Hideo Umeuchi

Antipruritic activity of the κ-opioid receptor agonist, TRK-820

The effects of the κ-opioid receptor agonist, TRK-820, (−)-17-(cyclopropylmethyl)-3, 14β-dihydroxy-4, 5α-epoxy-6β-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride, on the itch sensation were compared with those of histamine H1 receptor antagonists, using the mouse pruritogen-induced scratching model. Peroral administration of TRK-820 reduced the numbers of substance P- or histamine-induced scratches dose dependently. No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments, indicating that the inhibition of scratches was not due to the effect on general behavior. Furthermore, the scratching inhibitory activity of TRK-820 was dose dependently antagonized by the specific κ-opioid receptor antagonist, nor-binaltorphimine, suggesting that the inhibitory activity was mediated via κ-opioid receptors. Histamine H1 receptor antagonists, chlorpheniramine and ketotifen, did not inhibit substance P-induced scratches, or did so only partially. Both antihistamines inhibited the histamine-induced scratches completely. These results suggest that TRK-820 has antipruritic activity which is mediated by κ-opioid receptors, and is effective in both antihistamine-sensitive and -resistant pruritus.

In vitro and in vivo pharmacological characterization of the main metabolites of nalfurafine hydrochloride

Pharmacological characterization of the main metabolites of nalfurafine hydrochloride ((E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; a selective κ-opioid receptor agonist and an antipruritic for uremic pruritus in hemodialysis patients in Japan) such as 17-decyclopropylmethylated nalfurafine (de-CPM), 3-glucuronide of nalfurafine (NFA-G) and 3-glucuronide of 17-decyclopropylmethylated nalfurafine (de-CPM-G) was performed in vitro (human opioid receptor radioligand binding assay and forskolin-stimulated cyclic adenosine monophosphate (cAMP) assay) and in vivo (substance P-induced scratching behavior in mice). These main metabolites of nalfurafine showed the low affinities for human κ-, μ- and δ-opioid receptors except for the affinity of de-CPM to κ-opioid receptor (inhibition constant (Ki) values: 5.95nmol/l), which was 24 times lower than that of nalfurafine. Moreover, the main metabolites of nalfurafine had much lower agonistic activities than that of nalfurafine for three opioid receptors in forskolin-stimulated cAMP assays. In the substance P-induced mouse scratching behavior, the subcutaneous administration of each metabolite did not statistically significantly reduce the scratching behavior at doses up to 1000μg/kg which was 100 times higher than the effective dose of nalfurafine. These findings suggest that the main metabolites of nalfurafine do not make any contribution to its pharmacological actions including antipruritic effects in vivo.