Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2018 Jun 01;17512:2204-2218. doi: 10.1111/bph.14089.
Show Gene links
Show Anatomy links
Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain.
Lee JYP
,
Saez NJ
,
Cristofori-Armstrong B
,
Anangi R
,
King GF
,
Smith MT
,
Rash LD
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: Acid-sensing ion channels (ASICs) are primary acid sensors in mammals, with the ASIC1b and ASIC3 subtypes being involved in peripheral nociception. The antiprotozoal drug diminazene is a moderately potent ASIC inhibitor, but its analgesic activity has not been assessed.
EXPERIMENTAL APPROACH: We determined the ASIC subtype selectivity of diminazene and the mechanism by which it inhibits ASICs using voltage-clamp electrophysiology of Xenopus oocytes expressing ASICs 1-3. Its peripheral analgesic activity was then assessed relative to APETx2, an ASIC3 inhibitor, and morphine, in a Freund's complete adjuvant (FCA)-induced rat model of inflammatory pain.
KEY RESULTS: Diminazene inhibited homomeric rat ASICs with IC50 values of ~200-800 nM, via an open channel and subtype-dependent mechanism. In rats with FCA-induced inflammatory pain in one hindpaw, diminazene and APETx2 evoked more potent peripheral antihyperalgesia than morphine, but the effect was partial for APETx2. APETx2 potentiated rat ASIC1b at concentrations 30-fold to 100-fold higher than the concentration inhibiting ASIC3, which may have implications for its use in in vivo experiments.
CONCLUSIONS AND IMPLICATIONS: Diminazene and APETx2 are moderately potent ASIC inhibitors, both inducing peripheral antihyperalgesia in a rat model of chronic inflammatory pain. APETx2 has a more complex ASIC pharmacology, which must be considered when it is used as a supposedly selective ASIC3 inhibitor in vivo. Our use of outbred rats revealed responders and non-responders when ASIC inhibition was used to alleviate inflammatory pain, which is aligned with the concept of number-needed-to-treat in human clinical studies.
LINKED ARTICLES: 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.
Akopian,
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
1999, Pubmed
Akopian,
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
1999,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Voltage-gated ion channels.
2017,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand-gated ion channels.
2017,
Pubmed
Anangi,
Functional expression in Escherichia coli of the disulfide-rich sea anemone peptide APETx2, a potent blocker of acid-sensing ion channel 3.
2012,
Pubmed
,
Xenbase
Avsaroglu,
Differences in response to anaesthetics and analgesics between inbred rat strains.
2007,
Pubmed
Baron,
Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives.
2015,
Pubmed
Blanchard,
Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea anemone toxin APETx2.
2012,
Pubmed
,
Xenbase
Bohlen,
A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain.
2011,
Pubmed
,
Xenbase
Bourinet,
Calcium-permeable ion channels in pain signaling.
2014,
Pubmed
Chen,
Diarylamidines: high potency inhibitors of acid-sensing ion channels.
2010,
Pubmed
,
Xenbase
Chen,
Roles of ASIC3, TRPV1, and NaV1.8 in the transition from acute to chronic pain in a mouse model of fibromyalgia.
2014,
Pubmed
Chiu,
Bacteria activate sensory neurons that modulate pain and inflammation.
2013,
Pubmed
Cristofori-Armstrong,
Xenopus borealis as an alternative source of oocytes for biophysical and pharmacological studies of neuronal ion channels.
2015,
Pubmed
,
Xenbase
Cristofori-Armstrong,
Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms.
2017,
Pubmed
Curtis,
Experimental design and analysis and their reporting: new guidance for publication in BJP.
2015,
Pubmed
Deval,
ASIC3, a sensor of acidic and primary inflammatory pain.
2008,
Pubmed
Deval,
Acid-sensing ion channels in postoperative pain.
2011,
Pubmed
Diochot,
A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons.
2004,
Pubmed
,
Xenbase
Diochot,
Black mamba venom peptides target acid-sensing ion channels to abolish pain.
2012,
Pubmed
,
Xenbase
Dorofeeva,
Mechanisms of non-steroid anti-inflammatory drugs action on ASICs expressed in hippocampal interneurons.
2008,
Pubmed
Dubé,
Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels.
2005,
Pubmed
Ferreira,
Antinociception produced by systemic, spinal and supraspinal administration of amiloride in mice.
1999,
Pubmed
Izumi,
Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis.
