Abstract
Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2.
This is a preview of subscription content, log in via an institution to check access.
Reproduced with permission from Springer Nature
Reproduced with permission from Springer Nature
Reproduced with permission from Springer Nature
Reproduced with permission from Springer Nature
Similar content being viewed by others
Data Availablity
Data is available from the corresponding author (BAB) on request.
References
Akuzawa N, Obinata H, Izumi T et al (2007) Morphine is an exogenous ligand for MrgX2, a G-protein coupled receptor for cortistatin. J Cell Anim Biol 2:4–9
Ali H (2017) Emerging roles for MAS-related G protein-coupled receptor-X2 in host defence peptide, opioid, and neuropeptide-mediated inflammatory reactions. Adv Immunol 136:123–162. https://doi.org/10.1016/bs.ai.2017.06.002
Alkanfari I, Gupta K, Jahan T et al (2018) Naturally occurring missense MRGPRX2 variants display loss of function phenotype for mast cell degranulation in response to substance P, hemokinin-1, human β-defensin-3, and icatibant. J Immunol 201:343–349. https://doi.org/10.4049/jimmunol.170179324
Allen JA, Roth BL (2011) Strategies to discover unexpected targets for drugs active at G protein coupled receptors. Annu Rev Pharmacol Toxicol 51:117–144. https://doi.org/10.1146/annurev-pharmtox-010510-100553
Allen JW, Horais KA, Tozier NA (2006) Opiate pharmacology of intrathecal granulomas. Anesthesiology 105:590–598. https://doi.org/10.1097/00000542-200609000-00025
Aronson JK (2016). In: Aronson JK (ed) Meyler’s side effects of drugs, 16th edn. Elsevier, Oxford, pp 1111–1127
Ayudhya CCN, Roy S, Alkanfari, et al (2019) Identification of gain and loss of function missense variants in MRGPRX2’s transmembrane and intracellular domains for mast cell activation by substance P. Int J Mol Sci 20:5247. https://doi.org/10.3390/ijms20215247
Ayudhya CCN, Amponnawarat a, Roy S, et al (2021) MRGPRX2 activation by rocuronium: insights from studies with human skin mast cells and missense variants. Cells 10:156. https://doi.org/10.3390/cells10010156
Babina M (2020) The pseudo-allergic/neurogenic route of mast cell activation via MRGPRX2: discovery, functional programs, regulation, relevance to disease, and relation with allergic stimulation. Itch 5(2):e32. https://doi.org/10.1097/itx.0000000000000032
Babina M, Wang Z, Roy S et al (2021) MRGPRX2 is the codeine receptor of human skin mast cells: desensitization through β-arrestin and lack of correlation with the FcεRI pathway. J Invest Dermatol 141:1286–96.e4. https://doi.org/10.1016/j.jid.2020.09.01
Babina M, Wang Z, Li Z et al (2022) FcERI- and MRGPRX2-evoked acute degranulation responses are fully additive in human skin mast cells. Allergy 77:1906–1909. https://doi.org/10.1111/all.15270
Bahri R, Custovic A, Korosec P et al (2018) Mast cell activation test in the diagnosis of allergic disease and anaphylaxis. J Allergy Clin Immunol 142:485–496. https://doi.org/10.1016/j.jaci.2018.01.043
Baldo BA (2021) Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin syndrome. Arch Toxicol 95:2627–2642. https://doi.org/10.1007/s00204-021-03068-2
Baldo BA, Fisher MM (1983) Anaphylaxis to muscle relaxant drugs: cross-reactivity and molecular basis of binding of IgE antibodies detected by radioimmunoassay. Mol Immunol 20:1393–1400. https://doi.org/10.1016/0161-5890(83)90171-2
Baldo BA, Pham NH (1994) Structure-activity studies on drug-induced anaphylactic reactions. Chem Res Toxicol 7:703–721. https://doi.org/10.1021/tx00042a001
Baldo BA, Pham NH (2012) Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two. Anaesth Intensive Care 40:216–235. https://doi.org/10.1177/0310057X1204000204
Baldo BA, Pham NH (2021) Drug allergy: clinical aspects, diagnosis, mechanisms structure-activity relationships, 2nd edn. Springer Nature, Cham, pp 3–8 (74-80, 324-354, 418–433). https://doi.org/10.1007/978-3-030-51740-3
