Effect of a New α&lt;sub&gt;2&lt;/sub&gt;δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

Ohashi, Kazuhiko; Kawai, Mitsuhisa; Ninomiya, Norifumi; Taylor, Charles P.; Kurebayashi, Yoichi

doi:10.1159/000110737

Cited by 17 publications

(6 citation statements)

References 53 publications

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“…Modulation of Ca v 2.2 channel activity is implied in the pharmacodynamics of pain-relieving compounds, such as other Gi-coupled receptor agonists, eg, opioids, cannabinoids, neuropeptide Y, and substance P. 7,78,81,87,91 Also, the neuropathic pain analgesics gabapentin and pregabalin 28 inhibit Ca v 2.2mediated synaptic transmission. 6,88 Gabapentinoids are effective in reducing visceral pain and preventing spinal neuronal activation associated with CRD in animals 62,69,79 and have been suggested to be treatments for IBS. 11 A direct inhibitor of Ca v 2.2 channel activity, ziconotide, is currently used clinically for pain therapy, although it is limited to the intrathecal route.…”

Section: Discussionmentioning

confidence: 99%

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels

Lucarini¹,

Coppi²,

Micheli³

et al. 2020

Pain

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Pharmacological tools for chronic visceral pain management are still limited and inadequate. A 3 adenosine receptor (A 3 AR) agonists are effective in different models of persistent pain. Recently, their activity has been related to the block of N-type voltage-gated Ca 21 channels (Ca v 2.2) in dorsal root ganglia (DRG) neurons. The present work aimed to evaluate the efficacy of A 3 AR agonists in reducing postinflammatory visceral hypersensitivity in both male and female rats. Colitis was induced by the intracolonic instillation of 2,4dinitrobenzenesulfonic acid (DNBS; 30 mg in 0.25 mL 50% EtOH). Visceral hypersensitivity was assessed by measuring the visceromotor response and the abdominal withdrawal reflex to colorectal distension. The effects of A 3 AR agonists (MRS5980 and Cl-IB-MECA) were evaluated over time after DNBS injection and compared to that of the selective Ca v 2.2 blocker PD173212, and the clinically used drug linaclotide. A 3 AR agonists significantly reduced DNBS-evoked visceral pain both in the postinflammatory (14 and 21 days after DNBS injection) and persistence (28 and 35 days after DNBS) phases. Efficacy was comparable to effects induced by linaclotide. PD173212 fully reduced abdominal hypersensitivity to control values, highlighting the role of Ca v 2.2. The effects of MRS5980 and Cl-IB-MECA were completely abolished by the selective A 3 AR antagonist MRS1523. Furthermore, patch-clamp recordings showed that A 3 AR agonists inhibited Ca v 2.2 in dorsal root ganglia neurons isolated from either control or DNBS-treated rats. The effect on Ca 21 current was PD173212-sensitive and prevented by MRS1523. A 3 AR agonists are effective in relieving visceral hypersensitivity induced by DNBS, suggesting a potential therapeutic role against abdominal pain.

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Section: Discussionmentioning

confidence: 99%

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels

Lucarini¹,

Coppi²,

Micheli³

et al. 2020

Pain

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“…New α 2 δ ligands are starting to appear in literature, but to date, only one of these, PD-217014, which has similar binding affinity at the α 2 δ binding site as pregabalin, has been investigated in an animal model of visceral hypersensitivity (Ohashi et al, 2008). In the TNBS model described previously, oral dosing of PD-217014 (3–100 mg/kg) dose-dependently inhibited the reduction in colonic nociception threshold observed 7 days after TNBS administration.…”

Section: Pre-clinical Models Of Gi Sensation and Motilitymentioning

confidence: 99%

Alpha 2 Delta (α2δ) Ligands, Gabapentin and Pregabalin: What is the Evidence for Potential Use of These Ligands in Irritable Bowel Syndrome

Gale¹,

Houghton²

2011

Front. Pharmacol.

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Irritable bowel syndrome (IBS) is a complex disorder that is characterized by abdominal pain and altered bowel habit, and often associates with other gastrointestinal symptoms such as feelings of incomplete bowel movement and abdominal bloating, and extra-intestinal symptoms such as headache, dyspareunia, heartburn, muscle pain, and back pain. It also frequently coexists with conditions that may also involve central sensitization processes, such as fibromyalgia, irritable bladder disorder, and chronic cough. This review examines the evidence to date on gabapentin and pregabalin which may support further and continued research and development of the α2δ ligands in disorders characterized by visceral hypersensitivity, such as IBS. The distribution of the α2δ subunit of the voltage-gated calcium channel, possible mechanisms of action, pre-clinical data which supports an effect on motor–sensory mechanisms and clinical evidence that points to potential benefits in patients with IBS will be discussed.

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“…This study identified reduced presynaptic Ca 2+ channels and smaller auditory nerve fiber terminals synapsing on cochlear nucleus bushy cells to be associated with a specific hearing impairment resulting from the loss of a 2 d-3. Other related compounds include 4-methylpregabalin and similar molecules (Ohashi et al, 2008;Corrigan et al, 2009). These compounds were not designed as drugs with a 2 d binding in mind; rather, they were intended to increase GABA A receptor activation.…”

mentioning

confidence: 99%

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

903

992

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Effect of a New α<sub>2</sub>δ Ligand PD-217014 on Visceral Hypersensitivity Induced by 2,4,6-Trinitrobenzene Sulfonic Acid in Rats

Cited by 17 publications

References 53 publications

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels

Acute visceral pain relief mediated by A3AR agonists in rats: involvement of N-type voltage-gated calcium channels

Alpha 2 Delta (α2δ) Ligands, Gabapentin and Pregabalin: What is the Evidence for Potential Use of These Ligands in Irritable Bowel Syndrome

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

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