Thebaine induces anaphylactic reactions via the MRGPRX2 receptor pathway on mast cells

Cell Immunol. 2022 May:375:104514. doi: 10.1016/j.cellimm.2022.104514. Epub 2022 Apr 2.

Abstract

Morphine derivatives are clinically important anesthetic and sedative drugs, which often show anaphylactic side effects. Mas-related G-protein coupled receptor member X2 (MRGPRX2) triggers mast cell degranulation, which is important process in anaphylactic reactions. MRGPRX2-HEK293 and LAD2 cell membrane chromatographic (CMC) models were used to screen morphine derivatives binding to MRGPRX2. Furthermore, most morphine derivatives significantly enhanced Ca2+ mobilization. More importantly, thebaine was found to effectively promote histamine release. Thebaine induced the increased release of β-hexosaminidase and high secretion level of cytokines, confirming that thebaine could further trigger anaphylactic reactions and promote subsequent inflammatory reactions. Moreover, the ability of thebaine inducing degranulation and the release of allergenic mediators in mast cells was significantly decreased after MRGPRX2 knockdown, which proved that MRGPRX2 is the key media for thebaine-induced anaphylactic reactions. Significant hind paw swelling and hypothermia in mice after injecting thebaine suggested that thebaine could trigger anaphylactic reactions in vivo.

Keywords: Anaphylactic reactions; Cell membrane chromatography; MRGPRX2; Morphine derivatives; Thebaine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphylaxis* / chemically induced
  • Animals
  • Cell Degranulation
  • HEK293 Cells
  • Humans
  • Mast Cells*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins* / genetics
  • Receptors, G-Protein-Coupled* / genetics
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, Neuropeptide* / genetics
  • Thebaine* / adverse effects

Substances

  • MRGPRX2 protein, human
  • Nerve Tissue Proteins
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Thebaine