Inhibition of morphine tolerance and dependence by LY274614, a competitive NMDA receptor antagonist / 中华麻醉学杂志

ABSTRACT

Objective To investigate the effect of competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY274614 [(?)-6-phosphonomethyl-decahydroisoquinolin-3-carboxylic acid] on the development of morphine tolerance and dependence.Methods Male Spraque-Dawley rats were rendered tolerant and dependent by subcutaneous injection of morphine(15mg/kg body weight) three times a day for 10 consecutive days. LY274614 (2, 4, 6 mg/kg body weight) was also given subcutaneously by subcutaneous injection. Antinociception was measured by tail-flick (TF) test. Tail was exposed to the heat source(a beam of high intensity light). The time from the beginning of exposure to removal of tail from the path of the heat source was taken as latency. The baseline TF latency without medication was 4-5 seconds. A ten-second maximum exposure to the heat source was used to minimize damage to tissue during the multiple measurements. Morphine prolonged TF latency. With the development of tolerance TF latency gradually returned to baseline value. Physical dependence on morphine was assessed by abstinence syndrome precipitated by subcutaneous injecting naloxone 10 mg/kg on the tenth day. According to method of Blasig, the number of jumping/30min after naloxone injection was recorded as an index pf abstinence syndrome. Rats were randomly divided into 8 groups (n=6-8). Each group received morphine 15 mg/kg or normal saline (NS) 1.5 ml/kg+LY274614 (2.0,4.0,6.0 mg/kg) or NS, group 1 morphine+NS; group 2 NS+NS; group 3morphine+LY274614 (2mg/kg); group 4 NS+LY274614 (2mg/kg); group 5 morphine+LY274614 (4mg/kg); group 6 NS+LY274614 (4mg/kg); group 7 morphine+LY274614 (6mg/kg); group 4 NS+LY274614 (6mg/kg).Results LY274614 itself did not have analgesic action, but if used with morphine, it did inhibit the development of tolerance. In group 5 and 7 the decrease in TF latency was more gradual than that in morphine+saline group. 4 and 6 mg/kg LY274614 reduced the number of jumping/30min following naloxone injection.Conclusions LY274614 can inhibit morphine tolerance and dependence rendered by consecutive subcutaneous morphine injection.