Morphine reduces spinal c-fos expression dose-dependently during experimental laparotomy in pigs: A combined pharmacokinetic and surgical study

The pharmacokinetics of intravenous morphine 2.5 mg/kg (n = 4) and 10 mg/kg (n = 4) in plasma and cerebrospinal fluid (CSF) of pigs was studied. Plasma half-life was 1.0 ± 0.1 h and the main metabolite was morphine-3-glucuronide, whereas morphine-6-glucuronide was negligible. CSF morphine concentration peaked after 20–30 min (2.5 mg/kg) and 60–120 min (10 mg/kg), and elimination half-life was 3.5 ± 0.3 h. Subsequently, the effect of morphine on surgery-induced spinal nociception in pigs subjected to unilateral laparotomy was evaluated by stereological quantification of the total number of Fos-like-immunoreactive (Fos-LI) spinal neurons of the dorsal horn. Surgery (n = 4) induced 91,680 ± 14,974 Fos-LI neurons ipsilaterally and morphine reduced this number to 45,771 ± 8755 following the 2.5 mg/kg dose (p < 0.01; n = 6) and 14,981 ± 2327 following the 10 mg/kg dose (p < 0.001; n = 6). These results indicate that morphine dose-dependently reduces the number of surgery-induced Fos-LI neurons in the spinal cord. As even a high dose of morphine does not reduce spinal c-fos expression to basal level, it may be appropriate to use other analgesics simultaneously with morphine during surgery.