Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound.
A novel compound, FR64822(N-(4-pyridylcarbamoyl)amino 1,2,3,6,-tetrahydropyridine), displays antinociceptive activities in a variety of assays with mice and rats. It has a strong antinociceptive activity in the acetic acid writhing test (ED50 = 1.8 mg/kg p.o.), whereas it has little antinociceptive activity in the tail flick test. The antinociceptive profile is similar to that of nefopam but different from that of anti-inflammatory agents. The involvement of monoamines in the mechanism of action of FR64822 was investigated. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive activity of FR64822, when tested against acetic acid writhing. A similar reduction of activity was found in mice pretreated with sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, but not with Sch23390 (0.25 mg/kg), a dopamine D1 receptor antagonist. Pretreatment with p-chlorophenylalanine, yohimbine and naloxone hardly affected the antinociceptive activity of FR64822. These results were compared with those for nefopam and clonidine. It is suggested that FR64822 induces antinociceptive activity through a novel mechanism of action, indirect stimulation of dopamine D2 receptors, which differs from that of nefopam in that no specific neurotransmission could be determined in nefopam analgesia.
Ohkubo
Y
Y
Basic Research Group, Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Ibaraki, Japan.
Nomura
K
K
Yamaguchi
I
I
D000085:Acetates; D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009340:Nefopam / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D010147:Pain Measurement; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012110:Reserpine / Q000494:pharmacology
D000085:Acetates; D000700:Analgesics; D018492:Dopamine Antagonists; D011725:Pyridines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C073992:FR 64822; D009340:Nefopam; D012110:Reserpine; D003000:Clonidine; D019342:Acetic Acid; D004298:Dopamine