Takashi Endoh1,*, Atsushi Tajima1, Naoki Izumimoto1,
Tomohiko Suzuki1, Akiyoshi Saitoh1, Tsutomu Suzuki2,
Minoru Narita2,4, Junzo Kamei3, Leon F. Tseng4,
Hirokazu Mizoguchi4 and Hiroshi Nagase1
1Pharmaceutical Laboratories, Toray Industries Inc., 1111
Tebiro, Kamakura, Kanagawa 248-8555, Japan
2Department of Toxicology and 3Department of Pathophysiology
and Therapeutics, Faculty of Pharmaceutical Science, Hoshi University, 2-4-41
Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
4Department of Anesthesiology, Medical College of Wisconsin,
Milwaukee, WI 53226, USA
*Corresponding author. Present address for correspondence: Toxicology Laboratory,
Pharmaceutical Laboratories, Toray Industries Inc., 3-1-2 Sonoyama, Otsu,
Shiga 520-0842, Japan
FAX: +81-77-533-8692, E-mail: takashi_endo@nts.toray.co.jp
Abstract: TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan
hydrochloride) has been shown to be a potent opioid k-receptor
agonist with pharmacological properties different from those produced by
k1-opioid receptor agonists in rodents.
To ascertain whether or not these properties of TRK-820 would be extended
to primates, the antinociceptive effect of TRK-820 was evaluated in cynomolgus
monkeys by the hot-water tail-withdrawal procedure. TRK-820 given intramuscularly
(i.m.) produced a potent antinociceptive effect that was 295- and 495-fold
more potent than morphine with the 50｡C and 55｡C hot-water tests, respectively,
and 40-fold more potent than U-50,488H and 1,000-fold more potent than pentazocine
in the 50｡C hot-water test. The duration of antinociceptive effects of TRK-820
treatment (0.01 and 0.03 mg/kg, i.m.) lasted more than 6 h, which was much
longer than those of U-50,488H. The antinociception produced by the higher
dose (0.03 mg/kg, i.m.) of TRK-820 was not inhibited by nor-binaltorphimine
(3.2 and 10 mg/kg, s.c.) or by naloxone (0.1 mg/kg, s.c.), although the
antinociception induced by a lower dose of TRK-820 (0.01 mg/kg, i.m.) was
inhibited by nor-binaltorphimine (10 mg/kg, s.c.). The same doses of nor-binaltorphimine
and naloxone effectively inhibited the antinociception induced by the higher
doses of U-50,488H (1.0 mg/kg, i.m.) and morphine (10 mg/kg, i.m.), respectively.
These results indicate that the antinociception induced by TRK-820 is less
sensitive to nor-binaltorphimine and suggest that it is mediated by the
stimulation of a subtype of k-opioid receptor different
from the k1-opioid receptor in cynomolgus
monkeys.
Keywords: k-Opioid agonist, Antinociceptive
effect, TRK-820, Cynomolgus monkey, k-Opioid receptor
subtype
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