Kappa Opioid-Oxytocin Interactions During Long-Term Partner Separation: Insights from PET Imaging in Titi Monkeys (Plecturocebus cupreus)

Authors

Paulus, J. P., Manca, C., D Almeida, A., Caceres, A., Sosnowski, M. J., Hobson, B. A., Chaudhari, A. J., Bales, K. L.

Abstract

Social bonds are fundamental to health and well-being, and their disruption through partner separation is associated with significant physiological and psychological consequences. The kappa opioid receptor (KOR) system has been proposed as a key modulator of oxytocin (OT) release during partner separation, with prolonged separation hypothesized to trigger KOR downregulation in the paraventricular nucleus of the hypothalamus that disinhibits OT release over time (Bales & Rogers, 2022), yet this model has not previously been tested with in vivo neuroimaging in a primate. The present study used positron emission tomography (PET) with the KOR-selective radiotracer [11C]GR103545 to examine KOR availability across brain regions implicated in social bonding and separation distress in 16 pair-bonded titi monkeys using a within-subject two-week separation paradigm. Plasma OT, cerebrospinal fluid OT, and plasma cortisol were collected at each scan as complementary indices of peripheral and central OT signaling and physiological stress. We hypothesized that long-term separation would downregulate KORs in the hypothalamus and pituitary, indexed by reduced non-displaceable binding potential (BPND), consistent with the Bales and Rogers model, and increase plasma OT consistent with KOR downregulation disinhibiting OT release. Partner separation significantly elevated plasma cortisol in both sexes, confirming the physiological stress of the manipulation. A significant Condition x Sex interaction was observed for plasma OT, reflecting a crossover pattern in which males, who had significantly higher plasma OT than females at baseline, showed a significant decrease during separation while females showed a non-significant increase, though the sex difference during separation did not reach significance. KOR availability was significantly reduced in the nucleus accumbens during separation, with a non-significant trend toward reduction in the anterior cingulate cortex, while no significant condition effects were observed in the remaining a priori regions. No significant sex effects or Condition x Sex interactions were observed in any a priori PET region. Together, these findings provide the first in vivo neuroimaging evidence of KOR system engagement during partner separation in a pair-bonded primate species, and reveal a sex-dependent OT response to separation that extends and adds nuance to the Bales and Rogers (2022) framework.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Aug 2026.

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