G Protein Inactivation as a Mechanism for Addiction Treatment

The endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norbinaltorphimine (norBNI)-like antagonists, have been suggested to act by causing KOR inactivation through a c-Jun-kinase mechanism rather than by competitive inhibition.

In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produced long-lasting KOR inactivation.

Neither nalfurafine nor nalmefene is a completely selective KOR ligand, but KOR inactivation was observed at doses 10- to 100-fold lower than necessary for mu opioid receptor actions. KOR inactivation is sex dependent, and we show that nalfurafine causes peroxide production only during estrus (low-estrogen state) or after progesterone treatment of female mice. Because KOR inactivation recovers slowly, daily treatment with submaximal drug doses causes accumulating inhibition. Daily microdosing with nalfurafine or nalmefene blocked KORs responsible for antinociceptive effects, blocked KORs mediating stress-induced aversion, mitigated KOR-mediated dysphoria during acute and protracted withdrawal in opioid-dependent mice, and blocked KOR-induced prolactin secretion. In contrast, KORs mediating the diuretic and antipruritic effects were not regulated by JNK (c-Jun N-terminal kinase).

Both nalfurafine and nalmefene have long histories of safety and use in humans and could potentially be repurposed for the treatment of dynorphin-mediated stress disorders.