Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. (15th March 2018)

• Record Type: Journal Article
• Authors: Imam, Mohammad Zafar; Kuo, Andy; Ghassabian, Sussan; Smith, Maree T.
• Is Part Of: Neuropharmacology. Volume 131(2018)
• Page Start: 238
• Page End: 255
• Publication Date: 2018-03-15
• Subjects: Opioids -- Analgesia -- Adverse effects -- Mechanisms -- Constipation -- Nausea -- Vomiting -- Respiratory depression; 5-HT 5-hydroxytryptamine -- 7TMRs 7-transmembrane spanning G-protein coupled receptors -- AC adenylyl cyclase -- β-arr1 β-arrestin1 -- β-arr2 β-arrestin2 -- ACh acetylcholine -- APJ apelin receptor -- cAMP cyclic adenosine monophosphate -- CaM II Ca2+ /calmodulin-dependent protein kinase II -- CB1 cannabinoid receptor 1 -- CCR5 chemokine receptor 5 -- CTZ Chemoreceptor trigger zone -- D2 Dopamine 2 receptor -- DADLE [d-Ala2 -- d-Leu5]-enkephalin DOP -- delta-opioid DPLPE -- [d-Pen2 Pen5]-enkephalin -- DRN dorsal raphe nucleus -- ERK extracellular signal-regulated kinase -- GIRK G-protein-coupled inwardly rectifying potassium -- GIT gastrointestinal tract -- GRK G-protein receptor kinase -- GRP gastrin-releasing peptide receptor -- H1 Histamine 1 receptor -- HMN hypoglossal motor nucleus -- ICC interstitial cells of Cajal -- JNK c-Jun N-terminal kinase -- KO knock-out -- KOP kappa-opioid -- mAChR muscarinic acetylcholine receptor -- MAPK mitogen-activated protein kinase -- ME [Met5]encephalin -- MOP mu-opioid -- MP myenteric plexus -- MRN median raphe nucleus -- MRR medullary raphe region -- NAcc nucleus accumbens -- NK1 neurokinin -- NO nitric oxide -- NOP nociceptin/orphanin FQ peptide -- NMDA N-methyl-d-aspartate -- NOS nitric oxide synthase -- NTS nucleus tractus solitaries -- OIC opioid-induced constipation -- OINV opioid-induced nausea and vomiting -- OIRD opioid-induced respiratory depression -- OPr opioid receptor -- PDGFRα(+) platelet-derived growth factor receptor α positive -- PKA protein kinase A -- PKC protein kinase C -- PLC phospholipase C -- PLD2 phospholipase D2 -- POMC pro-opiomelanocortin -- PP2A protein phosphatase 2A -- preBötC preBötzinger complex -- RGS4 regulator of G-protein signalling protein 4 -- SMC smooth muscle cell -- SNSR4 sensory neuron-specific receptor -- SP submucosal plexus -- SSTR1A somatostatin receptor1A -- TLR4 Toll-like receptor 4 -- TRPV1 transient receptor potential vanilloid type 1 -- VA vestibular apparatus -- VC vomiting centre -- VIP vasoactive intestinal peptide -- VPAC vasoactive intestinal peptide receptor -- WT wild-type; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.12.032
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Opioids evoke analgesia through activation of opioid receptors (predominantly the μ opioid receptor) in the central nervous system. Opioid receptors are abundant in multiple regions of the central nervous system and the peripheral nervous system including enteric neurons. Opioid-related adverse effects such as constipation, nausea, and vomiting pose challenges for compliance and continuation of the therapy for chronic pain management. In the post-operative setting opioid-induced depression of respiration can be fatal. These critical limitations warrant a better understanding of their underpinning cellular and molecular mechanisms to inform the design of novel opioid analgesic molecules that are devoid of these unwanted side-effects. Research efforts on opioid receptor signalling in the past decade suggest that differential signalling pathways and downstream molecules preferentially mediate distinct pharmacological effects. Additionally, interaction among opioid receptors and, between opioid receptor and non-opioid receptors to form signalling complexes shows that opioid-induced receptor signalling is potentially more complicated than previously thought. This complexity provides an opportunity to identify and probe relationships between selective signalling pathway specificity and in vivo production of opioid-related adverse effects. In this review, we focus on current knowledge of the mechanisms thought to transduce opioid-induced gastrointestinal adverse effects (constipation, nausea, vomiting) and respiratory depression. Highlights: Review of currently understood mechanisms of opioid-related gastrointestinal and respiratory side-effects. The cellular mechanisms underpinning these opioid related side-effects are poorly understood. New insight on these mechanisms is opening new frontiers for discovery of novel opioids with improved side effects profile.