Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment.

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

Short and Long-Term Changes in Social Odor Recognition and Plasma Cytokine Levels Following Oxygen (16O) Ion Radiation Exposure.

Future long-duration space missions will involve travel outside of the Earth's magnetosphere protection and will result in astronauts being exposed to high energy and charge (HZE) ions and protons. Exposure to this type of radiation can result in damage to the central nervous system and deficits in numerous cognitive domains that can jeopardize mission success. Social processing is a cognitive domain that is important for people living and working in groups, such as astronauts, but it has received little attention in terms of HZE ion exposure. In the current study, we assessed the effects of whole-body oxygen ion (16O; 1000 MeV/n) exposure (1 or 10 cGy) on social odor recognition memory in male Long-Evans rats at one and six months following exposure. Radiation exposure did not affect rats' preferences for a novel social odor experienced during Habituation at either time point. However, rats exposed to 10 cGy displayed short and long-term deficits in 24-h social recognition. In contrast, rats exposed to 1 cGy only displayed long-term deficits in 24-h social recognition. While an age-related decrease in Ki67+ staining (a marker of cell proliferation) was found in the subventricular zone, it was unaffected by radiation exposure. At one month following exposure, plasma KC/GRO (CXCL1) levels were elevated in the 1 cGy rats, but not in the 10 cGy rats, suggesting that peripheral levels of this cytokine could be associated with intact social recognition at earlier time points following radiation exposure. These results have important implications for long-duration missions and demonstrate that behaviors related to social processing could be negatively affected by HZE ion exposure.

Whole-Body Oxygen (16O) Ion-Exposure-Induced Impairments in Social Odor Recognition Memory in Rats are Dose and Time Dependent.

Future long-duration space missions will involve travel outside of the Earth's magnetosphere, which will result in increased radiation exposure for astronauts. Exposure could permanently damage multiple tissues, including the central nervous system (CNS), and result in deleterious effects on cognition and behavior during and beyond the mission. Here, we assessed the effects of whole-body oxygen ion (16O; 1,000 MeV/n) exposure (5 or 25 cGy) on social odor recognition memory in male Long-Evans rats at one and six months after exposure. At one month postirradiation, all rats displayed a preference for a novel 1 (N1) social odor experienced during the habituation phase. When assessed for recognition memory 24 h later, only sham-irradiated rats spent more time exploring a second novel social odor (novel 2, N2), whereas rats irradiated with 5 or 25 cGy 16O ions did not show a preference for the N2 odor compared to the N1 odor experienced 24 h earlier, thus displaying a memory deficit for recall of the social odor encountered 24 h prior. At six months postirradiation, rats exposed to 25 cGy showed persistent deficits in 24 h recognition memory, while the 5 cGy-exposed rats did not. Thus, 24 h recognition memory was apparently recovered at six months postirradiation for the low, but not the higher, dose of 16O ions. Both irradiated groups displayed similar numbers of Ki67+ cells, a marker of cell proliferation, in the subventricular zone. These results further demonstrate that space-relevant 16O ion exposure has deleterious effects on the CNS, which are related to both radiation dose and time after exposure.