Suppression of Acute Herpetic Pain-Related Responses by the κ-Opioid Receptor Agonist (-)-17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-trans-3-(3-furyl) Acrylamido] Morphinan Hydrochloride (TRK-820) in Mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 309; no. 1; p. 36
• Main Authors: Ichiro Takasaki, Tomohiko Suzuki, Atsushi Sasaki, Kaoru Nakao, Mikito Hirakata, Kiyoshi Okano, Toshiaki Tanaka, Hiroshi Nagase, Kimiyasu Shiraki, Hiroshi Nojima, Yasushi Kuraishi
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.04.2004
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.059816

(-)-17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[ N -methyl-3- tran s-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) is a κ-opioid receptor agonist that has pharmacological characteristics different from typical κ-opioid receptor agonists. This study was conducted to determine the antiallodynic and antihyperalgesic effects of TRK-820 in a mouse model of acute herpetic pain and to compare them with those of the κ-opioid receptor agonist enadoline and the μ-opioid receptor agonist morphine. Percutaneous inoculation with herpes simplex virus type-1 induced tactile allodynia and mechanical hyperalgesia in the hind paw on the inoculated side. TRK-820 (0.01–0.1 mg/kg p.o.), enadoline (1–10 mg/kg p.o.) and morphine (5–20 mg/kg p.o.) dose dependently inhibited the allodynia and hyperalgesia, but the antiallodynic and antihyperalgesic dose of enadoline markedly decreased spontaneous locomotor activity. The antinociceptive action of TRK-820 (0.1 mg/kg) was completely antagonized by pretreatment with norbinaltorphimine, a κ-opioid receptor antagonist, but not by naltrexone, a μ-opioid receptor antagonist. Repeated treatment with morphine (20 mg/kg, four times) resulted in the reduction of antiallodynic and antihyperalgesic effects, whereas the inhibitory potency of TRK-820 (0.1 mg/kg) was almost the same even after the fourth administration. There was no cross-tolerance in antinociceptive activities between TRK-820 and morphine. Intrathecal and intracerebroventricular, but not intraplantar, injections of TRK-820 (10–100 ng/site) suppressed the allodynia and hyperalgesia. These results suggest that TRK-820 inhibits acute herpetic pain through κ-opioid receptors in the spinal and supraspinal levels. TRK-820 may have clinical efficacy in acute herpetic pain with enough safety margins.