins and neurotrophins, microglia and astrocytes are proposed to be involved in nociceptive transmission, especially in conditions of persistent, pathological pain. The specific action on dorsal horn neurons of agents released from astrocytes, such as glutamate, has been, however, poorly investigated. By using patch-clamp and confocal microscope calcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsal horn lamina II neurons following astrocyte activation. Results obtained revealed that stimuli that triggered Ca(2+) elevations in astrocytes, such as the purinergic receptor agonist BzATP and low extracellular Ca(2+), induce in lamina II neurons slow inward currents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons from other central nervous system regions, these currents (i) are insensitive to tetrodotoxin (TTX), (ii) are blocked by the NMDA receptor (NMDAR) antagonist d-AP5, (iii) lack an AMPA component, and (iv) have slow rise and decay times. Ca(2+) imaging also revealed that astrocytic glutamate evokes NMDAR-mediated episodes of synchronous activity in groups of substantia gelatinosa neurons. Importantly, in a model of peripheral inflammation, the development of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDAR-mediated astrocyte-to-neuron signalling thus represents a novel pathway that may contribute to the control of central sensitization in pathological pain.
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http://dx.doi.org/10.1113/jphysiol.2009.180570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834942PMC
March 2010

Postnatal development shifts the balance of pain descending control.

Authors:
Rita Bardoni

J Physiol 2009 Jun;587(Pt 12):2711-2

Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi, 287, 41100-Modena, Italy.

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http://dx.doi.org/10.1113/jphysiol.2009.174565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718227PMC
June 2009

BDNF as a pain modulator.

Prog Neurobiol 2008 Jul 26;85(3):297-317. Epub 2008 Apr 26.

Dipartimento di Morfofisiologia Veterinaria, University of Turin, Turin, Italy.

At least some neurotrophins may be powerful modulators of synapses, thereby influencing short- and long-term synaptic efficiency. BDNF acts at central synapses in pain pathways both at spinal and supraspinal levels. Neuronal synthesis, subcellular storage/co-storage and release of BDNF at these synapses have been characterized on anatomical and physiological grounds, in parallel with trkB (the high affinity BDNF receptor) distribution. Histological and functional evidence has been provided, mainly from studies on acute slices and intact animals, that BDNF modulates fast excitatory (glutamatergic) and inhibitory (GABAergic/glycinergic) signals, as well as slow peptidergic neurotrasmission in spinal cord. Recent studies have unraveled some of the neuronal circuitries and mechanisms involved, highlighting the key role of synaptic glomeruli in lamina II as the main sites for such a modulation.
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http://dx.doi.org/10.1016/j.pneurobio.2008.04.004DOI Listing
July 2008

Presynaptic functional trkB receptors mediate the release of excitatory neurotransmitters from primary afferent terminals in lamina II (substantia gelatinosa) of postnatal rat spinal cord.

Dev Neurobiol 2008 Mar;68(4):457-75

Dipartimento di Morfofisiologia Veterinaria, Università di Torino, Via Leonardo da Vinci 44, 10095 Grugliasco, Italy.

A subset of primary sensory neurons produces BDNF, which is implicated in control of nociceptive neurotransmission. We previously localized full-length trkB receptors on their terminals within lamina II. To functionally study these receptors, we here employed patch-clamp recordings, calcium imaging and immunocytochemistry on slices from 8-12 days post-natal rats. In this preparation, BDNF (100-500 ng/mL) enhances the release of sensory neurotransmitters (glutamate, substance P, CGRP) in lamina II by acting on trkB receptors expressed by primary afferent fibers of the peptidergic nociceptive type (PN-PAFs). Effect was blocked by trk antagonist K252a or anti-trkB antibody clone 47. A pre-synaptic mechanism was demonstrated after (i) patch-clamp recordings where the neurotrophin induced a significant increase in frequency, but not amplitude, of AMPA-mediated mEPSCs, (ii) real time calcium imaging, where sustained application of BDNF evoked an intense response in up to 57% lamina II neurons with a significant frequency rise. Antagonists of ionotropic glutamate receptors and NK(1) receptors completely inhibited the calcium response to BDNF. Reduction of CGRP (a specific marker of PN-PAFs) and substance P content in dorsal horn following BDNF preincubation, and analysis of the calcium response after depletion with capsaicin, confirmed that the neurotrophin presynaptically enhanced neurotransmitter release from PN-PAFs. This is the first demonstration that trkB receptors expressed by PN-PAF terminals in lamina II are functional during postnatal development. Implications of this finding are discussed considering that BDNF can be released by these same terminals and microglia, a fraction of which (as shown here) contains BDNF also in unactivated state.
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http://dx.doi.org/10.1002/dneu.20605DOI Listing
March 2008

BDNF-mediated modulation of GABA and glycine release in dorsal horn lamina II from postnatal rats.

