Abstract
(-)-17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-trans-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.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.059816.
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ABBREVIATIONS: HSV-1, herpes simplex virus type-1; DRG, dorsal root ganglion; i.pl., intraplantar; nor-BNI, norbinaltorphimine; TRK-820, (-)-17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-3-trans-3-(3-furyl) acrylamido] morphinan hydrochloride; PCR, polymerase chain reaction; ANOVA, analysis of variance; GR89696, methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; U-50,488H, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide; ICI-199,441, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]-acetamide; ICI 204448, (R,S)-N-[2-(N-methyl-3,4-dichloro-phenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride.
- Received September 9, 2003.
- Accepted November 25, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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