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cis - N -Substituted N -normetazocine enantiomers possess peculiar pharmacological profiles. Indeed, dextro enantiomers bind with high affinity σ 1 receptor while opposite enantiomers bind opioid receptors. In spite of their stereochemistry, cis - N -2-phenylethyl N -normetazocine (phenazocine) enantiomers showed mixed opioid/σ 1 receptor profiles and a significant in vivo analgesia. To the best of our knowledge, there is no information available regarding the evaluation of σ 1 pharmacological profile in the antinociceptive effects of (+) - and (−) - phenazocine. Therefore, the present study was designed to ascertain this component by in vitro and in vivo studies. In particular, we tested the σ 1 affinity of both enantiomers by a predictive binding assay in absence or presence of phenytoin (DPH). Our results showed that DPH (1 mM) did not increase the σ 1 receptor affinity of (+) - and (−) - phenazocine (K i = 3.8 ± 0.4 nM, K i = 85 ± 2.0 nM, respectively) suggesting a σ 1 antagonist profile of both enantiomers. This σ 1 antagonistic component of two phenazocine enantiomers was corroborated by in vivo studies in which the selective σ 1 receptor agonist PRE - 084, was able to unmask their σ 1 antagonistic component associated with the opioid activity. The σ 1 antagonistic component of (+)- and (−) - phenazocine may justify their analgesic activity and it suggests that they may constitute useful lead compounds to develop new ligands with this dual activity. [ABSTRACT FROM AUTHOR]