Characterization of the Antihyperalgesic Action of a Novel Peripheral Mu-opioid Receptor Agonist-Loperamide

Nozaki-Taguchi, Natsuko; Yaksh, Tony L.

doi:10.1097/00000542-199901000-00029

Cited by 79 publications

(60 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…the action of loperamide appears to be related to the activation of opioid receptors in peripheral tissue as loperamide does not cross the central nervous system (8). moreover, loperamide-induced action is effectively abolished by cyprodime, suggesting an activation of opioid µ-receptors by loperamide in prostatic relaxation.…”

Section: Discussionmentioning

confidence: 96%

“…thus, another opioid µ-receptor involved in this action of loperamide was considered. there is no doubt that loperamide is an agonist of peripheral opioid µ-receptors (8,24). recently, the opioid µ-receptors have been divided into 3 subtypes, including µ-1, µ-2 and µ-3 (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we identified opioid µ-receptor expression in rat prostates, and prostatic relaxation was induced by the activation of opioid µ-receptors using loperamide (6). loperamide was introduced as a peripheral agonist of opioid µ-receptors with poor ability to penetrate the bloodbrain barrier (7,8). Some analgesic agents have also revealed relaxant effects in smooth muscle (9,10).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Lu¹,

Chung²

2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. the merit of opioid µ-receptor activation in the improvement of benign prostatic hyperplasia (Bph) remains obscure. in the present study, we used loperamide to identify the subtype of opioid µ-receptors involved in prostatic relaxation and investigate the possible mechanism of this relaxation. prostate strips were isolated from 12-week-old male Wistar rats for identification of isometric tension. The prostate strips were precontracted with either 1 µmol/l phenylephrine or 50 mmol/l Kcl. the decrease in muscle tone (relaxation) was then characterized after cumulative administration of loperamide (0.1 to 10 µmol/l) into the organ bath for the concentration-dependent study. Pretreatment with specific blockers or antagonists was carried out to compare the changes in loperamide-induced relaxation. loperamide produced a marked relaxation in the isolated prostates precontracted with phenylephrine or Kcl in a dose-dependent manner. this relaxation was abolished by cyprodime, a selective opioid µ-receptor antagonist, but was not modified by naloxonazine at a dose sufficient to block the opioid µ-1 receptors. treatment with an agonist for opioid µ-1 receptors also failed to modify the muscle tone. moreover, the relaxation by loperamide was attenuated by glibenclamide at a dose sufficient to block ATP-sensitive K + channels. in addition, this action of loperamide was abolished by protein kinase a (pKa) inhibitor and enhanced by the inhibitor of phosphodiesterase for cyclic amp (camp). Our results suggest that loperamide induces prostatic relaxation through activation of opioid µ-2 receptors via the camp-pKa pathway to open atp-sensitive K + channels. IntroductionBenign prostatic hyperplasia (Bph) occurs frequently in older men and is associated with lower urinary tract symptoms causing obstruction of the proximal urethra and urinary flow disturbances (1). In clinics, medical treatments for BPH include widely used α-1 antagonists and 5-α-reductase inhibitors. however, the side effects, such as postural hypotension, erectile dysfunction and ejaculatory difficulty, disturb the quality of life of these patients (2,3). therefore, development of a more effective therapy for the treatment of Bph is urgent and necessary.loperamide is widely used in the clinic for a variety of diarrheal syndromes, including acute and nonspecific (infectious) diarrhea (4,5). Recently, we identified opioid µ-receptor expression in rat prostates, and prostatic relaxation was induced by the activation of opioid µ-receptors using loperamide (6). loperamide was introduced as a peripheral agonist of opioid µ-receptors with poor ability to penetrate the bloodbrain barrier (7,8). Some analgesic agents have also revealed relaxant effects in smooth muscle (9,10). (+)-tramadol was found to activate peripheral opioid µ-receptors to exhibit a concentration-dependent relaxation of aorta (11). Basically, the opioid µ-receptors have been divided into 3 subtypes, including µ-1, µ-2 and µ-3 opioid receptors (12). however, activation of opioid µ-1 receptors ...

