RELATIONSHIP BETWEEN ANALGESIA AND EXTRACELLULAR MORPHINE IN BRAIN AND SPINAL-CORD IN AWAKE RATS

Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (FAG) including the dorsal raphe, and the late ral hypothalamus were measured by microdialysis in awake rats after in traperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrations in all areas showed similar time courses: mor phine was detected in the first dialysate sample (13-15 min) and maxim al concentrations were reached at 45 min after injection. When in vivo recoveries of morphine from the spinal cord and brain areas were take n into account, no significant differences between morphine concentrat ions in the various areas were found. The relationship between extrace llular morphine concentrations and morphine-induced analgesic behavior was investigated by simultaneously measuring morphine in the dialysat e and its analgesic effect in the paw-withdrawal and tail-flick tests. In all areas sampled, the extracellular concentrations of morphine at different times after i.p. injection, significantly correlated with t he magnitude of behavioral analgesia assessed by either test. The high est correlation was obtained between extracellular concentrations of m orphine in the spinal cord and FAG and behavioral analgesia assessed i n the paw-withdrawal test. Our data indicate that, after systemic inje ction, morphine is evenly distributed throughout the spinal cord and b rain including potential anatomical sites of morphine's analgesic acti on. We estimate that the minimal extracellular morphine concentration in spinal cord that is required to produce a significant increase in n ociceptive threshold is approximately 100 pg/25 mu l, which correspond s to a tissue concentration of about 100 ng/g of morphine.