Effect of asimadoline, a κ opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome

Delvaux, Michel; Beck, A. A. H.; Jacob, Jutta; Bouzamondo, Hakim; Weber, Frank T.; Frexinos, Jacques

doi:10.1111/j.1365-2036.2004.01922.x

Cited by 89 publications

(65 citation statements)

References 35 publications

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“…The failure of these peripherally restricted agonists to block acid-induced depression of ICSS suggests that 1) stimulation of peripheral receptors may not be sufficient to block prodepressant manifestations of pain, such as pain-related functional impairment or depression of mood, and 2) peripherally restricted agonists may consequently be less efficacious as analgesics than NSAIDs or opioid agonists. Moreover, this conclusion is consistent with clinical reports that peripherally restricted agonists such as the nonpeptide asimadoline often fail to produce significant analgesia and sometimes exacerbate pain (Machelska et al, 1999;Delvaux et al, 2004;Szarka et al, 2007;Mangel et al, 2008). However, as a caveat to this conclusion, it should be noted that peripheral distribution of ffir, ICI204448, and related compounds is not absolute, and high doses can be expected to result in sufficient central nervous system penetration to produce centrally mediated effects that may oppose and limit any peripherally mediated blockade of pain-related behavioral depression.…”

Section: Discussionsupporting

confidence: 78%

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Negus¹,

O'Connell²,

Morrissey³

et al. 2011

J Pharmacol Exp Ther

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Opioid receptor agonists that do not readily cross the bloodbrain barrier are peripherally restricted and distribute poorly to the central nervous system after systemic administration. Peripherally restricted agonists have promise as candidate analgesics, because they may produce antinociception mediated by peripheral receptors more potently than they produce undesirable sedative and psychotomimetic effects mediated by central receptors. The present study used assays of painrelated stimulation and depression of behavior in rats to compare effects of 1) two peripherally restricted agonists [the, 2) a centrally penetrating agonist (salvinorin A), and 3) several reference drugs, including a nonsteroidal antiinflammatory drug (NSAID; ketoprofen). Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response and depress intracranial self-stimulation (ICSS) maintained by the delivery of electrical brain stimulation to the medial forebrain bundle. Acid-stimulated stretching was blocked by ketoprofen, the peripherally restricted agonists, and salvinorin A. However, acid-induced depression of ICSS was blocked only by ketoprofen. The peripherally restricted agonists had little effect, and salvinorin A exacerbated acidinduced depression of ICSS. These results suggest that peripherally restricted agonists may be safer than centrally penetrating agonists but less efficacious than NSAIDS or opioid receptor agonists to block pain-related depression of behavior; however, the peripheral selectivity of ffir and ICI204448 is limited, and future studies with agonists capable of greater peripheral selectivity are warranted.

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Section: Discussionsupporting

confidence: 78%

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Negus¹,

O'Connell²,

Morrissey³

et al. 2011

J Pharmacol Exp Ther

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“…Experimental studies exhibited that fedotozine and asimadoline are among agonists of κ-opioid receptors which can significantly reduce pain sensation. 78,79 In a clinical trial on patients with IBS, fedotozine significantly decreased volume or pressure stimuli perception. Likewise, in another clinical study, asimadoline alleviated functional dyspepsia symptoms, particularly hyperalgesia.…”

Section: -77mentioning

confidence: 99%

The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

Farzaei

Bahramsoltani

Abdollahi

et al. 2016

J Neurogastroenterol Motil

152

122

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Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH. (J Neurogastroenterol Motil 2016;22:558-574)

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“…Asimadoline is a κ-opioid receptor agonist currently in development for the management of patients with IBS-D with moderate-to-severe pain (Table 2) [Delvaux et al 2004;Mangel et al 2008;Mangel and Hicks, 2012;Szarka et al 2007]. In a phase II, dose-ranging study of patients with IBS with a mean abdominal pain score of 1.5 (on a scale of 0 to 3, with 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain), treatment with asimadoline 0.15, 0.5, or 1 mg twice daily for 12 weeks did not improve response (i.e.…”

Section: Targeting Opioid Receptorsmentioning

confidence: 99%

New and emerging therapies for the treatment of irritable bowel syndrome: an update for gastroenterologists

Foxx‐Orenstein

2016

Therap Adv Gastroenterol

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Effect of asimadoline, a κ opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome

Cited by 89 publications

References 35 publications

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

Effects of Peripherally Restricted κ Opioid Receptor Agonists on Pain-Related Stimulation and Depression of Behavior in Rats

The Role of Visceral Hypersensitivity in Irritable Bowel Syndrome: Pharmacological Targets and Novel Treatments

New and emerging therapies for the treatment of irritable bowel syndrome: an update for gastroenterologists

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