title: Effect of repeated administration of TRK-820, a kappa-opioid receptor agonist, on tolerance to its antinociceptive and sedative actions.
abstract: Repeated administration of micro-opioid receptor agonist, morphine induces tolerance not only to the antinociceptive effect but also to other pharmacological effects, resulting in shortened working duration and decreased efficacy. But less is known about kappa-opioid agonist-induced tolerance. The tolerance-development potency of kappa-opioid receptor agonists with a focus on TRK-820 was characterized. After five administrations of kappa-opioid receptor agonists, TRK-820 (0.1-0.8 mg/kg), U-50,488H (10-80 mg/kg) and ICI-199,441 (0.025-0.2 mg/kg) subcutaneously over 3 days, tolerance to the antinociceptive effects, assessed by an acetic acid-induced abdominal constriction test, developed in a repeated dose-dependent manner. The tolerance-development potency of TRK-820 was the least among these kappa-opioid receptor agonists. Similarly, TRK-820 and U-50,488H induced tolerance to their sedative effects as judged by a wheel-running test in mice. Greater tolerance was developed to the sedative effect than to the antinociceptive effect in both compounds. After repeated administration, the number of kappa-opioid receptors in the mouse brain was reduced by U-50,488H (80 mg/kg) but not by TRK-820 (0.4 mg/kg). There was no change of the affinity by the treatment with both compounds. These results demonstrated that the kappa-opioid receptor agonists developed tolerance both to the antinociceptive and the sedative effects, though the tolerance to the sedative effect developed more readily than tolerance to the antinociceptive effect. The difference in the potency for down-regulating the kappa-opioid receptors in the brain may account for the tolerance-development potency of the compounds.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 1111, Tebiro Kamakura, Kanagawa, 248-8555 Japan. Tomohiko_Suzuki@nts.toray.co.jp
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Naoki
authors.initials: N
authors.lastname: Izumimoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takezawa
authors.forename: Morihiro
authors.initials: M
authors.lastname: Fujimura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Togashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Endoh
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D044482:Benzeneacetamides / Q000378:metabolism / Q000494:pharmacology; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D051379:Mice; D009019:Morphinans / Q000008:administration & dosage / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000502:physiology; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D044482:Benzeneacetamides; D009019:Morphinans; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C058468:ICI 199441; C111212:TRK 820; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine; C045444:U 69593