Potent σ₁-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine modulates basal and N-methyl-D-aspartate-evoked nitric oxide production in vivo

Background and Purpose - σ-Receptor ligands ameliorate ischemic neuronal injury and modulate neuronal responses to N-methyl-D-aspartate (NMDA) receptor stimulation. Because NMDA-evoked synthesis of nitric oxide (NO) may play an important role in excitotoxic-mediated injury, we tested the hypothesis that σ-receptor ligands attenuate basal and NMDA-evoked NO production in the striatum in vivo. Methods - Microdialysis probes were placed bilaterally into the striatum of halothane-anesthetized adult Wistar rats. Rats were divided into 7 treatment groups and perfused with artificial cerebrospinal fluid (aCSF) containing 3 μmol/L [¹⁴C]L-arginine for 2 to 3 hours followed by NMDA in various combinations with the following drugs: L- nitroarginine (L-NNA); the σ₁-receptor ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP); the selective σ₁-receptor antagonist 1- (cyclopropylmethyl)-4-(2'-oxoethyl) piperidine hydrobromide (DuP 734); and the noncompetitive NMDA receptor blocker MK-801 in aCSF. Right-left differences between [¹⁴C]L-citrulline in the effluent from rats treated with different drug combinations were assumed to reflect differences in NO production. Results - After a 3-hour loading period with [¹⁴C]L-arginine, addition of 1 mmol/L NMDA increased [¹⁴C]L-citrulline recovery compared with aCSF alone. This NMDA-evoked increase was inhibited by 1 mmol/L of L- NNA and PPBP. Perfusion of 1 mmol/L of the σ₁-receptor antagonist DuP 734 with 1 mmol/L PPBP augmented NMDA-evoked [¹⁴C]L-citrulline recovery compared with perfusion with PPBP and NMDA. MK-801 attenuated the basal as well as NMDA-evoked [¹⁴C]L-citrulline recovery. PPBP did not cause any further attenuation in the basal and NMDA-evoked [¹⁴C]L-citrulline recovery in the presence of MK-801. Conclusions - These data indicate that a σ₁- receptor ligand attenuates basal as well as NMDA-evoked NO production: Because the attenuated NO production was reversed by DuP 734, PPBP appears to act as an agonist at the σ₁-receptor. Attenuated NO production by σ₁- receptor agonists provides one possible mechanism for focal ischemic neuroprotection.