Suppression of acute herpetic pain-related responses by the kappa-opioid receptor agonist (-)-17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-beta-[n-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) in mice

Abstract

(-)-17-Cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6beta-[N-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) is a kappa-opioid receptor agonist that has pharmacological characteristics different from typical kappa-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 kappa-opioid receptor agonist enadoline and the mu-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 kappa-opioid receptor antagonist, but not by naltrexone, a mu-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 kappa-opioid receptors in the spinal and supraspinal levels. TRK-820 may have clinical efficacy in acute herpetic pain with enough safety margins.