Oxytocin receptor dysfunction during neurodevelopment programs lasting pain hypersensitivity and sex-specific cognitive deficits

Early life stress (ELS), modeled in rodents through neonatal maternal separation (NMS), induces lasting behavioral and molecular alterations including pain hypersensitivity, anxiety-like behaviors, and cognitive deficits. While NMS disrupts the oxytocinergic system, the specific contribution of oxytocin receptor (OTR) dysfunction during critical neurodevelopmental periods remains unclear. Here, we investigated whether neonatal OTR blockade alone could recapitulate key features of the NMS phenotype. Control rats received daily injections of the selective OTR antagonist d(CH2)5-Tyr(Me)-[Orn8]-vasotocin (dOVT) during postnatal days 2-12, matching the NMS period. At adulthood, behavioral assessments revealed that control+dOVT animals exhibited mechanical and cold thermal hypersensitivity similar to NMS rats, though hot thermal sensitivity was unaffected. Anxiety-like behaviors observed in NMS animals were not reproduced by dOVT treatment. Notably, sex-specific spatial memory deficits emerged: male NMS and female control+dOVT rats showed impaired object location recognition, while females and males in their respective opposite groups remained unaffected. Molecular analyses of spinal cord tissue revealed significant downregulation of GAD65, BDNF, and CD11b in control+dOVT animals. Chloride cotransporters NKCC1 and KCC2 exhibited sexual dimorphism with opposite changes in NMS males versus females and different responses to dOVT. These expressions yet converged on an elevated NKCC1/KCC2 ratio in both sexes, indicating compromised chloride homeostasis despite sex-divergent molecular pathways. These findings demonstrate that developmental OTR dysfunction likely contributes to nociceptive and cognitive consequences of ELS, while anxiety-like phenotypes probably involve additional mechanisms. This work highlights OTR as a critical mediator of neurodevelopmental programming and a potential therapeutic target for mitigating ELS-related disorders.