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Article ; Online: Opioid-induced hyperalgesia: Are thalamic T-type calcium channels treatment targets?

Todorovic, Slobodan M

2022 Volume 132, Issue 24

Abstract: Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. ...

Abstract	Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.
MeSH term(s)	Animals ; Humans ; Analgesics, Opioid/adverse effects ; Calcium Channels, T-Type/genetics ; Calcium Channels, T-Type/therapeutic use ; Hyperalgesia/chemically induced ; Hyperalgesia/drug therapy ; Pain ; Remifentanil/adverse effects ; Pain, Postoperative
Chemical Substances	Analgesics, Opioid ; Calcium Channels, T-Type ; Remifentanil (P10582JYYK)
Language	English
Publishing date	2022-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI165977
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Opioid-induced hyperalgesia

Slobodan M. Todorovic

The Journal of Clinical Investigation, Vol 132, Iss

Are thalamic T-type calcium channels treatment targets?

2022 Volume 24

Abstract	Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the CaV3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.
Keywords	Medicine ; R
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Role of Neuroactive Steroids in Analgesia and Anesthesia: An Interesting Comeback?

Jevtovic-Todorovic, Vesna / Todorovic, Slobodan M

Biomolecules

2023 Volume 13, Issue 11

Abstract: Published evidence over the past few decades suggests that general anesthetics could be neurotoxins especially when administered at the extremes of age. The reported pathology is not only at the morphological level when examined in very young and aged ... ...

Abstract	Published evidence over the past few decades suggests that general anesthetics could be neurotoxins especially when administered at the extremes of age. The reported pathology is not only at the morphological level when examined in very young and aged brains, given that, importantly, newly developing evidence suggests a variety of behavioral impairments. Since anesthesia is unavoidable in certain clinical settings, we should consider the development of new anesthetics. A promising and safe solution could be a new family of anesthetics referred to as neuroactive steroids. In this review, we summarize the currently available evidence regarding their anesthetic and analgesic properties.
MeSH term(s)	Neurosteroids ; Anesthesia ; Anesthetics/pharmacology ; Brain/pathology ; Analgesia
Chemical Substances	Neurosteroids ; Anesthetics
Language	English
Publishing date	2023-11-15
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom13111654
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Article ; Online: The Mechanisms of Plasticity of Nociceptive Ion Channels in Painful Diabetic Neuropathy.

Joksimovic, Sonja L / Jevtovic-Todorovic, Vesna / Todorovic, Slobodan M

Frontiers in pain research (Lausanne, Switzerland)

2022 Volume 3, Page(s) 869735

Abstract: Treating pain in patients suffering from small fiber neuropathies still represents a therapeutic challenge for health care providers and drug developers worldwide. Unfortunately, none of the currently available treatments can completely reverse symptoms ... ...

Abstract	Treating pain in patients suffering from small fiber neuropathies still represents a therapeutic challenge for health care providers and drug developers worldwide. Unfortunately, none of the currently available treatments can completely reverse symptoms of either gain or loss of peripheral nerve sensation. Therefore, there is a clear need for novel mechanism-based therapies for peripheral diabetic neuropathy (PDN) that would improve treatment of this serious condition. In this review, we summarize the current knowledge on the mechanisms and causes of peripheral sensory neurons damage in diabetes. In particular, we focused on the subsets of voltage-gated sodium channels, TRP family of ion channels and a Ca
Language	English
Publishing date	2022-03-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	2673-561X
ISSN (online)	2673-561X
DOI	10.3389/fpain.2022.869735
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: The role of voltage-gated calcium channels in the mechanisms of anesthesia and perioperative analgesia.

Joksimovic, Sonja L / Jevtovic-Todorovic, Vesna / Todorovic, Slobodan M

Current opinion in anaesthesiology

2022 Volume 35, Issue 4, Page(s) 436–441

Abstract: Purpose of review: A family of neuronal voltage-gated calcium channels (VGCCs) have received only recently a significant consideration regarding the mechanisms of anesthesia because VGCC inhibition may be important in anesthetic action by decreasing ... ...