Baldo BA, Fisher MM, Pham NH (2009) On the origin and specificity of antibodies to neuromuscular blocking (muscle relaxant) drugs: an immunochemical perspective. Clin Exp Allergy 39:325–344. https://doi.org/10.1111/j.1365-2222.2008.03171.x
Ballantyne JC, Loach AB, Carr DB (1988) Itching after epidural and spinal opiates. Pain 33:149–160. https://doi.org/10.1016/0304-3959(88)90085-1
Barke KE, Hough LB (1993) Opiates, mast cells and histamine release. Life Sci 53:1391–1399. https://doi.org/10.1016/0024-3205(93)90581-m
Barnea G, Strapps W, Herrada G et al (2008) The genetic design of signaling cascades to record receptor activation. Proc Nat Acad Sci 105:64–69. https://doi.org/10.1073/pnas.0710487105
Barth H, Giertz H, Schmal A et al (1987) Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents and Actions 20:310–313. https://doi.org/10.1007/BF02074699
Blunk JA, Schmelz M, Zeck S et al (2004) Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 98:364–370. https://doi.org/10.1213/01.ANE.0000097168.32472.0D
Bowdle TA, Even A, Shen DD (2004) Methadone for the induction of anesthesia: plasma histamine concentration, arterial blood pressure, and heart rate. Anesth Analg 98:1692–1697. https://doi.org/10.1213/01.ANE.0000114085.20751.20
Brashear RE, Kelly MT, White AC (1974) Elevated plasma histamine after heroin and morphine. J Lab Clin Med 83:451–457
Casale TB, Bowman S, Kaliner M (1984) Induction of human cutaneous mast cell degranulation by opiates and endogenous opioid peptides: evidence for opiate and nonopiate receptor participation. J Allergy Clin Immunol 73:775–781. https://doi.org/10.1016/0091-6749(84)90447-0
Coombs RRA, Gell PGH (1968) Classification of allergic reactions responsible for drug hypersensitivity reactions. In: Coombs RRA, Gell PGH (eds) Clinical aspects of immunology, 2nd edn. Davis, Philadelphia, pp 575–596
Cop N, Decuyper II, Faber MA et al (2017) Phenotypic and functional characterization of in vitro cultured human mast cells. Cytom B Clin Cytom 92:348–354. https://doi.org/10.1002/cyto.b.21399
Cop N, Ebo DG, Bridts CH et al (2018) Influence of IL-6, IL-33, and TNF-alpha on human mast cell activation: lessons from single cell analysis by flow cytometry. Cytom B Clin Cytom 94:405–411. https://doi.org/10.1002/cyto.b.21547
Crabbe Erush S (1996) Narcotic Allergy. P&T 21:250–252,292
Decuyper II, Ebo DG, Uyttebroek AP et al (2016) Quantification of specific IgE antibodies in immediate drug hypersensitivity: more shortcomings than potentials? Clin Chim Acta 460:184–189. https://doi.org/10.1016/j.cca.2016.06.043
Decuyper II, Mangodt EA, Van Gasse AL et al (2017) In vitro diagnosis of immediate drug hypersensitivity anno 2017: potentials and limitations. Drugs R&D 17:265–278. https://doi.org/10.1007/s40268-017-0176-x
Easton MP, Bailey PL (2001) Cardiovascular pharmacology of anesthetics. In: Estafanous FG, Barash PG, Reves JG (eds) Cardiac anesthesia: principles and practice. Lipincott Williams & Wilkins, Philadelphia, pp 295–318
Ebo DG, Van der Poorten M-L, Elst J et al (2021) Immunoglobulin E cross-linking or MRGPRX2 activation: clinical insights from rocuronium hypersensitivity. Br J Anaesth 126:e27–e29. https://doi.org/10.1016/j.bja.2020.10.006
Elst J, Sabato V, Faber MA (2020a) RNA Silencing: a model to explore the MRGPRX2-pathway in cultured human mast cells. J Allergy Clin Immunol 145(AB249):Abst809. https://doi.org/10.1016/j.jaci.2019.12.104
Elst J, Sabato V, Hagendorens MM et al (2020b) Measurement and functional analysis of the mas-related G protein-coupled receptor MRGPRX2 on human mast cells and basophils. In: Gibbs BF, Falcone FH (eds) Basophils and Mast cells: methods and protocols, methods in molecular biology, vol 2163. Springer Science+Business Media, New York, pp 219–226. https://doi.org/10.1007/978-1-0716-0696-4_18
