Numerous studies demonstrate the promise of ****** peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of ****** peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-********** analogs. ****** receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa ****** receptors (MOR, DOR and KOR), while selectivity for mu ****** receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and ****** receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED₅₀ values ranging from 0.32–0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-****** receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg⁻¹, p.o.) administration. A higher oral dose (30 mg kg⁻¹. p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized ****** peptides synthesized by a Hantzsch-based macrocyclization strategy can retain ****** agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.