Differential blockade of morphine and morphine-6 beta-glucuronide analgesia by antisense oligodeoxynucleotides directed against MOR-1 and G-protein alpha subunits in rats.
An antisense oligodeoxynucleotide directed against the 5'-untranslated region of MOR-1 blocks the analgesic actions of the mu 1 analgesics morphine and [D-Ala2,D-Leu5]enkephalin (DADL) when they are microinjected into the periaqueductal gray. In contrast, morphine-6 beta-glucuronide (M6G) analgesia is unaffected by this treatment. Antisense oligodeoxynucleotides directed against distinct Gi alpha subunits also distinguish between morphine and M6G analgesia. A probe targeting Gi alpha 2 blocks morphine analgesia, as previously reported, but is inactive against M6G analgesia. Conversely, an antisense oligodeoxynucleotide against Gi alpha 1 inhibits M6G analgesia without affecting morphine analgesia. The antisense oligodeoxynucleotide directed against G(o)alpha is ineffective against both compounds. These results confirm the prior association of Gi alpha 2 with morphine analgesia and strongly suggests that M6G acts through a different opioid receptor, as revealed by its insensitivity towards the MOR-1 antisense probe and differential sensitivity towards G-protein alpha subunit antisense oligodeoxynucleotides.
Rossi
G C
GC
George Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Standifer
K M
KM
Pasternak
G W
GW
D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D008297:Male; D008845:Microinjections; D008969:Molecular Sequence Data; D009020:Morphine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009022:Morphine Derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000235:genetics*
D000700:Analgesics; D000701:Analgesics, Opioid; D004745:Enkephalins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D016376:Oligonucleotides, Antisense; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D016308:Enkephalin, Leucine-2-Alanine; C035349:morphine-6-glucuronide; D009020:Morphine; D019204:GTP-Binding Proteins