The pronociceptive effect of ondansetron in the setting of P-glycoprotein inhibition.
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.
Scott
Jason A
JA
Department of Anesthesiology, Columbia University, New York, New York 10032, USA.
Wood
Margaret
M
Flood
Pamela
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D005260:Female; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000378:metabolism*; D017294:Ondansetron / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D011650:Pulmonary Alveoli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017294:Ondansetron; D007530:Isoflurane