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Updated: May 24, 2025
Assessing Changes in Volatile General Anesthetic Sensitivity of Mice after Local or Systemic Pharmacological Intervention
Published on: October 16, 2013
Microtubule-modulating drugs alter sensitivity to isoflurane in mice
Na Li1, Zerong You1,2, Yang Ren2
1MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
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.
Insights
Microtubule-targeting drugs alter sensitivity to isoflurane anesthesia. Some drugs increase sensitivity and shorten emergence, while others decrease sensitivity and prolong induction, impacting anesthetic management.
Area of Science:
- Anesthesiology
- Pharmacology
- Cell Biology
Background:
- Microtubules (MTs) are implicated as targets for inhalational anesthetics.
- Chemotherapy drugs and opioids that target MTs can affect their stability and function.
- The impact of prolonged use of these drugs on anesthetic potency and timing remains unclear.
Purpose of the Study:
- To investigate the effects of prolonged administration of microtubule-targeting drugs on anesthetic sensitivity and timing.
- To determine how drugs like epothilone D, paclitaxel, vinblastine, and morphine influence isoflurane anesthesia induction and emergence.
Main Methods:
- Male CD1 mice received prolonged treatment (>2 weeks) with epothilone D, paclitaxel, vinblastine, or morphine.
- Anesthetic sensitivity was assessed using the loss of righting reflex (LORR) response to isoflurane.
- Anesthesia induction and emergence times were measured after exposure to a fixed concentration of isoflurane (1.2%).
Main Results:
- Epothilone D and vinblastine shifted the LORR response curve leftward, indicating increased sensitivity to isoflurane.
- Morphine caused a rightward shift (decreased sensitivity), while paclitaxel had a marginal rightward shift.
- Morphine prolonged induction time and shortened emergence time, whereas vinblastine reduced induction time and shortened emergence time compared to saline controls.
Conclusions:
- Microtubule-modulating drugs significantly alter both anesthetic sensitivity and the timing of anesthesia induction and emergence.
- These findings suggest a role for microtubules in modulating anesthetic effects, with implications for clinical anesthetic dosing.
- Results in mice may inform perioperative care for cancer patients receiving MT-targeting therapies or opioids.