Elst J, van der Poorten MM, Faber MA et al (2020c) Mast cell activation tests: a proof of concept. Br J Anaesth 125:970–975. https://doi.org/10.1016/j.bja.2020.06.024
Elst J, Sabato V, Faber MA et al (2021) MRGPRX2 and immediate drug hypersensitivity: insights from cultured human mast cells. J Investig Allergol Clin Immunol 31:489–499. https://doi.org/10.18176/jiaci.0557
Elst J, van der Poorten M-LM, Van Gasse AL et al (2022) Tryptase release does not discriminate between IgE- and MRGPRX2-mediated activation in human mast cells. Clin Exp Allergy 52:797–800. https://doi.org/10.1111/cea.14110
Ennis M, Schneider C, Nehring E, et al (1991) Histamine release induced by opioid analgesics: a comparative study using porcine mast cells. Agents and Actions 33(20):2. https://doi.org/10.1007/BF01993116
Evans AGJ, Nasmyth A, Stewart HC (1952) The fall of blood pressure caused by intravenous morphine in the rat and the cat. Br J Pharmacol Chemother 7:542–552. https://doi.org/10.1111/j.1476-5381.1952.tb00720.x
Falcone FH, Wan D, Barwary N et al (2018) RBL cells as models for in vitro studies of mast cells and basophils. Immunol Rev 282:47–57. https://doi.org/10.1111/imr.12628
Feldberg W, Paton WDM (1951) Release of histamine from skin and muscle in the cat by opium alkaloids and other histamine liberators. J Physiol 114:490–509. https://doi.org/10.1113/jphysiol.1951.sp004639
Fisher MM, Baldo BA (2000) Immunoassays in the diagnosis of anaphylaxis to neuromuscular blocking drugs: the value of morphine for the detection of IgE antibodies in allergic subjects. Anaesth Intensive Care 28:167–170. https://doi.org/10.1177/0310057X0002800207
Fisher MM, Harle DG, Baldo BA (1991) Anaphylactoid reactions to narcotic analgesics. Clin Rev Allergy 9:309–318. https://doi.org/10.1007/BF02802310
Florvaag E, Johansson SGO, Oman H et al (2005) Prevalence of IgE antibodies to morphine. Relation to the high and low incidences of NMBA anaphylaxis in Norway and Sweden, respectively. Acta Anaesthesiol Scand 49:437–444. https://doi.org/10.1111/j.1399-6576.2004.00591.x
Fujisawa D, Kashiwakura J-I, Kita H et al (2014) Expression of mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria. J Allergy Clin Immunol 134:622–633. https://doi.org/10.1016/j.jaci.2014.05.004
Gaudenzio N, Sibilano R, Marichal T et al (2016) Different activation signals induce distinct mast cell degranulation strategies. J Clin Invest 126:3981–3998. https://doi.org/10.1172/JCI85538
Grosman N (1981) Histamine release from isolated rat mast cells: effect of morphine and related drugs and their interaction with compound 48/80. Agents and Actions 11:196–203. https://doi.org/10.1007/BF01967614
Grosman N, Jensen SM, Johansen FF (1982) Histamine release from isolated rat mast cells induced by opiates: effect of sterical configuration and calcium. Agents and Actions 12:417–424. https://doi.org/10.1007/BF01965920
Harle DG, Baldo BA, Coroneos NJ et al (1989) Anaphylaxis following administration of papaveretum. Case report: implication of IgE antibodies that react with morphine and codeine, and identification of an allergenic determinant. Anesthesiology 71:489–494
Harle DG, Baldo BA, Fisher MM (1990) Immunoassays employing substituted ammonium compounds other than neuromuscular blocking drugs to increase the detection of IgE antibodies to these drugs. Mol Immunol 27:1039–1045. https://doi.org/10.1016/0161-5890(90)90127-l
Hermens JM, Ebertz JM, Hanifn JM et al (1985) Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 62:124–129. https://doi.org/10.1097/00000542-198502000-00005
Higashijima T, Uzu S, Nakajima T et al (1988) Mastoparan, a peptide toxin from wasp venom, mimics receptor by activating GTP-binding regulatory proteins (G proteins). J Biol Chem 263:6491–6494
Higashijima T, Burnier J, Ross EM (1990) Regulation of Gi and Go by mastoparan, related amphiphilic peptides, and hydrophobic amines. Mechanism and structural determinants of activity. J Biol Chem 265:14176–14186
