scholarly journals Peripherally Acting μ-Opioid Receptor Antagonists for the Treatment of Opioid-Related Side Effects: Mechanism of Action and Clinical Implications

2017 ◽  
Vol 31 (6) ◽  
pp. 658-669 ◽  
Author(s):  
John M. Streicher ◽  
Edward J. Bilsky
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Mechanism Of Action ◽  
Bowel Dysfunction ◽  
Cardiac Risk ◽  
Common Side Effect ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonists ◽  
Opioid Administration

Opioid receptors are distributed throughout the central and peripheral nervous systems and on many nonneuronal cells. Therefore, opioid administration induces effects beyond analgesia. In the enteric nervous system (ENS), stimulation of µ-opioid receptors triggers several inhibitory responses that can culminate in opioid-induced bowel dysfunction (OBD) and its most common side effect, opioid-induced constipation (OIC). OIC negatively affects patients’ quality of life (QOL), ability to work, and pain management. Although laxatives are a common first-line OIC therapy, most have limited efficacy and do not directly antagonize opioid effects on the ENS. Peripherally acting µ-opioid receptor antagonists (PAMORAs) with limited ability to cross the blood-brain barrier have been developed. The PAMORAs approved by the U S Food and Drug Administration for OIC are subcutaneous and oral methylnaltrexone, oral naloxegol, and oral naldemedine. Although questions of cost-effectiveness and relative efficacy versus laxatives remain, PAMORAs can mitigate OIC and improve patient QOL. PAMORAS may also have applications beyond OIC, including reducing the increased cardiac risk or potential tumorigenic effects of opioids. This review discusses the burden of OIC and OBD, reviews the mechanism of action of new OIC therapies, and highlights other potential opioid-related side effects mediated by peripheral opioid receptors in the context of new OIC therapies.

Functional localization of specific receptors mediating gastrointestinal motor correlates of vomiting

1989 ◽  
Vol 256 (1) ◽  
pp. G92-G99 ◽  
Author(s):  
I. M. Lang ◽  
J. Marvig
Keyword(s):  
Small Intestine ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Agonist ◽  
Sch 23390 ◽  
Receptor Antagonists ◽  
Motor Responses ◽  
Opioid Receptor Agonist ◽  
Opioid Receptor Antagonists ◽  
Gastrointestinal Motor

The gastrointestinal motor correlates of vomiting consist of two contractile events, 1) a giant retrogradely propagated contraction of the upper small intestine, the retrograde giant contraction (RGC) and 2) a series of post-RGC phasic contractions that occur primarily in the lower small intestine. The effects of cholinergic, dopaminergic, serotonergic, and opioid receptor antagonists and an opioid receptor agonist on vomiting and its gastrointestinal motor correlates initiated by apomorphine (APO), CuSO4, or cholecystokinin octapeptide (CCK-8) were determined in awake dogs. Atropine blocked the retrograde giant contraction only, and hexamethonium blocked all jejunoileal motor responses activated by APO, CuSO4, or CCK-8. Domperidone blocked all effects of APO only, whereas haloperidol, methysergide, 1-(1-naphthyl) piperazine, and fentanyl blocked or inhibited responses to both APO and CuSO4. None of the dopaminergic, serotonergic, or opioid receptor antagonists or the opioid receptor agonist affected the gastrointestinal motor responses to CCK-8. Cinanserin or Sch 23390 had no effect on any of the responses activated by APO, CuSO4, or CCK-8. These results suggested that D2 dopaminergic and 5-HT2 serotonergic receptors of the emetic central pattern generator mediate vomiting and its gastrointestinal motor correlates, whereas opioid receptors may mediate tonic inhibition of these responses. In addition, peripheral muscarinic or nicotinic cholinergic receptors but not peripheral 5-HT2, dopaminergic, or opioid receptors mediate the gastrointestinal motor correlates of vomiting.

scholarly journals Analgesia linked to Nav1.7 loss of function requires µ- and δ-opioid receptors

2018 ◽  
Vol 3 ◽  
pp. 101 ◽  
Author(s):  
Vanessa Pereira ◽  
Queensta Millet ◽  
Jose Aramburu ◽  
Cristina Lopez-Rodriguez ◽  
Claire Gaveriaux-Ruff ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Mutant Mice ◽  
Null Mouse ◽  
Channel Blockers ◽  
Null Mutant ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonists ◽  
Null Mutant Mice

