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The Journal of Neuroscience, October 1, 2001, 21(19):7788-7792

Potentiation of Opioid Analgesia in Dopamine₂ Receptor Knock-Out Mice: Evidence for a Tonically Active Anti-Opioid System

Michael A. King¹, Sheri Bradshaw², Albert H. Chang¹, John E. Pintar², and Gavril W. Pasternak¹

¹ Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and ² Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854

Dopamine systems are intimately involved with opioid actions. Pharmacological studies suggest an important modulatory effect of dopamine and its receptors on opioid analgesia. We have now examined these interactions in a knock-out model in which the dopamine₂ (D₂) receptor has been disrupted. Loss of D₂ receptors enhances, in a dose-dependent manner, the analgesic actions of the µ analgesic morphine, the ₁ agonist U50,488H and the ₃ analgesic naloxone benzoylhydrazone. The responses to the  opioid analgesic [D-Pen²,D-Pen⁵]enkephalin were unaffected in the knock-out animals. Loss of D₂ receptors also potentiated spinal orphanin FQ/nociceptin analgesia. Antisense studies using a probe targeting the D₂ receptor revealed results similar to those observed in the knock-out model. The modulatory actions of D₂ receptors were independent of  receptor systems because the  agonist (+)-pentazocine lowered opioid analgesia in all mice, including the D₂ knock-out group. Thus, dopamine D₂ receptors represent an additional, significant modulatory system that inhibits analgesic responses to µ and  opioids.

Key words: analgesia; dopamine; dopamine receptor; D₂ receptor; knock-out; antisense; anti-opioid; nociception; analgesic

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21197788-05$05.00/0

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