Intrauterine position has long-term influence on brain mu-opioid receptor density and behaviour in mice

In multiparous rodents, a naturally occurring variation in degree of exposure to sex steroids during the prenatal phase of sexual differentiation derives from the in-utero proximity to opposite sex foetuses. So far, the studies on intrauterine position (IUP) phenomenon have mostly focused on traits relating to reproduction and behaviour, while its influence on neurochemical substrates and pharmacological response has been largely unexplored. We investigated possible variations in the function and the profile of expression of the mu-opioid receptor system in three groups of adult mice from known IUP: 2M mice (located between two males), 0M (between two females), and 1M (between a male and a female). Autoradiographic study revealed in female mice that proximity to at least a male in utero (1M and 2M position) resulted associated at adulthood with an increased density of midbrain mu-opioid receptors. Behavioural observations were conducted following injection with the specific mu-opioid agonist Fentanyl (at 0, 0.01 or 0.05 mg/kg IP). A drug-conditioned place preference test confirmed that 1M and 2M subjects were also more sensitive to the rewarding effects of the drug, since mice spent significantly more time in the drug-paired compartment than 0M subjects. In a hot-plate test, 2M subjects showed levels of drug-induced analgesia that were much higher than other IUP groups. No reliable differences were observed between the IUP groups for locomotor activity upon drug treatment. Overall, these data indicate for the first time that the organisation of the mu-opioid receptor system in the brain, as well as a differential vulnerability to abuse of opiate drugs can be modulated by epigenetic variables such as the prenatal in utero contiguity to male foetuses.