Background: Functional deletion of the Scn9a (sodium voltage-gated channel alpha subunit 9) gene encoding sodium channel Nav1.7 makes humans and mice pain-free. Opioid signalling contributes to this analgesic state. We have used pharmacological and genetic approaches to identify the opioid receptors involved in this form of analgesia. We also examined the regulation of proenkephalin expression by the transcription factor Nfat5 that binds upstream of the Penk gene. Methods: We used specific µ-, δ- and κ-opioid receptor antagonists alone or in combination to examine which opioid receptors were necessary for Nav1.7 loss-associated analgesia in mouse behavioural assays of thermal pain. We also used µ- and δ-opioid receptor null mutant mice alone and in combination in behavioural assays to examine the role of these receptors in Nav1.7 knockouts pain free phenotype. Finally, we examined the levels of Penk mRNA in Nfat5-null mutant mice, as this transcription factor binds to consensus sequences upstream of the Penk gene. Results: The pharmacological block or deletion of both µ- and δ-opioid receptors was required to abolish Nav1.7-null opioid-related analgesia. κ-opioid receptor antagonists were without effect. Enkephalins encoded by the Penk gene are upregulated in Nav1.7 nulls. Deleting Nfat5, a transcription factor with binding motifs upstream of Penk, induces the same level of enkephalin mRNA expression as found in Nav1.7 nulls, but without consequent analgesia. These data confirm that a combination of events linked to Scn9a gene loss is required for analgesia. Higher levels of endogenous enkephalins, potentiated opioid receptors, diminished electrical excitability and loss of neurotransmitter release together contribute to the analgesic phenotype found in Nav1.7-null mouse and human mutants. Conclusions: These observations help explain the failure of Nav1.7 channel blockers alone to produce analgesia and suggest new routes for analgesic drug development.

scholarly journals S1277 The Role of Peripherally Acting µ-Opioid Receptor Antagonists (PAMORA) in Pediatric Opioid-Induced Bowel Dysfunction

2021 ◽  
Vol 116 (1) ◽  
pp. S586-S587
Author(s):  
Thu Pham ◽  
James Noel ◽  
Robert Noel ◽  
Lucile McLoughlin ◽  
Chris Moreau ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Bowel Dysfunction ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonists

Negative inotropic and chronotropic effects of δ-opioid receptor antagonists are mediated via non-opioid receptors

2006 ◽  
Vol 141 (4) ◽  
pp. 420-423 ◽  
Author(s):  
L. N. Maslov ◽  
Yu. B. Lishmanov ◽  
E. I. Barzakh ◽  
T. V. Lasukova ◽  
K. K. Rice ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Opioid Receptors ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonists ◽  
Chronotropic Effects ◽  
Δ Opioid Receptor

The opioid bowel syndrome: A review of pathophysiology and treatment

2005 ◽  
Vol 1 (3) ◽  
pp. 153 ◽  
Author(s):  
Mellar P. Davis, MD, FCCP
Keyword(s):  
Opioid Receptor ◽  
Terminally Ill ◽  
Bowel Dysfunction ◽  
Receptor Antagonists ◽  
Specific Therapy ◽  
Terminally Ill Patients ◽  
Opioid Receptor Antagonists

Opioids are responsible for 25 percent of constipation in terminally ill patients. Patients in pain require prophylaxis to prevent opioid bowel syndrome (OBS). Laxatives are the treatment of choice, but are marginally effective. The development of quaternary opioid receptor antagonists is a step toward target-specific therapy for opioidinduced bowel dysfunction. This review will discuss the pathophysiology and management of OBS.

Behavioral Effects of Opioid Receptor Antagonists in Psychopathologic States

1983 ◽  
Vol 6 (3) ◽  
pp. 403-414 ◽  
Author(s):  
David S. Janowsky ◽  
Lewis L. Judd ◽  
Leighton Y. Huey ◽  
Samuel Craig Risch ◽  
David S. Segal
Keyword(s):  
Opioid Receptor ◽  
Behavioral Effects ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonists
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