Dev Neurobiol 2007 Jun;67(7):960-75

Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Recent studies show that excitatory glutamatergic transmission is potentiated by BDNF in superficial dorsal horn, both at the pre- and the postsynaptic site. The role of BDNF in modulating GABA and glycine-mediated inhibitory transmission has not been fully investigated. To determine whether the neurotrophin is effective in regulating the spontaneous release of the two neurotransmitters, we have recorded miniature inhibitory postsynaptic currents (mIPSCs) in lamina II of post-natal rats. We show that application of BDNF enhanced the spontaneous release of GABA and glycine, in presence of tetrodotoxin. The effect was blocked by the trk-receptor inhibitor k-252a. Amplitude and kinetics of mIPSCs were not altered. Evoked GABA and glycine IPSCs (eIPSCs) were depressed by BDNF and the coefficient of variation of eIPSC amplitude was significantly increased. By recording glycine eIPSCs with the paired-pulse protocol, an increase of paired-pulse ratio during BDNF application was observed. We performed parallel ultrastructural studies to unveil the circuitry involved in the effects of BDNF. These studies show that synaptic interactions between full length functional trkB receptors and GABA-containing profiles only occur at non peptidergic synaptic glomeruli of types I and II. Expression of trkB in presynaptic vesicle-containing dendrites originating from GABAergic islet cells, indicates these profiles as key structures in the modulation of inhibitory neurotransmission by the neurotrophin. Our results thus describe a yet uncharacterized effect of BDNF in lamina II, giving further strength to the notion that the neurotrophin plays an important role in pain neurotransmission.
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http://dx.doi.org/10.1002/dneu.20401DOI Listing
June 2007

Presynaptic NMDA receptors modulate glutamate release from primary sensory neurons in rat spinal cord dorsal horn.

J Neurosci 2004 Mar;24(11):2774-81

Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy.

NMDA receptors have the potential to produce complex activity-dependent regulation of transmitter release when localized presynaptically. In the somatosensory system, NMDA receptors have been immunocytochemically detected on presynaptic terminals of primary afferents, and these have been proposed to drive release of substance P from central terminals of a subset of nociceptors in the spinal cord dorsal horn. Here we report that functional NMDA receptors are indeed present at or near the central terminals of primary afferent fibers. Furthermore, we show that activation of these presynaptic receptors results in an inhibition of glutamate release from the terminals. Some of these NMDA receptors may be expressed in the preterminal axon and regulate the extent to which action potentials invade the extensive central arborizations of primary sensory neurons.
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http://dx.doi.org/10.1523/JNEUROSCI.4637-03.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729523PMC
March 2004

Development of nociceptive synaptic inputs to the neonatal rat dorsal horn: glutamate release by capsaicin and menthol.

J Physiol 2003 May 4;549(Pt 1):231-42. Epub 2003 Apr 4.

Department of Anatomy and Developmental Biology, University College London, UK.

To study the postnatal development of nociceptive synaptic inputs in the superficial dorsal horn of the neonatal rat spinal cord, we examined the effect of capsaicin and menthol on glutamatergic mEPSCs in postnatal day (P) 0-1, P5-6 and P9-11 slices of spinal cord. Capsaicin (100 nM to 2 microM) increased the mEPSC frequency in a concentration-dependent manner at all ages tested, with a significant enhancement of the effect between P5 and P10. This effect was sensitive to vanilloid receptor (VR) antagonists. The elevation in mEPSC frequency occurred at concentrations of capsaicin (100 nM) that did not alter the distribution of mEPSC amplitudes and was abolished by a dorsal rhizotomy, demonstrating that capsaicin acts via presynaptic VR1 receptors localized on primary afferents. Menthol significantly increased the mEPSC frequency with a similar developmental pattern to capsaicin without consistently affecting mEPSC amplitude. The increase in mEPSC frequency following capsaicin did not depend on transmembrane calcium influx since it persisted in zero [Ca2+]o. The facilitation of spontaneous glutamate release by capsaicin was sufficient to evoke action potentials in neonatal dorsal horn neurons but was accompanied by a block of EPSCs evoked by electrical stimulation of the dorsal root. These results indicate that VR1-expressing nociceptive primary afferents form functional synaptic connections in the superficial dorsal horn from birth and that activation of the VR1 receptor increases spontaneous glutamate release via an undetermined mechanism. In addition, the data suggest that immature primary afferents express functional menthol receptors that are capable of modulating transmitter release. These results have important functional implications for infant pain processing.
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http://dx.doi.org/10.1113/jphysiol.2003.040451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2342935PMC
May 2003

Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release.

Neuron 2002 Jul;35(1):135-46

Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.

No direct evidence has been found for expression of functional AMPA receptors by dorsal root ganglion neurons despite immunocytochemical evidence suggesting they are present. Here we report evidence for expression of functional AMPA receptors by a subpopulation of dorsal root ganglion neurons. The AMPA receptors are most prominently located near central terminals of primary afferent fibers. AMPA and kainate receptors were detected by recording receptor-mediated depolarization of the central terminals under selective pharmacological conditions. We demonstrate that activation of presynaptic AMPA receptors by exogenous agonists causes inhibition of glutamate release from the terminals, possibly via primary afferent depolarization (PAD). These results challenge the traditional view that GABA and GABA(A) receptors exclusively mediate PAD, and indicate that PAD is also mediated by glutamate acting on presynaptically localized AMPA and kainate receptors.
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http://dx.doi.org/10.1016/s0896-6273(02)00729-8DOI Listing
July 2002