Johnzon C-F, Rönnberg E, Pejler G (2016) The role of mast cells in bacterial infection. Am J Pathol 186:4–14. https://doi.org/10.1016/j.ajpath.2015.06.024
Kaliner M, Shelhamer JH, Ottesen EA (1982) Efects of infused histamine: correlation of plasma histamine levels and symptoms. J Allergy Clin Immunol 69:283–289. https://doi.org/10.1016/s0091-6749(82)80005-5
Kjellberg F, Tramèr MR (2001) Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol 18:346–357. https://doi.org/10.1097/00003643-200106000-00002
Kroeze WK, Sassano MF, Huang X-P et al (2015) PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat Struct Mol Biol 22:362–369. https://doi.org/10.1038/nsmb.3014
Kumar K, Singh SI (2013) Neuraxial opioid-induced pruritus: an update. J Anaesthesiol Clin Pharmacol 29:303–307. https://doi.org/10.4103/0970-9185.117045
Kumar M, Duraisamy K, Chow B-K-C (2021) Unlocking the non-IgE-mediated pseudo-allergic reaction puzzle with mas-related G-protein coupled receptor member X2 (MRGPRX2). Cells 10:1033
Lansu K, Karpiak J, Liu J et al (2017) In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 13:529–536. https://doi.org/10.1038/nchembio.2334
Lawrence ID, Warner JA, Cohan VL et al (1987) Purifcation and characterization of human skin mast cells. Evidence for human mast cell heterogeneity. J Immunol 139:3062–3069
Lefkowitz RJ, Shenoy FJ (2005) Transduction of receptor signals by β-Arrestins. Science 308:512–517. https://doi.org/10.1126/science.1109237
Levy JH, Brister NW, Shearin A et al (1989) Wheal and fare responses to opioids in humans. Anesthesiology 70:756–760. https://doi.org/10.1097/00000542-198905000-00008
Leysen J, De Witte L, Sabato V et al (2013) IgE-mediated allergy to pholcodine and cross-reactivity to neuromuscular blocking agents: lessons from flow cytometry. Cytom B Clin Cytom 84:65–70. https://doi.org/10.1002/cyto.b.21074
Li PH, Ue KL, Wagner A et al (2017) Opioid hypersensitivity: predictors of allergy and role of drug provocation testing. J Allergy Clin Immunol Pract 5:1601–1606. https://doi.org/10.1016/j.jaip.2017.03.035
Lichtenstein LM, Foreman JC, Conroy MC et al (1979) Differences between histamine release from rat mast cells and human basophils and mast cells. In: Pepys J, Edwards AM (eds) The mast cell: its role in health and disease. Pitman Med, Tunbridge Wells, pp 83–96
Liu X-Y, Liu Z-C, Sun Y-G et al (2011) Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147:447–458. https://doi.org/10.1016/j.cell.2011.08.043
Liu R, Wang J, Zhao T et al (2018) Relationship between MRGPRX2 and pethidine hydrochloride- or fentanyl citrate-induced LAD2 cell degranulation. J Pharm Pharmacol 70:1596–1605. https://doi.org/10.1111/jphp.13009
McBride P, Jacobs R, Bradley D et al (1989) Use of plasma histamine levels to monitor cutaneous mast cell degranulation. J Allergy Clin Immunol 83:374–380. https://doi.org/10.1016/0091-6749(89)90121-8
McDonald J, Lambert DG (2015) Opioid receptors. BJA Edu 15:219–224
McNeil BD (2021) MRGPRX2 and adverse drug reactions. Front Immunol 12:676354. https://doi.org/10.3389/fimmu.2021.676354
McNeil BD, Pundir P, Meeker S et al (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519:237–241. https://doi.org/10.1038/nature14022
Meixiong J, Anderson M, Limjunyawong N et al (2019) Activation of mast-cell-expressed mas-related G-protein-coupled receptors drives non-histaminergic itch. Immunity 50:1163–71.e5. https://doi.org/10.1016/j.immuni.2019.03.013
Mousli M, Bronner C, Landry Y et al (1990a) Direct activation of GTP-binding regulatory proteins (G-proteins) by substance P and compound 48/80. FEBS Lett 259:260–262. https://doi.org/10.1016/0014-5793(90)80023-c
Mousli M, Bueb JL, Bronner C et al (1990b) G protein activation: a receptor-independent mode of action for cationic amphiphilic neuropeptides and venom peptides. Pharmacol Sci 11:358–362. https://doi.org/10.1016/0165-6147(90)90179-c
