Microtubule-modulating drugs alter sensitivity to isoflurane in mice.

Background: Microtubules (MTs) have been postulated as one of the molecular targets underlying loss of consciousness induced by inhalational anesthetics. Microtubule-targeting chemotherapy drugs and opioids affect MT stability and function. However, the impact of prolonged administration of these drugs on anesthetic potency and anesthesia induction and emergence times remain unelucidated.

Methods: Epothilone D, paclitaxel, vinblastine or opioid morphine were administered alone for a prolonged period (> 2 weeks) to male CD1 mice and their sensitivity to incremental concentrations of isoflurane were examined using loss of righting reflex (LORR) response as a measure of sensivity. The induction and emergence time after administration and termination of fixed concentration of isoflurance (1.2%) were also assessed.

Results: Compared with saline treatment, epothilone D and vinblastine induced a leftward (more sensitive) shift of LORR response curves (95% confidence intervals for EC50: epothilone D, 0.75[0.73, 0.77] vs. saline, 0.97[0.96, 0.98]; vinblastine, 0.74[0.73, 0.75] vs. saline, 0.98[0.97, 0.99]). In contrast, morphine caused a rightward (more resistant) LORR response curve (morphine, 1.16[1.15, 1.17] vs. saline, 0.97[0.96, 0.98]), while paclitaxel produced a marginal but significant rightward shift of LORR (paclitaxel, 1.05[1.03, 1.06] vs. saline, 0.98[0.97, 0.99]). At concentration of 1.2% isoflurane, morphine treatment prolonged (275 ± 50) and vinblastine treatment reduced (96.5 ± 26) the anesthetic induction latency (in second) relative to saline treatment (211 ± 39). The latency of emergence from anesthesia was shorter in morphine (58 ± 20) and vinblastine-treated (98 ± 43) mice compared to saline (176 ± 50) treatment. The induction or emergence latencies of epothilone D or paclitaxel treatment did not differ from saline treatment between groups.

Conclusions: Microtubule-modulating drugs can affect not only sensitivity but also induction and emergence times to inhalational anesthetic isoflurane in mice. This study highlights a possible role of MTDs in modulating anesthetic effects in disparate directions, which has implications for anesthetic concentrations that should be used for induction, maintenance and emergence of anesthesia. These findings in rodents may have relevance to the perioperative care of cancer patients who receive MT-targeting chemotherapy drugs or even opioids for pain for prolonged periods.