Abstract

σ Ligands modulate opioid actions in vivo, with agonists diminishing morphine analgesia and antagonists enhancing the response. Using human BE(2)-C neuroblastoma cells that natively express opioid receptors and human embryonic kidney (HEK) cells transfected with a cloned μ opioid receptor, we now demonstrate a similar modulation of opioid function, as assessed by guanosine 5′-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) binding, by σ₁ receptors. σ Ligands do not compete opioid receptor binding. Administered alone, neither σ agonists nor antagonists significantly stimulated [³⁵S]GTPγS binding. Yet σ receptor selective antagonists, but not agonists, shifted the EC₅₀ of opioid-induced stimulation of [³⁵S]GTPγS binding by 3- to 10-fold to the left. This enhanced potency was seen without a change in the efficacy of the opioid, as assessed by the maximal stimulation of [³⁵S]GTPγS binding. σ₁ Receptors physically associate with μ opioid receptors, as shown by coimmunoprecipitation studies in transfected HEK cells, implying a direct interaction between the proteins. Thus, σ receptors modulate opioid transduction without influencing opioid receptor binding. RNA interference knockdown of σ₁ in BE(2)-C cells also potentiated μ opioid-induced stimulation of [³⁵S]GTPγS binding. These modulatory actions are not limited to μ and δ opioid receptors. In mouse brain membrane preparations, σ₁-selective antagonists also potentiated both opioid receptor and muscarinic acetylcholine receptor-mediated stimulation of [³⁵S]GTPγS binding, suggesting a broader role for σ receptors in modulating G-protein-coupled receptor signaling.