Integrated Investigation of Sex Differences in the Human Nociceptin/Orphanin FQ Receptor System: Postmortem Analyses and In Vivo [11C]NOP-1A Positron Emission Tomography Imaging

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ABSTRACT Background The nociceptin/orphanin FQ (NOP) system modulates pain, stress, and reward, with emerging evidence for sex-dependent biology. Despite NOP’s hypothesized role in psychopathologies with pronounced sex differences, little is known about sex-associated distribution of NOP receptors. Methods To fill this gap, we combined postmortem molecular analyses with in vivo [ 11 C]NOP-1A PET imaging. Western blot analyses examined four NOP receptor isoforms in two postmortem cohorts, and OPRL1 mRNA expression was quantified by qPCR. Guided by these findings, [ 11 C]NOP-1A PET data from 68 healthy adults were analyzed in corticolimbic and striatal regions implicated in affective and stress-related processes. Regional total distribution volume ( V T ) was estimated using Logan analysis and sex effects were assessed using mixed-effects models adjusting for age, body mass index, nicotine use, and race. Results Postmortem analyses highlighted higher 31.8 kDa isoform expression in men in the nucleus accumbens and amygdala, higher 39.9 kDa expression in the entorhinal cortex, and higher 42.6 kDa expression in women in the nucleus accumbens. OPRL1 mRNA expression was also higher in men, most notably in ventromedial prefrontal cortex. In vivo , PET analyses showed a significant main effect of sex, with higher V T in men, across basal ganglia regions and a significant sex-by-region interaction in ventromedial prefrontal cortex. Post hoc model-based contrasts indicated higher [ 11 C]NOP-1A V T in men in putamen, amygdala, and rostral anterior cingulate cortex in adjusted analyses. Conclusions Together, these multimodal findings highlight region-specific sex-related variation in the human NOP system across corticolimbic-striatal circuits and provide a basis for future studies of sex effects in NOP-related neuropsychiatric research.

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