title: The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain.
abstract: We examined the analgesic effect of the selective kappa opioid receptor agonist SA14867 and the balance of its antinociceptive and sedative effects. The ED(50) values of SA14867 after oral administration for acetic acid-induced writhing, first and second phases of the formalin test, and rotarod test in mice were 6.1, 9.3, 2.7, and 19.5mg/kg, respectively. These values were smaller than those of the conventional kappa receptor agonists asimadoline and U-50488H. However, the balance of the antinociceptive and sedative effects of SA14867 was better than those of the other two drugs. Orally administered SA14867 (0.1-1mg/kg) significantly improved the decreased pain threshold in a specific alternation of rhythm in an environmental temperature (SART)-stressed model by prophylactic and therapeutic treatment. Improvement in the decreased pain threshold of SA14867-treated animals was attenuated by the opioid receptor antagonist naloxone. Furthermore, orally administered asimadoline (10-100mg/kg) improved the decreased pain threshold in a SART-stressed model, but the doses were close to those known to induce sedative effects. In addition, SA14867 (0.1-1mg/kg) significantly inhibited the arthritis-induced decrease in the pain threshold. Subcutaneously administered morphine (0.1-1mg/kg) improved the decreased pain threshold in a SART-stressed model; on the contrary, morphine did not inhibit the arthritis-induced decrease in the pain threshold. Moreover, orally administered SA14867 (0.1-1mg/kg) strongly attenuated mechanical allodynia and thermal hyperalgesia in a sciatic nerve ligation model. These results suggest that SA14867 has analgesic effects on chronic pain and may serve as a new therapeutic agent for pain treatment.
authors.affiliation: Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan.
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Tsukahara-Ohsumi
authors.forename: Fumio
authors.initials: F
authors.lastname: Tsuji
authors.forename: Masashi
authors.initials: M
authors.lastname: Niwa
authors.forename: Taeko
authors.initials: T
authors.lastname: Hata
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Minoru
authors.initials: M
authors.lastname: Sasano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aono
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D059787:Acute Pain / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001168:Arthritis / Q000150:complications; D059350:Chronic Pain / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008026:Ligation; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors; D012584:Sciatic Nerve / Q000187:drug effects / Q000601:surgery; D013312:Stress, Physiological / Q000187:drug effects; D013644:Tartrates / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use; D013696:Temperature; D013844:Thiazoles / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C556960:3-acetyl-6-chloro-2-(2-(3-(N-(2-ethoxyethyl)-N-isopropylamino)propoxy)-5-methoxyphenyl)benzothiazoline O,O'-diacetyl-L-tartrate; D000081:Acetamides; D000700:Analgesics; D006993:Hypnotics and Sedatives; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D013644:Tartrates; D013844:Thiazoles; D009020:Morphine; C092095:asimadoline