Blockade of U50,488H analgesia by antisense oligodeoxynucleotides to a kappa-opioid receptor.
The recently cloned kappa-opioid receptor has binding characteristics consistent with those of a kappa 1-opioid receptor. Repeated intrathecal administration of an antisense oligodeoxynucleotide against the kappa 1-opioid receptor selectively lowers U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetemide) analgesia (P < 0.02) without affecting mu or delta analgesia. A mismatched antisense oligodeoxynucleotide in which 4 bases had been switched is inactive against U50,488H analgesia. These studies confirm at the molecular level traditional pharmacological studies implying a distinct receptor mechanisms for kappa 1 analgesia and demonstrate the utility of antisense approaches in studies of opioid pharmacology.
Chien
C C
CC
Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Brown
G
G
Pan
Y X
YX
Pasternak
G W
GW
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology; D006168:Guinea Pigs; D007278:Injections, Spinal; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism
D000700:Analgesics; D004745:Enkephalins; D016376:Oligonucleotides, Antisense; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-