title: Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system.
abstract: 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 dopamine(2) (D(2)) receptor has been disrupted. Loss of D(2) receptors enhances, in a dose-dependent manner, the analgesic actions of the mu analgesic morphine, the kappa(1) agonist U50,488H and the kappa(3) analgesic naloxone benzoylhydrazone. The responses to the delta opioid analgesic [d-Pen(2),d-Pen(5)]enkephalin were unaffected in the knock-out animals. Loss of D(2) receptors also potentiated spinal orphanin FQ/nociceptin analgesia. Antisense studies using a probe targeting the D(2) receptor revealed results similar to those observed in the knock-out model. The modulatory actions of D(2) receptors were independent of final sigma receptor systems because the final sigma agonist (+)-pentazocine lowered opioid analgesia in all mice, including the D(2) knock-out group. Thus, dopamine D(2) receptors represent an additional, significant modulatory system that inhibits analgesic responses to mu and kappa opioids.
authors.affiliation: Laboratory of Molecular Neuropharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: King
authors.forename: S
authors.initials: S
authors.lastname: Bradshaw
authors.forename: A H
authors.initials: AH
authors.lastname: Chang
authors.forename: J E
authors.initials: JE
authors.lastname: Pintar
authors.forename: G W
authors.initials: GW
authors.lastname: Pasternak
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D006579:Heterozygote; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010423:Pentazocine / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000172:deficiency* / Q000235:genetics; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists; D017480:Receptors, sigma / Q000819:agonists; D013469:Sulpiride / Q000494:pharmacology; D000097629:Nociceptin
chemical_list: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000701:Analgesics, Opioid; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D020881:Enkephalin, D-Penicillamine (2,5)-; D009020:Morphine; D009270:Naloxone; D016376:Oligonucleotides, Antisense; D018847:Opioid Peptides; D010423:Pentazocine; D017448:Receptors, Dopamine D2; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D013469:Sulpiride; D000097629:Nociceptin; C058380:naloxone benzoylhydrazone