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 (PAG) including the dorsal raphé, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrations in all areas showed similar time courses: morphine was detected in the first dialysate sample (13-15 min) and maximal concentrations were reached at 45 min after injection. When in vivo recoveries of morphine from the spinal cord and brain areas were taken into account, no significant differences between morphine concentrations in the various areas were found. The relationship between extracellular morphine concentrations and morphine-induced analgesic behavior was investigated by simultaneously measuring morphine in the dialysate 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 the magnitude of behavioral analgesia assessed by either test. The highest correlation was obtained between extracellular concentrations of morphine in the spinal cord and PAG and behavioral analgesia assessed in the paw-withdrawal test. Our data indicate that, after systemic injection, morphine is evenly distributed throughout the spinal cord and brain including potential anatomical sites of morphine's analgesic action. We estimate that the minimal extracellular morphine concentration in spinal cord that is required to produced a significant increase in nociceptive threshold is approximately 100 pg/25 microl, which corresponds to a tissue concentration of about 100 mg/g of morphine.