Abstract	Purpose of review: A family of neuronal voltage-gated calcium channels (VGCCs) have received only recently a significant consideration regarding the mechanisms of anesthesia because VGCC inhibition may be important in anesthetic action by decreasing neuronal excitability and presynaptic excitatory transmission. The T-type VGCCs channels (T-channels), although rarely involved in synaptic neurotransmitter release, play an important role in controlling neuronal excitability and in generating spontaneous oscillatory bursting of groups of neurons in the thalamus thought to be involved in regulating the state of arousal and sleep. Furthermore, these channels are important regulators of neuronal excitability in pain pathway. This review will provide an overview of historic perspective and the recent literature on the role of VGCCs and T-channel inhibition in particular in the mechanisms of action of anesthetics and analgesics. Recent findings: Recent research in the field of novel mechanisms of hypnotic action of anesthetics revealed significant contribution of the Ca V 3.1 isoform of T-channels expressed in the thalamus. Furthermore, perioperative analgesia can be achieved by targeting Ca V 3.2 isoform of these channels that is abundantly expressed in pain pathways. Summary: The review summarizes current knowledge regarding the contribution of T-channels in hypnosis and analgesia. Further preclinical and clinical studies are needed to validate their potential for developing novel anesthetics and new perioperative pain therapies.
MeSH term(s)	Analgesia ; Anesthesia ; Calcium Channels/metabolism ; Calcium Channels/therapeutic use ; Humans ; Pain/drug therapy ; Pain/etiology ; Pain/metabolism ; Protein Isoforms/metabolism ; Protein Isoforms/therapeutic use
Chemical Substances	Calcium Channels ; Protein Isoforms
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645203-6
ISSN	1473-6500 ; 0952-7907
ISSN (online)	1473-6500
ISSN	0952-7907
DOI	10.1097/ACO.0000000000001159
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Article: Distinct excitability of thalamocortical neurons correlates with the presence of cerebellar afferents.

Moreno, Myriam / Minjarez, Crystal / Todorovic, Slobodan M / Quillinan, Nidia

bioRxiv : the preprint server for biology

2023

Abstract: Thalamocortical (TC) neurons within the ventrolateral thalamus (VL) receive projections from the cerebellum and the basal ganglia (BG) to facilitate motor and non-motor functions. Tonic and rebound firing patterns in response to excitatory cerebellar and ...

Abstract	Thalamocortical (TC) neurons within the ventrolateral thalamus (VL) receive projections from the cerebellum and the basal ganglia (BG) to facilitate motor and non-motor functions. Tonic and rebound firing patterns in response to excitatory cerebellar and inhibitory BG inputs, respectively, are a canonical feature of TC neurons and plays a key role in signal processing. The intrinsic excitability of TC neurons has a strong influence on how they respond to synaptic inputs, however, it is unknown whether their afferents influence their firing properties. Understanding the input-specific firing patterns could shed light into movement disorders with cerebellar or BG involvement. Here, we used whole-cell electrophysiology in brain slices from C57BL/6 mice to investigate the firing of TC neurons with optogenetic confirmation of cerebellar or BG afferents. TC neurons with cerebellar afferents exhibited higher tonic and rebound firing rates than those with BG afferents. This increased firing was associated with faster action potential depolarization kinetics and a smaller afterhyperpolarization potential. We also found differences in the passive membrane properties and sag currents during hyperpolarization. Despite higher rebound firing in TC neurons with cerebellar afferents, there were no differences in T-type calcium channel function compared to those with BG inputs. These data suggest input-specific differences in sodium and SK, but not T-type calcium channels, impact firing properties in TC populations. Altogether, we showed that the pronounced divergence observed in TC neuron firing properties correlate with its heterogeneous anatomical connectivity, which could signify a distinct signal integration and processing by these neurons. Keypoints: Thalamocortical neurons in the VL with cerebellar afferents have higher intrinsic tonic and rebound firing properties than those with basal ganglia afferents.Membrane resistance and action potential depolarization slope were different based on the presence of cerebellar afferents.Despite elevated rebound burst firing, T-type mediated currents did not correlate with increased firing in neurons with cerebellar afferents.
Language	English
Publishing date	2023-05-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.26.542536
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Article ; Online: Thalamic T-Type Calcium Channels as Targets for Hypnotics and General Anesthetics.

Timic Stamenic, Tamara / Todorovic, Slobodan M

International journal of molecular sciences

2022 Volume 23, Issue 4

Abstract: General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, ... ...