2012,
Pubmed
Jensen,
Understanding the molecular basis of toxin promiscuity: the analgesic sea anemone peptide APETx2 interacts with acid-sensing ion channel 3 and hERG channels via overlapping pharmacophores.
2014,
Pubmed
Ji,
Estrogen modulation of morphine analgesia of visceral pain in female rats is supraspinally and peripherally mediated.
2007,
Pubmed
Jones,
Acid-induced pain and its modulation in humans.
2004,
Pubmed
Karczewski,
Reversal of acid-induced and inflammatory pain by the selective ASIC3 inhibitor, APETx2.
2010,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Krishtal,
A receptor for protons in the membrane of sensory neurons may participate in nociception.
1981,
Pubmed
Kulemina,
Prediction of off-target effects on angiotensin-converting enzyme 2.
2011,
Pubmed
Kuriakose,
Diminazene aceturate (Berenil) modulates LPS induced pro-inflammatory cytokine production by inhibiting phosphorylation of MAPKs and STAT proteins.
2014,
Pubmed
Lee,
Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain.
2018,
Pubmed
,
Xenbase
Lin,
Genetic exploration of the role of acid-sensing ion channels.
2015,
Pubmed
Marra,
Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids.
2016,
Pubmed
McGrath,
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
2015,
Pubmed
Mogil,
The genetic mediation of individual differences in sensitivity to pain and its inhibition.
1999,
Pubmed
Mogil,
Pain genetics: past, present and future.
2012,
Pubmed
Mogil,
Laboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translation.
2017,
Pubmed
Mogil,
Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction.
2011,
Pubmed
Moore,
Pregabalin for acute and chronic pain in adults.
2009,
Pubmed
Muralidharan,
Pain, analgesia and genetics.
2011,
Pubmed
Payne,
A novel selective and orally bioavailable Nav 1.8 channel blocker, PF-01247324, attenuates nociception and sensory neuron excitability.
2015,
Pubmed
Peigneur,
A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins.
2012,
Pubmed
,
Xenbase
Perrot,
Effects of intraplantar morphine on paw edema and pain-related behaviour in a rat model of repeated acute inflammation.
1999,
Pubmed
Rash,
Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future ….
2017,
Pubmed
Reeh,
Tissue acidosis in nociception and pain.
1996,
Pubmed
Reichling,
Critical role of nociceptor plasticity in chronic pain.
2009,
Pubmed
Reimers,
Identification of a cono-RFamide from the venom of Conus textile that targets ASIC3 and enhances muscle pain.
2017,
Pubmed
,
Xenbase
Riou,
Berenil induces the complete loss of kinetoblast DNA sequences in Trypanosoma equiperdum.
1980,
Pubmed
Rodrigues,
The peripheral antinociceptive effect induced by morphine is associated with ATP-sensitive K(+) channels.
2000,
Pubmed
Schmidt,
Diminazene Is a Slow Pore Blocker of Acid-Sensing Ion Channel 1a (ASIC1a).
2017,
Pubmed
,
Xenbase
Schwarz,
TRPA1 and TRPV1 Antagonists Do Not Inhibit Human Acidosis-Induced Pain.
2017,
Pubmed
Smith,
Pharmacogenetics of pain and analgesia.
2012,
Pubmed
Southan,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands.
2016,
Pubmed
Staniland,
Mice lacking acid-sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test.
2009,
Pubmed
Steen,
Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro.
1992,
Pubmed
Stein,
Unilateral inflammation of the hindpaw in rats as a model of prolonged noxious stimulation: alterations in behavior and nociceptive thresholds.
1988,
Pubmed
Ugawa,
Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors.
2002,
Pubmed
,
Xenbase
Voilley,
Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors.
2001,
Pubmed
Wang,
Serotonin facilitates peripheral pain sensitivity in a manner that depends on the nonproton ligand sensing domain of ASIC3 channel.
2013,
Pubmed
Waxman,
Regulating excitability of peripheral afferents: emerging ion channel targets.
2014,
Pubmed
Wiemuth,
The pharmacological profile of brain liver intestine Na+ channel: inhibition by diarylamidines and activation by fenamates.
2011,
Pubmed
,
Xenbase
Woolf,
Overcoming obstacles to developing new analgesics.
2010,
Pubmed
Yen,
Role of acid-sensing ion channel 3 in sub-acute-phase inflammation.
2009,
Pubmed
Yu,
A nonproton ligand sensor in the acid-sensing ion channel.
2010,
Pubmed
da Silva Serra,
Characterization of cutaneous and articular sensory neurons.
2016,
Pubmed
