In previous studies, early-life fibroblast growth factor-2 (FGF2) administration conferred resilience to developing anxiety-like behavior in vulnerable animals in adulthood. To follow up on this work, we administered FGF2 the day after birth to animals that differ in emotional behavior and further explored its long-term effects on affective behavior and circuitry. Selectively-bred "high responder" rats (bHRs) exhibit low levels of anxiety-like and depression-like behavior, whereas selectively-bred "low responders" (bLRs) display high levels of anxiety-like and depression-like behavior. We found that early-life administration of FGF2 decreased negative affect in bLRs during the early post-natal period, as indexed by 40 kHz ultrasonic vocalizations (USVs) in response to a brief maternal separation on PND11. FGF2 also increased positive affect during the juvenile period, as measured by 50 kHz USVs in response to heterospecific hand play ("tickling") after weaning. In general, we found that bHRs produced more 50 kHz USVs than bLRs. In adulthood, we measured opioid ligand and receptor expression in brain regions implicated in USV production and affect regulation by mRNA in situ hybridization. Within multiple affective brain regions, bHRs had greater expression of the mu opioid receptor than bLRs. FGF2 increased mu opioid expression in bLRs. The bLRs had more kappa and less delta receptor expression than bHRs, and FGF2 increased prodynorphin in bLRs. Our results provide support for further investigations into the role of growth factors and endogenous opioids in the treatment of disorders characterized by altered affect, such as anxiety and depression. Published by Elsevier B.V.