• Jason A Scott, Margaret Wood, and Pamela Flood.
• Department of Anesthesiology, Columbia University, New York, New York 10032, USA.
• Anesth. Analg. 2006 Sep 1; 103 (3): 742-6.

AbstractOndansetron is a potent antiemetic drug that acts through inhibition of the 5HT3 receptors for serotonin. Minimum alveolar concentration (MAC) for isoflurane is not affected by systemic ondansetron; however ondansetron is a substrate of P-glycoprotein, a transport pump expressed in the blood-brain barrier. Thus, we hypothesized that central nervous system concentrations of ondansetron might be reduced by the P-gp protein. As potent inhibitors of P-gp are in clinical trials to improve access of desirable chemotherapeutic and antibiotic drugs to the central nervous system, we studied the effect of ondansetron in the absence of extrusion by P-gp. Normal rats were given lumbar intrathecal ondansetron or vehicle. P-gp knockout mice and wild-type controls were treated with systemic ondansetron in the presence and absence of clinically used P-gp inhibitors. Nociception was assessed as thermal hindpaw withdrawal latency and immobility was assessed as isoflurane MAC. In rats, intrathecal ondansetron (20 g) increased thermal pain sensitivity by 20.0% +/- 5.8% (P < 0.01). Systemic ondansetron (2 mg/kg) increased pain sensitivity in P-gp knockout mice but had no effect in wild-type mice (P < 0.01). Systemic ondansetron had a small but statistically significant pronociceptive effect after treatment of wild-type mice with the P-gp inhibitor quinidine but not with cyclosporine or verapamil. Isoflurane MAC was not changed by intrathecal ondansetron in rats or systemically administered ondansetron in P-gp knockout mice. Intrathecal ondansetron can enhance thermal pain sensitivity. In the absence of P-gp protein, ondansetron can reach concentrations sufficient to increase pain sensitivity. Even with direct spinal application, ondansetron does not alter isoflurane MAC, supporting the idea that 5HT3 modulation does not play a role in general anesthetic immobility.

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