Abstract

Opioid analgesia is influenced by many factors, including the ς₁ receptor system. Current studies show the importance of supraspinal mechanisms in these ς₁ actions. Given supraspinally, the ς₁ receptor agonist (+)pentazocine diminished systemic μ, δ, κ₁, and κ₃opioid analgesia in CD-1 mice. There was a trend for the κ drugs to be more sensitive to the fixed dose of (+)pentazocine, although the differences did not achieve statistical significance. In contrast to its actions supraspinally, (+)pentazocine was without effect against morphine when both were given spinally. These findings are consistent with a supraspinal site of anti-opioid action of (+)pentazocine. Down-regulating supraspinal ς₁ binding sites using an antisense approach potentiated μ, δ, κ₁, and κ₃ analgesia in CD-1 mice. Although equally responsive to μ drugs, BALB-c mice are far less sensitive to κ analgesics than CD-1 mice. Earlier studies reported that these different responses to κ drugs between CD-1 and BALB-c were eliminated by the concurrent administration of haloperidol, a ς₁ antagonist. Antisense treatment of BALB-c mice markedly enhanced the response to κ drugs, as well as morphine. This enhanced response following antisense treatment was similar to that seen with haloperidol. These observations confirm the importance of ς₁ receptors as a modulatory system influencing the analgesic activity of opioid drugs.