sigma(1) Receptors have been implicated in the modulation of opioid analgesia. In the current study, we examined the role of sigma(1) systems in the periaqueductal gray (PAG), the rostroventral medulla (RVM), and the locus coeruleus (LC) of the rat, regions previously shown to be sensitive to morphine. Morphine was a potent analgesic in all three regions. Coadministration of the sigma(1) agonist (+)-pentazocine diminished the analgesic actions of morphine in all three regions, although the PAG was far less sensitive than the other two regions. Blockade of the sigma(1) receptors with haloperidol in the RVM markedly enhanced the analgesic actions of coadministered morphine, implying a tonic activity of the sigma(1) system in this region. This effect was mimicked by down-regulation of RVM sigma(1) receptors using an antisense approach. However, no tonic sigma(1) activity was observed in either the LC or the PAG. The RVM also was important in modulating analgesia elicited from morphine microinjected into the PAG. The analgesic actions of morphine given into the PAG could be attenuated by (+)-pentazocine placed into the RVM, whereas haloperidol in the RVM enhanced PAG morphine analgesia. These studies illustrate the pharmacological importance of sigma(1) receptors in the brainstem modulation of opioid analgesia.