Cyclic analogues of α‐conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain

Castro, Joel; Grundy, Luke; Deiteren, Annemie; Harrington, Andrea M.; O’Donnell, Tracey A.; Maddern, Jessica; Moore, Jessi; Garcia‐Caraballo, Sonia; Rychkov, Grigori Y.; Yu, Rilei; Kaas, Quentin; Craik, David J.; Adams, David J.; Brierley, Stuart M.

doi:10.1111/bph.14115

Cited by 39 publications

(50 citation statements)

References 63 publications

(158 reference statements)

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“…Consistent with this suggestion, peripheral administration of Vc1.1, a synthetic version of a GABA B receptor activating peptide, was shown to be anti‐nociceptive in a model of chronic visceral hypersensitivity (Castro et al . , ; Sadeghi et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, while several lines of evidence suggest GABA B receptors are present and functional in the GI tract, where GABA B agonists are not only analgesic but have shown to be an effective strategy for the attenuation of visceral hypersensitivity (Castro et al . , ; Sadeghi et al . ), these receptors do not appear to be engaged by endogenous GABA.…”

Section: Introductionmentioning

confidence: 99%

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Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Loeza‐Alcocer

McPherson

Gold

2019

The Journal of Physiology

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Key pointsr While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body.r Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability.r GABA A and GABA B are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception.r Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABA A receptors.r Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain.Abstract It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABA A or GABA B receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABA A and GABA B receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABA A and GABA B receptor agonists, the VMR was only consistently increased by GABA A receptor antagonists. These results suggest Emanuel Loeza-Alcocer received his PhD in neurobiology in the laboratory of Professor Rodolfo Delgado-Lezama in Mexico City. His research was focused on characterizing the GABAergic mechanisms underlying the presynaptic inhibition of sensory neurons. At present, he investigates peripheral GABAergic inhibitory mechanisms in the colon in the group of Michael Gold PhD at University of Pittsburgh, USA. His long-term goal is to understand how peripheral GABAergic inhibition modifies sensory perception in health and disease. E. Loeza-Alcocer and others J Physiol 597.13that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Loeza‐Alcocer

McPherson

Gold

2019

The Journal of Physiology

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“…Colonic compliance was studied at the end of each study protocol. Each mouse underwent graded distentions with air volumes at 20‐40‐60‐80 µL (each of 20‐second duration) delivered by a gastight syringe using a custom‐made balloon inserted in the colorectum, while monitoring and recording the corresponding colorectal pressure using Spike2 V.607 (Cambridge Electronic Design) and Philips CMS Patient Monitor System (M1109A/ M1041A) (Philips Medizin Systeme). Data presented in Figure S1A,B are expressed as delta from the minimum pressure achieved during the minimum distension (20 µL).…”

Section: Methodsmentioning

confidence: 99%

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

Theofanous

Florens

Appeltans

et al. 2020

Neurogastroenterology Motil

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Background Ephrin‐B2/EphB receptor signaling contributes to persistent pain states such as postinflammatory and neuropathic pain. Visceral hypersensitivity (VHS) is a major mechanism underlying abdominal pain in patients with irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) in remission, but the underlying pathophysiology remains unclear. Here, we evaluated the spinal ephrin‐B2/EphB pathway in VHS in 2 murine models of VHS, that is, postinflammatory TNBS colitis and maternal separation (MS). Methods Wild‐type (WT) mice and mice lacking ephrin‐B2 in Nav1.8 nociceptive neurons (cKO) were studied. VHS was induced by: 1. intracolonic instillation of TNBS or 2. water avoidance stress (WAS) in mice that underwent maternal separation (MS). VHS was assessed by quantifying the visceromotor response (VMRs) during colorectal distention. Colonic tissue and spinal cord were collected for histology, gene, and protein expression evaluation. Key Results In WT mice, but not cKO mice, TNBS induced VHS at day 14 after instillation, which returned to baseline perception from day 28 onwards. In MS WT mice, WAS induced VHS for up to 4 weeks. In cKO however, visceral pain perception returned to basal level by week 4. The development of VHS in WT mice was associated with significant upregulation of spinal ephrin‐B2 and EphB1 mRNA expression or protein levels in the TNBS model and upregulation of spinal ephrin‐B2 protein in the MS model. No changes were observed in cKO mice. VHS was not associated with persistent intestinal inflammation. Conclusions and Inferences Overall, our data indicate that the ephrin‐B2/EphB1 spinal signaling pathway is involved in VHS and may represent a novel therapeutic target.

