Spinal pretreatment with antisense oligodeoxynucleotides against exon-1, -4, or -8 of mu-opioid receptor clone leads to differential loss of spinal endomorphin-1-and endomorphin-2-induced antinociception in the mouse.
Intrathecal (i.t.) pretreatments with antisense oligodeoxynucleotides (AS ODNs) against exon-1, -4, or -8 of mu-opioid receptor clone (MOR-1) to knockdown different variants of MOR-1 on the antinociception induced by endomorphin-1, enomorphin-2, or [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) given i.t. were investigated in male CD-1 mice. The antinociception was measured with the tail-flick test. AS ODNs against exon-1 (5 microg) given i.t. once daily for 3 days attenuated the antinociception induced by endomorphin-1 and endomorphin-2 with the dose-response curves shifted to the right by 4.5- and 5.3-fold, respectively. AS ODNs against exon-4 (5 microg) attenuated the antinociception induced by endomorphin-1 and endomorphin-2 with the dose-response curves shifted to the right by 2.4- and 5.3-fold, respectively. However, AS ODNs against exon-8 (5 microg) attenuated only the antinociception induced by endomorphin-1, but not endomorphin-2 with the dose-response curves shifted to the right by 3.9- and 1.3-fold, respectively. One more day of pretreatment with antisense probes failed to further reduce the antinociception. The antinociception induced by DAMGO was attenuated by i.t. pretreatment with AS ODNs directed against exon-1, and, to a lesser extent, by AS ODNs directed against exon-8. The mismatch AS ODNs against respective exon-1, -4, and -8 failed to exert significant effects. The selective actions of antisense probes directed against different exons of the MOR-1 in attenuating the antinociception induced by endomorphin-1, endomorphin-2, and DAMGO suggest that multiple splice variants of the MOR-1 exist and support the view that different subtypes of mu-opioid receptors are involved in antinociception induced by endomorphin-1, endomorphin-2, and DAMGO.
Wu
Hsiang-En
HE
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Mizoguchi
Hirokazu
H
Terashvili
Maia
M
Leitermann
Randy J
RJ
Hung
Kuei-Chun
KC
Fujimoto
James M
JM
Tseng
Leon F
LF
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000235:genetics; D013116:Spinal Cord / Q000502:physiology*
D000701:Analgesics, Opioid; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C105294:endomorphin 2