Differential blockade of opioid analgesia by antisense oligodeoxynucleotides directed against various G protein alpha subunits.
Antisense oligodeoxynucleotides directed against various G protein alpha subunits differentially block the analgesic actions of mu-, delta-, and kappa-opioid agonists in mice. Intracerebroventricular administration of oligodeoxynucleotides targeting Gi alpha 2, G(o) alpha, and Gs alpha block supraspinal mu-opioid analgesia, whereas Gi alpha 2 and Gx/z alpha antisense probes block spinal mu analgesia. Although supraspinal and spinal morphine-6 beta-glucuronide (M6G) analgesia also is sensitive to these antisense treatments, its sensitivity profile differs from that of morphine, implying the existence of a different analgesic system. Gi alpha 1 and Gx/z alpha antisense probes block supraspinal M6G analgesia, whereas Gi alpha 1, Gi alpha 3, G(o) alpha, and Gx/z alpha antisense probes block spinal M6G analgesia. Spinal delta-opioid analgesia is blocked by antisense probes to all of the G protein alpha subunits tested, whereas kappa 1-opioid analgesia is sensitive to only Gq alpha. The kappa 3 agonist naloxone benzoylhydrazone produces its analgesia through supraspinal mechanisms and is blocked by Gi alpha 1, Gi alpha 3, Gs alpha, Gq alpha, and Gx/z alpha antisense oligodeoxynucleotides. Together, these results support the presence of seven different analgesic systems for these various opioid agonists.
Standifer
K M
KM
Cotzias Laboratory of Neuro-Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Rossi
G C
GC
Pasternak
G W
GW
D000698:Analgesia; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors*; D000818:Animals; D001483:Base Sequence; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000502:physiology
D000701:Analgesics, Opioid; D016376:Oligonucleotides, Antisense; D011957:Receptors, Opioid; D019204:GTP-Binding Proteins