Beta-endorphin (beta-EP) is generally classified as a mu and delta opioid receptor agonist but is also an agonist of the epsilon opioid receptor. Although several selective agonists and antagonists for mu, delta, and kappa opioid receptors are known, selective epsilon receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selective epsilon receptor agonist, 17-(cyclopropylmethyl)-4,5alpha-epoxy-3,6beta-dihydroxy-6,14-endoethenomorphinan-7alpha-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective epsilon receptor antagonist, 17-(cyclopropylmethyl)-4,5alpha-epoxy-6beta,21-epoxymethano-3-hydroxy-6,14-endoe-thenomorphinan-7alpha-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the non-hydrolyzable guanosine 5'-triphosphate analogue, guanosine 5'-(gamma-thio)-triphosphate (GTPgammaS), to the mouse pons/medulla membrane via activation of the epsilon receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, long-lasting, and dose-dependent antinociception in tail-flick and hot-plate tests. This antinociception induced by i.c.v. administered TAN-821 was blocked by i.c.v. pretreatment with the epsilon opioid receptor partial agonist beta-EP (1-27), but not the mu opioid receptor antagonist beta-FNA, the delta opioid receptor antagonist NTI, or the kappa opioid receptor antagonist nor-BNI. On the other hand, i.c.v. injection of TAN-1014 alone produced no antinociception, and i.c.v. pretreatment with TAN-1014 attenuated the antinociception induced by i.c.v beta-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selective epsilon receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of the epsilon opioid receptor.