Differential contribution of descending serotonergic and noradrenergic systems to central Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 (DAMGO) and morphine-induced antinociception in mice.
Differences in antinociceptive (inhibition of tail-flick response) action of morphine and Tyr-D-Ala2-Gly-NMePhe4-ol5 (DAMGO) were demonstrated by intracerebroventricular (i.c.v.) administration of these agonists along with intrathecal (i.t.) administration of a variety of antagonists: yohimbine, methysergide, naloxone and nor-binaltorphimine. Intracerebroventricular morphine analgesia was antagonized by either i.t. yohimbine or methysergide, whereas i.c.v. DAMGO analgesia was only antagonized by i.t. methysergide. Thus, for i.c.v. morphine-induced analgesia, descending spinal noradrenergic and serotonergic systems were involved, whereas for DAMGO analgesia, only the serotonergic system was involved. The dose-response curve for i.c.v. morphine reached a plateau at high doses, whereas i.c.v. DAMGO analgesia peaked at 10 ng and then decreased thereafter, producing a bell-shaped dose-response curve. This decrement in analgesic response could be reversed by low doses of i.t. methysergide and i.t. pindolol. It was concluded that activation of serotonin-1 (5-HT1) receptors plays a role in the decrease in analgesia from high doses of DAMGO. Combinations of i.t. morphine with i.t. 5-HT or i.t. clonidine produced additive or greater analgesic responses. Combinations of i.t. DAMGO with i.t. 5-HT or i.t. clonidine produced less than additive interactions. Part of the latter responses appeared to be due to activation of 5-HT1 receptors; blockade of these receptors by pindolol enhanced i.t. DAMGO-induced analgesia. Morphine and DAMGO differ further because i.c.v. morphine activated a descending antianalgesic pathway mediated by spinal dynorphin A(1-17), whereas i.c.v. DAMGO at a high dose did not. Thus, morphine and DAMGO differ in their modes of antinociceptive action as measured by the tail-flick response.
Arts
K S
KS
Research Service, Veterans Administration Medical Center, Milwaukee, Wisconsin.
Holmes
B B
BB
Fujimoto
J M
JM
D000698:Analgesia; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
D004745:Enkephalins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D015016:Yohimbine; D012701:Serotonin; D009020:Morphine; D003000:Clonidine; D008784:Methysergide