A novel insertional mutation in the mu-opioid receptor gene is associated with altered cortisol response to naloxone

Activation of the hypothalamic-pituitary-adrenal (HPA) axis is a physiological response to stress. Opioidergic pathways have a constitutionally maintained inhibitory effect on HPA activation, mediated by μ-opioid receptors expressed on corticotropin releasing factor (CRF)-expressing neurons. The opioid receptor antagonist, naloxone, activates CRF secretion by disinhibiting opioid tone and causes an increase in plasma cortisol. We have identified a subject who presented a uniquely severe adverse reaction to naloxone infusion, and a significantly blunted cortisol response to the drug. This subject carries a heterozygous mutation in the extracellular domain of the μ-opioid receptor, which causes the insertion of an extra glycine between residue 63 and 64 in the extracellular domain. Although a causal effect between the abnormality in the receptor and the unusual response to naloxone could not be proven, this insertion was not found in 300 normal chromosomes, indicating that, if it is a polymorphism, it is extremely rare.