Opioid toxicity: histamine, hypersensitivity, and MRGPRX2

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.

Automated summary

The pathophysiology of non-immune-mediated drug reactions has been explored through research on MRGPRX2, a human mast cell receptor that mediates adverse reactions without antibody priming. Activation of MRGPRX2 can cause mast cell degranulation and release of histamine, leading to symptoms such as flushing, headache, and skin reactions. Different opioids have varying histamine-releasing potencies and their correlation with MRGPRX2 activation and adverse cutaneous effects is still unknown. Ongoing research using basophil and mast cell tests based on insights from MRGPRX2 should provide further understanding of the relationship between histamine release, MRGPRX2 activation, and adverse reactions caused by opioids.