Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278080 (physical dependence)
 1,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The new cognition-enhancing agent nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7) was assessed for dependence liability in rats using the DAF (drug admixed food) method and an intravenous self-administration system. In the physical dependence test, nefiracetam and codeine phosphate were administered to rats mixed with food for 43 days in a gradually increasing dosage schedule, followed by feeding a drug-free normal diet to detect signs of withdrawal. After the withdrawal, rats in the nefiracetam treated groups showed no withdrawal symptoms (e.g. body weight loss) and exhibited greater body weight gains than control. On the other hand, rats in the codeine phosphate treated group showed overt withdrawal symptoms (e. g. soft stool, diarrhea, vocalization) and a significant body weight loss, suggesting development of physical dependence on the drug. It was concluded that nefiracetam did not possess physical dependence liability in rats. In the reinforcement liability test, through an indwelling cannula implanted into the right jugular vein rats were allowed to self-administer nefiracetam, morphine hydrochloride or pentobarbital for 14 days. Saline was administered to negative control animals for the same period. The daily frequency of self-administration increased progressively with time in rats of the morphine hydrochloride and pentobarbital groups. In the nefiracetam groups, it remained comparable to or was even lower than that in the saline control group. When compared with the saline control, the group mean frequency of self-administration showed a tendency to be small for nefiracetam, whereas the morphine hydrochloride and pentobarbital showed greater frequencies.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Drug dependence study of the new cognition-enhancing agent nefiracetam in rats. 801 97

Morphine is the most potent opioid analgesic currently available and its use is increasing for treatment of severe pain, however, long-term morphine exposure induces physical dependence/tolerance. Although the mechanisms underlying this phenomenon have not been established, several biochemical changes including intracellular cAMP systems and Ca2+ mobilization have been suggested. To evaluate the contribution of cAMP, we investigated the effects of nefiracetam [N-(2,6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl)acetamide] and phosphodiesterase inhibitors (theophylline, enprofylline and rolipram) on the development of morphine dependence/tolerance. Mice administered morphine (6 or 10 mg/kg, s.c.) twice daily for 5 days, showed withdrawal signs (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg/kg, i.p.), indicating the physical dependence to morphine. Further, the tolerance to antinociceptive effect of morphine was observed in these mice on the tail-flick test. However, coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, i.p.) with morphine during the pretreatment period, significantly reduced the withdrawal signs, moreover, the tolerance was significantly attenuated. Acute administration of nefiracetam failed to reduce the withdrawal signs and did not affect the antinociceptive effect of morphine in morphine-naive mice. Theophylline (3 or 10 mg/kg, p.o.) tended to attenuate the development of morphine dependence/tolerance. The present findings suggest that coadministration of compounds which increase cAMP level with morphine may be a useful strategy to attenuate the development of morphine dependence/tolerance in the clinic.
 ...
PMID:A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine. 981 8