Effects of kappa-agonist on the antinociception and locomotor enhancing action induced by morphine in mice.
The antinociception of intracerebroventricular injection (i.c.v.) of morphine was markedly abolished by pretreatment with naloxonazine (micro 1-antagonist), s.c.; beta-funaltrexamine (micro 1/micro 2-antagonist), i.c.v.; DSP-4 (noradrenaline neurotoxin), s.c.; or p-chlorophenylalanine (serotonin synthesis inhibitor), s.c. in the mouse 55 degrees C hot-plate assay. Pretreatment with nor-binaltorphimine (kappa-antagonist), i.c.v. or PCPA, s.c. drastically blocked the kappa-agonist U-50,488H-induced supraspinal antinociception. These findings indicate either noradrenergic or serotonergic involvement in the mediation of the antinociceptio of i.c.v.-morphine through mu-receptors. On the contrary, the antinociception of i.c.v.- U-50,488H through kappa-receptors appears to depend on the serotonergic but not noradrenergic systems. The antinociceptive interaction between the i.c.v.-morphine and -U-50,488H was an additive effect. On the other hand, i.c.v.-morphine dose-dependently increased the locomotion in mice, and this hyperlocomotion of morphine was drastically blocked by pretreatment with either beta-funaltrexamine, i.c.v. or 6-hydroxydopamine (dopamine depletor), i.c.v. I.c.v.-U-50,488H dose-dependently reduced the increasing locomotion of i.c.v.-morphine, but not that of s.c.-apomorphine (dopamine receptor agonist), and this effect of U-50,488H was completely reversed by pretreatment with nor-binaltorphimine, i.c.v. These results suggest that coadministration of kappa-agonists can suppress the dopamine-related hyperlocomotion of mu-agonists without decreasing the anti-nociception of mu-agonists in mice.
Narita
M
M
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Takahashi
Y
Y
Takamori
K
K
Funada
M
M
Suzuki
T
T
Misawa
M
M
Nagase
H
H
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists; D009294:Narcotics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000187:drug effects; D013566:Sympathomimetics / Q000494:pharmacology
D000700:Analgesics; D001596:Benzylamines; D009292:Narcotic Antagonists; D009294:Narcotics; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013566:Sympathomimetics; C051844:norbinaltorphimine; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C024524:beta-funaltrexamine; D009020:Morphine; C012102:DSP 4; D004298:Dopamine