LAUSR

ABSTRACT Hydrogen therapy is a new medical approach for a wide range of diseases. The effects of hydrogen on central nervous system‐related diseases have recently become increasingly appreciated, but little is known about whether hydrogen affects the morphine withdrawal process. This study aims to investigate the potential effects of hydrogen‐rich saline (HRS) administration on naloxone‐precipitated withdrawal symptoms and morphine withdrawal‐induced anxiety‐like behaviors. Mice received gradually increasing doses (25–100 mg/kg, i.p.) of morphine over 3 days. In the naloxone‐precipitated withdrawal procedure, the mice were treated with three HRS (20 &mgr;g/kg, i.p.) injections, and naloxone (1 mg/kg, i.p.) was given 30 min after HRS administration. Body weight, jumping behavior and wet‐dog shakes were immediately assessed. In the spontaneous withdrawal procedure, the mice were treated with HRS (20 &mgr;g/kg, i.p.) every 8‐h. Mice underwent naloxone‐precipitated or spontaneous withdrawal were tested for anxiety‐like behaviors in the elevated plus‐maze (EPM) and light/dark box (L/D box) paradigm, respectively. In addition, the levels of plasma corticosterone were measured. We found that HRS administration significantly reduced body weight loss, jumping behavior and wet‐dog shakes in mice underwent naloxone‐precipitated withdrawal, and attenuated anxiety‐like behaviors in the EPM and L/D box tests after naloxone‐precipitated withdrawal or a 2‐day spontaneous withdrawal period. Hypo‐activity or motor impairment after HRS administration was not observed in the locomotion tests. Furthermore, HRS administration significantly decreased the levels of corticosterone in morphine‐withdrawn mice. These are the first findings to indicate that hydrogen might ameliorate withdrawal symptoms and exert an anxiolytic‐like effect in morphine‐withdrawal mice. HIGHLIGHTSHRS alleviated naloxone‐precipitated withdrawal symptoms in morphine‐treated mice.HRS exerted an anxiolytic‐like effect in morphine‐withdrawn mice.HRS attenuated morphine withdrawal‐induced HPA axis hyper‐activation.