Sigma receptors modulate nicotinic receptor function in adrenal chromaffin cells

Neither the physiological function of sigma (σ) receptors nor the cellular mechanism responsible for the pharmacological effects of σ receptor ligands is known. We now report that σ receptor ligands noncompetitively inhibit nicotine-stimulated catecholamine release from bovine adrenal chromaffin cells in a concentration-dependent and reversible manner. The rank order of potency of ligands to inhibit nicotine-stimulated catecholamine release is significantly correlated (P < 0.005) with that observed in radioligand binding assays selective for the σ₁ receptor subtype. This naltrexone-insensitive effect is paralleled by an inhibition of nicotine-stimulated increases in [Ca²⁺J_i. Sigma ligands were without effect on catecholamine release or [Ca²⁺]_i in the absence of nicotine. In addition, nicotine accelerated the association of the σ receptor selective radioligand, [³H](+)pentazocine, to adrenal medullary homogenates while having no effect on the rate of ligand dissociation, consistent with a σ ligand binding site closely associated with and allosterically modulated by the nicotinic acetylcholine receptor. Thus, the actions of agonists at the nicotinic acetylcholine receptor in bovine chromaffin cells are modulated by σ₁ receptor selective ligands.