Itch/
pruritus is the most common side effect associated with spinal administration of
morphine given to humans for
analgesia. The aim of this study was to investigate the effectiveness of
kappa-opioid receptor (KOR) agonists with diverse chemical structures as
antipruritics and to elucidate the receptor mechanism underlying the
antipruritic effect in monkeys. In particular, previously proposed non-KOR-1 agonists, including
nalfurafine [
TRK-820, 17-cyclopropylmethyl-3,14 beta-dihydroxy-4,5 alpha-epoxy-6 beta-[N-methyl-trans-3-(3-furyl)acrylamido]
morphinan],
bremazocine [(+/-)-6-ethyl-1,2,3,4,5,6-hexahydro-3-[(1-hydroxycyclopropy)-methyl]-11,11-dimethyl-2,6-methano-3-benzazocin-8-ol], and
GR 89696 [4-[(3,4-dichlorophenyl)acetyl]-3-(1-pyrrolidinylmethyl)-1-piperazinecarboxylic
acid methyl
ester] were studied in various behavioral assays for measuring itch/scratching,
analgesia, and
respiratory depression. Systemic administration of
nalfurafine (0.1-1 microg/kg),
bremazocine (0.1-1 microg/kg), or
GR 89696 (0.01-0.1 microg/kg) dose-dependently attenuated intrathecal
morphine (0.03 mg)-induced scratching responses without affecting
morphine antinociception. The combination of intrathecal
morphine with these KOR agonists did not cause sedation. In addition, pretreatment with effective antiscratching doses of
nalfurafine,
bremazocine, or
GR 89696 did not antagonize systemic
morphine-induced antinociception and
respiratory depression. The dose-addition analysis revealed that there is no subadditivity for
nalfurafine in combination with
morphine in the antinociceptive effect. Furthermore, the KOR antagonist study revealed that antiscratching effects of both
nalfurafine and a prototypical KOR-1 agonist,
U-50488H [trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide], could be blocked completely by a selective KOR antagonist,
nor-binaltorphimine (3 mg/kg). These findings suggest that the agonist action on KOR mainly contributes to the effectiveness of these atypical KOR agonists as
antipruritics, and there is no evidence for KOR subtypes or mu-
opioid antagonist action underlying the effects of these KOR agonists. This mechanism-based study further supports the clinical potential of KOR agonists as
antipruritics under the context of spinal
opioid analgesia.