Striatal-enriched protein tyrosine phosphatase (STEP) is abundantly expressed in the striatum, which strongly expresses dopamine and opioid receptors and mediates the effects of many drugs of abuse. However, little is known about the role of STEP in opioid receptor function. In the present study, we generated STEP-targeted mice carrying a nonsense mutation (C230X) in the kinase interaction domain of STEP by screening the N-ethyl-N-nitrosourea (ENU)-driven mutant mouse genomic DNA library and subsequent in vitro fertilization. It was confirmed that the C230X nonsense mutation completely abolished functional STEP protein expression in the brain. STEP(C230X−/−) mice showed attenuated acute morphine-induced psychomotor activity and withdrawal symptoms, whereas morphine-induced analgesia, tolerance and reward behaviors were unaffected. STEP(C230X−/−) mice displayed reduced hyperlocomotion in response to intrastriatal injection of the μ-opioid receptor agonist DAMGO, but the behavioral responses to δ- and κ-opioid receptor agonists remained intact. These results suggest that STEP has a key role in the regulation of psychomotor action and physical dependency to morphine. These data suggest that STEP inhibition may be a critical target for the treatment of withdrawal symptoms associated with morphine.
Analgesia* ; Animals ; Brain ; Codon, Nonsense ; Dopamine ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ; Ethylnitrosourea ; Fertilization in Vitro ; Gene Library ; Mass Screening ; Mice ; Morphine* ; Phosphotransferases ; Protein Tyrosine Phosphatases ; Receptors, Opioid ; Reward* ; Street Drugs ; Substance Withdrawal Syndrome*

BACKGROUND: Preventing the need for long-term care (LTC) by identifying physical function risk factors are important to decrease the LTC burden. The objective of this study was to investigate whether grip strength and/or walking speed, which are components of the frailty definition, are associated with LTC in community-dwelling older and oldest people. METHODS: The participants were 1098 community-dwelling older and oldest people who had not received LTC at the baseline. The endpoint was receiving LTC after the baseline survey. The independent variables were grip strength and walking speed, and participants were divided into two groups based on these variables. The confounding factors were age, sex, the Japanese version of the Montreal Cognitive Assessment (MoCA-J), hypertension, diabetes mellitus, stroke, joint diseases, living alone, body mass index, and serum albumin. We calculated the hazard ratio of receiving LTC using the Cox proportional hazard model. RESULTS: Among the 1098 participants, 107 (9.7%) newly received LTC during the follow-up. Regarding the physical function, only slow walking speed was significantly correlated with LTC after adjusting for all confounding factors except the MoCA-J score (HR = 1.74, 95% CI = 1.10-2.75, P = .018). However, slow walking speed was still a risk factor for LTC after adjusting for the MoCA-J score and other confounding factors (HR = 1.64, 95% CI = 1.03-2.60, P = .037). CONCLUSIONS The findings from this study may contribute to a better understanding of slow walking speed as a factor related to LTC, which might be a criterion for disability prevention and could serve as an outcome measure for physical function in older people.
Aged ; Aged, 80 and over ; Exercise ; Female ; Humans ; Independent Living ; statistics & numerical data ; Japan ; Long-Term Care ; statistics & numerical data ; Male ; Proportional Hazards Models