Antagonism of a (+) N-allylnormetazocine stimulus by (-)PPAP and several structurally related analogs

Abstract

Employing rats trained to discriminate 5 mg/kg of the benzomorphan opioid (+) N-allylnormetazocine [(+)NANM] from vehicle, tests of stimulus generalization and antagonism were conducted to determine the influence of several potential σ-receptor ligands. It has been previously suggested that the (+)NANM stimulus may involve concurrent action at σ- and phencyclidine (PCP) receptors. Although the low-affinity σ-antagonist rimcazole was without stimulus-attenuating effect, three novel σ-ligands-(-)PPAP, CNS 3018, and CNS 3093 (ID 50 doses = 3.2, 6.7, and 4.5 mg/kg, respectively)-antagonized the (+)NANM stimulus in a dose-related fashion. The nonselective serotonergic agent 1-(3-trifluoromethyl)phenylpiperazine (TFMPP) produced partial generalization in (+)NANM-trained animals whereas buspirone, a 5-hydroxytryptamine 1A (5-HT 1A) agonist, attenuated (to 27% drug-appropriate responding) the (+)NANM stimulus. Because the prototypic 5-HT 1A agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) failed to attenuate the (+)NANM stimulus at pharmacologically relevant doses, it seems unlikely that the (+)NANM stimulus involves a 5-HT 1A mechanism. TFMPP and buspirone display modest affinity for σ-receptors and this may account for the present findings with these agents. The present results neither establish a role for σ involvement in the stimulus properties of (+)NANM nor eliminate a role for PCP receptors. They do, however, demonstrate that σ-ligands with little to no affinity for PCP receptors are capable of antagonizing the (+)NANM stimulus.