Abstract	General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects of general anesthetics on ion channels have been the subject of research since the publication of reports of direct actions of these drugs on ion channel proteins. In particular, there is considerable interest in T-type voltage-gated calcium channels that are abundantly expressed in the thalamus, where they control patterns of cellular excitability and thalamocortical oscillations during awake and sleep states. Here, we summarized and discussed our recent studies focused on the Ca
MeSH term(s)	Anesthetics, General/pharmacology ; Animals ; Calcium Channels, T-Type/drug effects ; Humans ; Hypnotics and Sedatives/pharmacology ; Membrane Potentials ; Mice ; Neurons/drug effects ; Neurons/metabolism ; Neurons/physiology
Chemical Substances	Anesthetics, General ; Calcium Channels, T-Type ; Hypnotics and Sedatives
Language	English
Publishing date	2022-02-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23042349
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Article ; Online: Alpha lipoic acid attenuates evoked and spontaneous pain following surgical skin incision in rats.

Joksimovic, Sonja Lj / Lamborn, Nathan / Jevtovic-Todorovic, Vesna / Todorovic, Slobodan M

Channels (Austin, Tex.)

2021 Volume 15, Issue 1, Page(s) 398–407

Abstract: Our previous studies have implicated ... ...

Abstract	Our previous studies have implicated Ca
MeSH term(s)	Animals ; Hyperalgesia ; Pain, Postoperative ; Rats ; Surgical Wound ; Thioctic Acid
Chemical Substances	Thioctic Acid (73Y7P0K73Y)
Language	English
Publishing date	2021-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2262854-X
ISSN	1933-6969 ; 1933-6969
ISSN (online)	1933-6969
ISSN	1933-6969
DOI	10.1080/19336950.2021.1907058
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: L-cysteine modulates visceral nociception mediated by the Ca

Ghodsi, Seyed Mohammadreza / Walz, MacKenzie / Schneider, Toni / Todorovic, Slobodan M

Pflugers Archiv : European journal of physiology

2022 Volume 474, Issue 4, Page(s) 435–445

Abstract: ... ...

Abstract	Ca
MeSH term(s)	Animals ; Calcium/metabolism ; Calcium Channels, N-Type/genetics ; Calcium Channels, N-Type/metabolism ; Calcium Channels, R-Type ; Cation Transport Proteins/metabolism ; Cysteine ; HEK293 Cells ; Humans ; Male ; Mice ; Nociception
Chemical Substances	Cacna1e protein, mouse ; Calcium Channels, N-Type ; Calcium Channels, R-Type ; Cation Transport Proteins ; Cysteine (K848JZ4886) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-03-10
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	6380-0
ISSN	1432-2013 ; 0031-6768
ISSN (online)	1432-2013
ISSN	0031-6768
DOI	10.1007/s00424-022-02674-y
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Uc I Zs.35: Show issues

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Article ; Online: Thalamic T-Type Calcium Channels as Targets for Hypnotics and General Anesthetics

Tamara Timic Stamenic / Slobodan M. Todorovic

International Journal of Molecular Sciences, Vol 23, Iss 2349, p

2022 Volume 2349

Abstract	General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects of general anesthetics on ion channels have been the subject of research since the publication of reports of direct actions of these drugs on ion channel proteins. In particular, there is considerable interest in T-type voltage-gated calcium channels that are abundantly expressed in the thalamus, where they control patterns of cellular excitability and thalamocortical oscillations during awake and sleep states. Here, we summarized and discussed our recent studies focused on the Ca V 3.1 isoform of T-channels in the nonspecific thalamus (intralaminar and midline nuclei), which acts as a key hub through which natural sleep and general anesthesia are initiated. We used mouse genetics and in vivo and ex vivo electrophysiology to study the role of thalamic T-channels in hypnosis induced by a standard general anesthetic, isoflurane, as well as novel neuroactive steroids. From the results of this study, we conclude that Ca V 3.1 channels contribute to thalamocortical oscillations during anesthetic-induced hypnosis, particularly the slow-frequency range of δ oscillations (0.5–4 Hz), by generating “window current” that contributes to the resting membrane potential. We posit that the role of the thalamic Ca V 3.1 isoform of T-channels in the effects of various classes of general anesthetics warrants consideration.
Keywords	t-type calcium channels ; general anesthesia ; hypnosis ; nonspecific thalamus ; EEG recording ; LFP recording ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	612
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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