Effects of low and high doses of selective sigma ligands: further evidence suggesting the existence of different subtypes of sigma receptors

Abstract

Several high affinity sigma (σ) ligands, such as DTG, JO-1784, (+)-pentazocine, BD-737 and L-687,384, administered at low doses act as agonists by potentiating N-methyl-d-aspartate (NMDA)-induced activation of pyramidal neurons in the CA₃ region of the rat dorsal hippocampus. This potentiation is dose-dependent at doses between 1 and 1000 µg/kg, IV but bell-shaped dose-response curves are obtained. Other σ ligands like haloperidol, BMY-14802, (+)3-PPP and NE-100 administered at low doses act as σ antagonists, since they do not modify the NMDA response but suppress the potentiation of the NMDA response induced by σ agonists. Because high doses of the σ agonists do not potentiate the NMDA response, the present experiments were undertaken to assess if, at high doses, these σ ligands could also act as σ antagonists and suppress the potentiation induced by low doses of a agonists. High doses of DTG, JO-1784, BD-737, and L-687,384, administered acutely, had an effect similar to that of low doses of haloperidol, by suppressing and preventing the potentiation induced by low doses of DTG, JO-1784, BD-737, L-687,384 and (+)-pentazocine. High doses of (+)-pentazocine suppressed the effect of a low dose of (+)-pentazocine but did not affect the potentiation induced by a low dose of the other σ agonists. The potentiation induced by a low dose of a σ ₁ agonist was not further increased by the subsequent administration of another low dose of a σ ₁ agonist. All together, these results strongly suggest that more than two subtypes of σ receptors exist in the CNS.