Nasser SM, Ewan PW (2001) Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Clin Exp Allergy 31:1014–1020
Navinés-Ferrer A, Serrano-Candelas E, Lafuente A et al (2018) MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia. Sci Rep 8:11628. https://doi.org/10.1038/s41598-018-29965-8
North RB, Cutchis PN, Epstein JA et al (1991) Spinal cord compression complicating subarachnoid infusion of morphine: case report and laboratory experience. Neurosurgery 29:778–784. https://doi.org/10.1097/00006123-199111000-00025
Nucynta® ER (Tapentadol) (2016). FDA prescribing information. Adverse reactions. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/200533s014lbl.pdf. Accessed 20 Aug 2022
Pearce FL, Ennis M, Truneh A et al (1981) Role of intra- and extracellular calcium in histamine release from peritoneal mast cells. Agents and Actions 11:51–54. https://doi.org/10.1007/BF01991455
Pham NH, Baldo BA, Puy RM (2001) Studies on the mechanism of multiple drug allergies. Structural basis of drug recognition. J Immunoassay Immunochem 22:47–73. https://doi.org/10.1081/IAS-100102897
Poyhia R, Hynynen M, Seppala T et al (2004) Pharmacodynamics and pharmacokinetics of high-dose oxycodone infusion during and after coronary artery by-pass grafting. J Cardiothorac Anesth 18:748–754. https://doi.org/10.1053/j.jvca.2004.08.013
Reber LL, Hernandez JD, Galli SJ (2017) The pathophysiology of anaphylaxis. J Allergy Clin Immunol 140:335–348. https://doi.org/10.1016/j.jaci.2017.06.003
Reddy VB, Graham TA, Azimi E (2017) A single amino acid in MRGPRX2 necessary for binding and activation by pruritogens. J Allergy Clin Immunol 140:1726–1728. https://doi.org/10.1016/j.jaci.2017.05.046
Reich A, Szepietowski JC (2010) Opioid-induced pruritus: an update. Clin Exp Dermatol 35:2–6. https://doi.org/10.1111/j.1365-2230.2009.03463.x
Rybak MJ, Bailey EM, Warbasse LH (1992) Absence of “Red Man Syndrome” in patients being treated with vancomycin or high-dose teicoplanin. Antimicrob Agent Chemother 36:1204–1207. https://doi.org/10.1128/AAC.36.6.120459
Sabato V, Van Gasse AL, Cop N et al (2017) The mas-related G protein-coupled receptor MRGPRX2 is expressed on human basophils and up-regulated upon activation. J Allergy Clin Immunol 139:AB168. https://doi.org/10.1016/j.jaci.2016.12.550
Sabato V, Elst J, Van Houdt M et al (2020) Surface expression of MRGPRX2 on resting basophils: an area of controversy. Allergy 75:2421–2422
Santos AF, Couto-Francisco N et al (2018) A novel human mast cell activation test for peanut allergy. J Allergy Clin Immunol 142:689–691. https://doi.org/10.1016/j.jaci.2018.03.011
Schmidt-Rondon E, Wang Z, Malkmus SA et al (2018) Effects of opioid and nonopioid analgesics on canine wheal formation and cultured human mast cell degranulation. Toxicol Appl Pharmacol 338:54–64. https://doi.org/10.1016/j.taap.2017.10.017
Shtessel M, Limjunyawong N, Oliver ET et al (2021) MRGPRX2 activation causes increased skin reactivity in patients with chronic spontaneous urticaria. J Invest Dermatol 141(678–81):e672. https://doi.org/10.1016/j.jid.2020.06.030
Sollmann T, Pilcher JD (1917) Endermic reactions. J Pharmacol Exp Ther 9:305–340
Southern C, Cook JM, Neetoo-Isseljee Z et al (2013) Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen 18:599–609. https://doi.org/10.1177/1087057113475480
Sromek AW, Provencher BA, Russell S et al (2014) Preliminary pharmacological evaluation of enantiomeric morphinans. ACS Chem Neurosci 5:93–99. https://doi.org/10.1021/cn400205z
Stellato C, Cirillo R, de Paulis A et al (1992) Human basophil/mast cell releasability. IX. Heterogeneity of the effects of opioids on mediator release. Anesthesiology 77:932–940. https://doi.org/10.1097/00000542-199211000-00016
Subramanian H, Gupta K, Ali H (2016) Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases. J Allergy Clin Immunol 138:700–710. https://doi.org/10.1016/j.jaci.2016.04.051
