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From the Department of Anesthesiology, Columbia University, New York, New York.
Address correspondence and reprint requests to Pamela Flood, MD, Assistant Professor, Department of Anesthesiology, Columbia University, 630 West 168th Street, New York, NY 10032. Address e-mail to pdf3{at}columbia.edu.
Abstract
Ondansetron 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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