Vol. 300, Issue 3, 1070-1074, March 2002

₁ Receptor Modulation of Opioid Analgesia in the Mouse

Jianfeng Mei and Gavril W. Pasternak

The Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, Program in Neurosciences, Cornell University Graduate School of Medical Sciences, New York, New York

Opioid analgesia is influenced by many factors, including the ₁ receptor system. Current studies show the importance of supraspinal mechanisms in these ₁ actions. Given supraspinally, the ₁ receptor agonist (+)pentazocine diminished systemic µ, , ₁, and ₃ opioid analgesia in CD-1 mice. There was a trend for the  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 ₁ binding sites using an antisense approach potentiated µ, , ₁, and ₃ analgesia in CD-1 mice. Although equally responsive to µ drugs, BALB-c mice are far less sensitive to  analgesics than CD-1 mice. Earlier studies reported that these different responses to  drugs between CD-1 and BALB-c were eliminated by the concurrent administration of haloperidol, a ₁ antagonist. Antisense treatment of BALB-c mice markedly enhanced the response to  drugs, as well as morphine. This enhanced response following antisense treatment was similar to that seen with haloperidol. These observations confirm the importance of ₁ receptors as a modulatory system influencing the analgesic activity of opioid drugs.