GABAB Receptors and Pain

Benke, Dietmar

doi:10.1007/7854_2020_130

Cited by 14 publications

(16 citation statements)

References 172 publications

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“…GABA B receptor physiology and pharmacology in pain processing has been studied extensively and the modulation of HVA N-type calcium channels and/or GIRK channels by the GABA B receptor agonists, GABA and baclofen, is a recognized analgesic mechanism (Benke, 2020;Enna & McCarson, 2016;Malcangio, 2018). Vc1.1, consistent with previous studies supporting GIRK's antinociception role in models of neuropathic pain (Ippolito et al, 2005;Marker et al, 2005) and via satellite glial cells of the trigeminal ganglia (Takeda et al, 2015).…”

Section: Discussionsupporting

confidence: 77%

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Bony

McArthur

Finol‐Urdaneta

et al. 2021

British J Pharmacology

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Background and Purpose: Activation of GIRK channels via G protein-coupled GABA B receptors has been shown to attenuate nociceptive transmission. The analgesic α-conotoxin Vc1.1 activates GABA B receptors resulting in inhibition of Ca v 2.2 and Ca v 2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic α-conotoxins on recombinant and native GIRK-mediated K + currents and on neuronal excitability.Experimental Approach: The effects of analgesic α-conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly-rectifying K + currents in HEK293T cells recombinantly co-expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABA B receptors. The effects of α-conotoxin Vc1.1 and baclofen were studied on GIRK-mediated K + currents and the passive and active electrical properties of adult mouse dorsal root ganglion neurons. Key Results: Analgesic α-conotoxins Vc1.1, RgIA, and PeIA potentiate inwardly-rectifying K + currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABA B receptors. GABA B receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin-sensitive G protein and is inhibited by the selective GABA B receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABA B receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability. Conclusions and Implications: This is the first report of GIRK channel potentiation via allosteric α-conotoxin Vc1.1-GABA B receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.

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Section: Discussionsupporting

confidence: 77%

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Bony

McArthur

Finol‐Urdaneta

et al. 2021

British J Pharmacology

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“…GABA B receptor biology and pharmacology in pain processing has been studied extensively and the modulation of HVA N-type calcium channels and/or GIRK channels by GABA B R agonists, GABA and baclofen, is a recognized mechanism of action (Malcangio, 2018; Benke, 2020). Our findings propose another plausible mechanism of action through which analgesic α-conotoxin Vc1.1 regulates membrane excitability in sensory neurons.…”

Section: Discussionmentioning

confidence: 99%

Analgesic α-conotoxins modulate GIRK1/2 channels via GABA_Breceptor activation and reduce neuroexcitability

Bony

McArthur

Finol‐Urdaneta

et al. 2020

Preprint

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Activation of G protein-coupled inwardly rectifying potassium (GIRK or Kir3) channels leads to membrane hyperpolarization and dampening of neuronal excitability. Here we show that the analgesic α-conotoxin Vc1.1 potentiates inwardly rectifying K+ currents (IKir) mediated through native and recombinant GIRK1/2 channels by activation of the G protein-coupled GABAB receptor (GABABR) via a Pertussis toxin (PTX)-sensitive G protein. Recombinant co-expression of human GIRK1/2 subunits and GABABR in HEK293T cells resulted in a Ba2+-sensitive IKir potentiated by baclofen and Vc1.1 which was inhibited by PTX, intracellular GDP-β-S, or the GABABR-selective antagonist CGP 55845. In adult mouse DRG neurons, GABABR-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell resting membrane potential with concomitant reduction of excitability consistent with Vc1.1 and baclofen analgesic effects in vivo. This study provides new insight into Vc1.1 as an allosteric agonist for GABABR-mediated potentiation of GIRK channels and may aid in the development of novel non-opioid treatments for chronic pain.

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“…This receptor has been considered a valuable target for the treatment of chronic pain due to extensive evidence that they are involved in the regulation of pain signaling. 35 , 36 …”

Section: Discussionmentioning

confidence: 99%

TRPV1 and GABAB1 in the Cerebrospinal Fluid-Contacting Nucleus are Jointly Involved in Chronic Inflammatory Pain in Rats

Xu¹,

Yan²,

Yuan³

et al. 2022

JPR

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Objective To assess the receptors of TRPV1 and GABA B1 receptors that were colocalized in cerebrospinal fluid contacting nucleus (CSF-contact nucleus) of chronic inflammatory pain (CIP) rats bringing inspiration for reducing chronic pain. Methods A rat model of CIP was constructed by plantar injection of complete Freund’s adjuvant (CFA), and the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured 1, 3, 5, 7, 10, and 14 days after plantar injection. In the first part of the experiment, rats with CIP were divided into the immunofluorescence group and the coimmunoprecipitation (Co-IP) group (n = 6). Rats in the immunofluorescence group were injected with the retrograde tracer CB conjugated with Alexa Fluor 594 into the lateral ventricle two days before the injection of CFA into the plantar surface of the left paw. Three days later, rats that exhibited hyperalgesia were perfused, and their brains were extracted and used for double immunofluorescence staining of the CSF-contacting nucleus. Rats in the Co-IP group were anesthetized and dissected 3 days after CFA injection, and fresh brain segments containing the CSF-contacting nucleus were collected for Co-IP to assess the colocalization of TRPV1 and GABA B1 in the CSF-contacting nucleus (n = 6). In the second part of the experiment, SD rats were divided into the normal saline group (control group) and the CFA group. Fresh CSF-contacting nucleus-containing tissues were collected for Western blot analysis 3 days after plantar injection to observe the changes in TRPV1 and GABA B1 expression in the CSF-contacting nucleus. Results TRPV1 and GABA B1 were co-expressed in the CSF-contacting nucleus in rats with CIP, and their expression was upregulated. Conclusion TRPV1 and GABA B1 in the CSF-contacting nucleus are jointly involved in CIP in rats, and there is a direct or indirect link between TRPV1 and GABA B1 .

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GABAB Receptors and Pain

Cited by 14 publications

References 172 publications

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Analgesic α-conotoxins modulate GIRK1/2 channels via GABA_Breceptor activation and reduce neuroexcitability

TRPV1 and GABAB1 in the Cerebrospinal Fluid-Contacting Nucleus are Jointly Involved in Chronic Inflammatory Pain in Rats

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GABAB Receptors and Pain

Cited by 14 publications

References 172 publications

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability

Analgesic α-conotoxins modulate GIRK1/2 channels via GABABreceptor activation and reduce neuroexcitability

TRPV1 and GABAB1 in the Cerebrospinal Fluid-Contacting Nucleus are Jointly Involved in Chronic Inflammatory Pain in Rats

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Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Analgesic α-conotoxins modulate GIRK1/2 channels via GABA_Breceptor activation and reduce neuroexcitability