Sydbom A (1988) Characteristics of beta-endorphin-induced histamine release from rat serosal mast cells. Comparison with neurotensin, dynorphin and compound 48/80. Naunyn Schmiedebergs Arch Pharmacol 338:567–572. https://doi.org/10.1007/BF00179331
Tatemoto K, Nozaki Y, Tsuda R et al (2006) Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors. Biochem Biophys Res Commun 349:1322–1328. https://doi.org/10.1016/j.bbrc.2006.08.177
Tharp MD, Kagey-Sobotka A, Fox CC (1987) Functional heterogeneity of human mast cells from different anatomic sites: in vitro responses to morphine sulfate. J Allergy Clin Immunol 79:646–653. https://doi.org/10.1016/s0091-6749(87)80162-8
Toll L, Bruchas MR, Calo G et al (2016) Nociceptin/ophanim FQ receptor structure, signaling, ligands, functions, and interactions with opioid systems. Pharmacol Rev 68:419–457. https://doi.org/10.1124/pr.114.009209
Van Gasse AL, Hagendorens MM, Sabato V et al (2015) IgE to poppy seed and morphine are not useful tools to diagnose opiate allergy. J Allergy Clin Immunol Pract 3:396–399. https://doi.org/10.1016/j.jaip.2014.12.002
Van Gasse AL, Sabato V, Faber MA et al (2017) An alternative explanation for immediate hypersensitivity reactions to opioids. J Allergy Clin Immunol Pract 5:1806. https://doi.org/10.1016/j.jaip.2017.08.016
Van Gasse AL, Elst J, Bridts CH et al (2019) Rocuronium hypersensitivity: does off-target occupation of the MRGPRX2 receptor play a role? J Allergy Clin Immunol Pract 7:998–1003. https://doi.org/10.1016/j.jaip.2018.09.034
Varricchi G, Pecoraro A, Loffredo S et al (2019) Heterogeneity of human mast cells with respect to MRGPRX2 receptor expression and function. Front Cell Neurosci 13:299. https://doi.org/10.3389/fncel.2019.00299
Wedi B, Gehring M, Kapp A (2020a) The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: expression and function. Allergy 75:2229–2242. https://doi.org/10.1111/all.14213
Wedi B, Gehring M, Kapp A, Reply to Sabato V, et al (2020b) Surface expression of MRGPRX2 expression on resting basophils: an area of controversy. Allergy 75:2424–2427
Withington DE, Patrick JA, Reynolds F (1993) Histamine release by morphine and diamorphine in man. Anaesthesia 48:26–29. https://doi.org/10.1111/j.1365-2044.1993.tb06785.x
Yaksh TL, Eddinger KA, Kokubu S et al (2019) Mast cell degranulation and fibroblast activation in the morphine-induced spinal mass: role of mas-related G protein-coupled receptor signaling. Anesthesiology 131:132–147. https://doi.org/10.1097/ALN.0000000000002730
Zhang T, Che D, Liu R et al (2017) Typical antimicrobials induce mast cell degranulation and anaphylactoid reactions via MRGPRX2 and its murine homologue MRGPRB2. Eur J Immunol 47:1949–1958. https://doi.org/10.1002/eji.201746951
Acknowledgements
The authors thank Drs DG Ebo and J Elst for helpful comments on the manuscript.
Funding
No funding was received to assist in the preparation of this review.
Author information
Authors and Affiliations
Contributions
BAB conceived the study, undertook the literature review, prepared figures, and wrote the paper. NHP contributed to the literature review, prepared figures, and helped review the manuscript. Both authors approved the final draft of the review and agree to be accountable for all aspects of the work.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that influenced the work reported here.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Brian A. Baldo and Nghia H. Pham are retired. The positions and affiliations listed are those prior to retirement.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Baldo, B.A., Pham, N.H. Opioid toxicity: histamine, hypersensitivity, and MRGPRX2. Arch Toxicol 97, 359–375 (2023). https://doi.org/10.1007/s00204-022-03402-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-022-03402-2