Multiplicative interaction between intrathecally and intracerebroventricularly administered mu opioid agonists but limited interactions between delta and kappa agonists for antinociception in mice.
Simultaneous action of morphine on supraspinal and spinal sites produces a multiplicative interaction for antinociception which may be important for the analgesia produced by systemically administered morphine. The purpose of this study was to see whether other agonists with more receptor selective opioid actions than morphine would also produce this multiplicative interaction. DAMPGO (Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5), DPDPE (D-Pen2, D-Pen5, enkephalin) and U50-488H, opioid agonists highly selective for mu, delta and kappa receptors, respectively, were administered alone i.c.v. or intrathecally (i.t.) or in combination (i.c.v. plus i.t.) to determine ED50 values for the tail-flick response in mice. These ED50 values were examined isobolographically in relation to the theoretical additive ED50 values by the potency ratio method. First, DAMPGO given i.cv and i.t. was similar to morphine, indicating that simultaneous supraspinal and spinal mu agonist administration produce the multiplicative interaction. Second, concurrent administration of DPDPE or U50,488H, i.c.v. and i.t., as well as cross-over combinations of DPDPE at one and U50,488H at the other site, produced additive interactions only. The multiplicative interaction was a property characteristic of mu but not delta and kappa agonists. Based on the similarity between morphine and DAMPGO, it was postulated that both mu agonists act on redundant descending pain inhibitory pathways to produce multiplication. A second mechanism for multiplicative interaction was based on the difference between DAMPGO and morphine.(ABSTRACT TRUNCATED AT 250 WORDS)
Roerig
S C
SC
Research Service, Veterans Administration Medical Center, Milwaukee, Wisconsin.
Fujimoto
J M
JM
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects*
D000701:Analgesics, Opioid; D004745:Enkephalins; D011759:Pyrrolidines; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-