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“…To assess the effects of Cn2 on colonic nociceptor mechanosensitivity, we performed single afferent recordings from splanchnic nerves as described (Osteen et al 2016;Castro et al 2017Castro et al , 2018Inserra et al 2017). Briefly, the colon and rectum (5-6 cm) was removed from C57BL/6 mice.…”

Section: Single Fibre Experiments From Colonic Splanchnic Nervesmentioning

confidence: 99%

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Israel

Tanaka

Castro

et al. 2019

The Journal of Physiology

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Key points Voltage‐gated sodium channels are critical for peripheral sensory neuron transduction and have been implicated in a number of painful and painless disorders. The β‐scorpion toxin, Cn2, is selective for NaV1.6 in dorsal root ganglion neurons. NaV1.6 plays an essential role in peripheral sensory neurons, specifically at the distal terminals of mechanosensing fibres innervating the skin and colon. NaV1.6 activation also leads to enhanced response to mechanical stimulus in vivo. This works highlights the use of toxins in elucidating pain pathways moreover the importance of non‐peripherally restricted NaV isoforms in pain generation. Abstract Peripheral sensory neurons express multiple voltage‐gated sodium channels (NaV) critical for the initiation and propagation of action potentials and transmission of sensory input. Three pore‐forming sodium channel isoforms are primarily expressed in the peripheral nervous system (PNS): NaV1.7, NaV1.8 and NaV1.9. These sodium channels have been implicated in painful and painless channelopathies and there has been intense interest in them as potential therapeutic targets in human pain. Emerging evidence suggests NaV1.6 channels are an important isoform in pain sensing. This study aimed to assess, using pharmacological approaches, the function of NaV1.6 channels in peripheral sensory neurons. The potent and NaV1.6 selective β‐scorpion toxin Cn2 was used to assess the effect of NaV1.6 channel activation in the PNS. The multidisciplinary approach included Ca2+ imaging, whole‐cell patch‐clamp recordings, skin–nerve and gut–nerve preparations and in vivo behavioural assessment of pain. Cn2 facilitates NaV1.6 early channel opening, and increased persistent and resurgent currents in large‐diameter dorsal root ganglion (DRG) neurons. This promotes enhanced excitatory drive and tonic action potential firing in these neurons. In addition, NaV1.6 channel activation in the skin and gut leads to increased response to mechanical stimuli. Finally, intra‐plantar injection of Cn2 causes mechanical but not thermal allodynia. This study confirms selectivity of Cn2 on NaV1.6 channels in sensory neurons. Activation of NaV1.6 channels, in terminals of the skin and viscera, leads to profound changes in neuronal responses to mechanical stimuli. In conclusion, sensory neurons expressing NaV1.6 are important for the transduction of mechanical information in sensory afferents innervating the skin and viscera.

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Cyclic analogues of α‐conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain

Abstract: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Cited by 39 publications

References 63 publications

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

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Cyclic analogues of α‐conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain

Abstract: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Cited by 39 publications

References 63 publications

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

Ephrin‐B2 signaling in the spinal cord as a player in post‐inflammatory and stress‐induced visceral hypersensitivity

NaV1.6 regulates excitability of mechanosensitive sensory neurons

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Na_V1.6 regulates excitability of mechanosensitive sensory neurons