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Lu¹,

Chung²

2011

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

show abstract

“…However, opioid receptors are known to be present on cutaneous sensory nerves in rats 19 and humans. 18 The peripheral administration of opioids has been found to produce analgesia without systemic side effects in animals 15 and humans in response to clinical 4,12 and experimentally induced pain. 7,14 Peripherally administered opioids produce negligible analgesia in uninflamed tissue but potent analgesia in inflamed tissue.…”

Section: Introductionmentioning

confidence: 99%

Naloxone Antagonizes the Local Antihyperalgesic Effect of Fentanyl in Burnt Skin of Healthy Humans

Robertson

Drummond

Hammond

2007

The Journal of Pain

View full text Add to dashboard Cite

The aim of this study was to investigate local opioid effects in the inflamed skin of healthy human volunteers. To induce inflammation, the circular tip of a 10-mm diameter probe was heated to 48ºC and applied for 120 s to a site on each forearm of 24 healthy participants. Thirty minutes later, 0.2 mL normal saline was injected subcutaneously into one inflamed site, and the opioid antagonist naloxone hydrochloride (80 µg in 0.2 mL)was injected subcutaneously into the other inflamed site. Participants completed tests of pain sensitivity (heat pain thresholds, heat pain ratings and mechanical pain ratings) before and after the injections. Fentanyl citrate (10 µg in 0.2 mL) was then injected into the pre-treated sites, and pain sensitivity was measured again. The thermal injuries produced thermal and mechanical hyperalgesia which did not differ between the saline and naloxone sites. After the fentanyl injections, decreases in thermal and mechanical hyperalgesia were greater at the saline site than the naloxone site. These findings demonstrate that pre-treatment with naloxone blocks local opioid effects produced by the subcutaneous injection of a low dose of fentanyl in the inflamed skin of healthy humans.Thus, peripheral opioid receptors could be a therapeutic target for painful cutaneous disorders.Perspective: This article demonstrates that activation of opioid receptors in the skin inhibits sensitivity to painful mechanical and thermal stimuli. Thus, local application of low-dose opioid medications could relieve painful skin disorders.

show abstract

“…After the activation of opioid μ-receptors, tramadol is an effective treatment to handle the pain in clinic with some non-opioid effects [15], while loperamide is a peripheral agonist that does not cross the blood-brain barrier and lacks the side-effects produced by centrally acting opiates [16]. Due to the short half-life of opioid peptides, we used loperamide to evaluate the effect of opioid μ-receptor activation on insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Tzeng

Liu²

2005

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis: This study investigated the role of opioid μ-receptor activation in the improvement of insulin resistance. Methods: Myoblast C 2 C 12 cells were cultured with IL-6 to induce insulin resistance. Radioactive 2-deoxyglucose (2-DG) uptake was used to evaluate the effect of loperamide on insulin-stimulated glucose utilisation. Protein expression and phosphorylation in insulinsignalling pathways were detected by immunoblotting. Results: The insulin-stimulated 2-DG uptake was reduced by IL-6. Loperamide reversed this uptake, and the uptake was inhibited by blockade of opioid μ-receptors. Insulin resistance induced by IL-6 was associated with impaired expression of the insulin receptor (IR), IR tyrosine autophosphorylation, IRS-1 protein content and IRS-1 tyrosine phosphorylation. Also, an attenuated p85 regulatory subunit of phosphatidylinositol 3-kinase, Akt serine phosphorylation and the protein of glucose transporter subtype 4 were observed in insulin resistance. Loperamide reversed IL-6-induced decrement of these insulin signals. Conclusions/interpretation: Opioid μ-receptor activation may improve IL-6-induced insulin resistance through modulation of insulin signals to reverse the responsiveness of insulin. This provides a new target in the treatment of insulin resistance.

show abstract

Characterization of the Antihyperalgesic Action of a Novel Peripheral Mu-opioid Receptor Agonist-Loperamide

Abstract: Loperamide, a peripherally acting mu opioid agonist, applied topically at the site of inflammation possesses a significant antihyperalgesic action without any systemic side effects.

Cited by 79 publications

References 23 publications

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Prostatic relaxation induced by loperamide is mediated through activation of opioid μ-2 receptors in vitro

Naloxone Antagonizes the Local Antihyperalgesic Effect of Fentanyl in Burnt Skin of Healthy Humans

Activation of opioid μ-receptors by loperamide to improve interleukin-6-induced inhibition of insulin signals in myoblast C2C12 cells

Contact Info

Product

Resources

About