Nalfurafine has been used clinically in Japan for treatment of itch in kidney dialysis patients and in patients with chronic
liver diseases. A one-year post-marketing study showed
nalfurafine to be safe and efficacious without producing side effects of typical KOR agonists such as
anhedonia and psychotomimesis. In this chapter, we summarize in vitro characterization and in vivo preclinical studies on
nalfurafine. In vitro,
nalfurafine is a highly potent and moderately selective KOR full agonist; however, whether it is a biased KOR agonist is a matter of debate. In animals,
nalfurafine produced anti-pruritic effects in a dose range lower than that caused side effects, including conditioned place aversion (CPA), hypolocomotion, motor
incoordination, consistent with the human data. In addition,
nalfurafine showed antinociceptive effects in several
pain models at doses that did not cause the side effects mentioned above. It appears to be effective against inflammatory
pain and mechanical
pain, but less so against thermal
pain, particularly high-intensity thermal
pain.
U50,488H and
nalfurafine differentially modulated several signaling pathways in a brain region-specific manners. Notably,
U50,488H, but not
nalfurafine, activated the mTOR pathway, which contributed to U50,488H-induced CPA. Because of its lack of side effects associated with typical KOR agonists,
nalfurafine has been investigated as a combination
therapy with an MOR
ligand for
pain treatment and for its effects on
opioid use disorder and
alcohol use disorder, and results indicate potential usefulness for these indications. Thus, although in vitro data regarding uniqueness of
nalfurafine in terms of signaling at the KOR are somewhat equivocal, in vivo results support the assertion that
nalfurafine is an atypical KOR agonist with a significantly improved side-effect profile relative to typical KOR agonists.