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NEUROPHARMACOLOGY

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

Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences (I.T., A. S., H.N., Y.K.) and Department of Virology, Faculty of Medicine (K.S.), Toyama Medical and Pharmaceutical University, Toyama, Japan; and Pharmaceutical Research Laboratories, Toray Industries Inc., Kamakura, Japan (T.S., K.N., M.H., K.O., T.T., H.N.)

(-)-17-Cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride (TRK-820) is a -opioid receptor agonist that has pharmacological characteristics different from typical -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 -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 -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 -opioid receptors in the spinal and supraspinal levels. TRK-820 may have clinical efficacy in acute herpetic pain with enough safety margins.

Address correspondence to: Dr. Yasushi Kuraishi, Department of Applied Pharmacology Faculty of Pharmaceutical Sciences Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: kuraisiy{at}ms.toyama-mpu.ac.jp