Newly Published
Perioperative Medicine  |   December 2019
Reduced Sensitivity to Anesthetic Agents upon Lesioning the Mesopontine Tegmental Anesthesia Area in Rats Depends on Anesthetic Type
Author Notes
  • From the Department of Cell and Developmental Biology, Institute of Life Sciences and the Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem, Israel.
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication December 25, 2018. Accepted for publication November 13, 2019.
    Submitted for publication December 25, 2018. Accepted for publication November 13, 2019.×
  • Correspondence: Address correspondence to Dr. Minert: Department of Cell and Developmental Biology, Institute of Life Sciences 3-516, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel. anne.minert@mail.huji.ac.il. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Pharmacology
Perioperative Medicine   |   December 2019
Reduced Sensitivity to Anesthetic Agents upon Lesioning the Mesopontine Tegmental Anesthesia Area in Rats Depends on Anesthetic Type
Anesthesiology Newly Published on December 13, 2019. doi:https://doi.org/10.1097/ALN.0000000000003087
Anesthesiology Newly Published on December 13, 2019. doi:https://doi.org/10.1097/ALN.0000000000003087
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Lesions of the mesopontine tegmental anesthesia area in the brainstem render rats strongly insensitive to pentobarbital

  • The effects of mesopontine tegmental anesthesia area lesions on responses to other anesthetics have not been previously reported

What This Article Tells Us That Is New:

  • Targeted microinjection of ibotenic acid into the mesopontine tegmental anesthesia area in adult rats led to an up to twofold loss in anesthetic potency of etomidate and propofol

  • In contrast, the potency of ketamine, medetomidine, and alfaxolone/alfadolone was unaffected

  • These observations suggest that the mesopontine tegmental anesthesia area of the brainstem may serve as a key structure to selectively mediate transition from wakefulness into an anesthetic state in response to γ-aminobutyric acid–mediated anesthetics

Background: The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid–mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents.

Methods: Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose–response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16).

Results: As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls).

Conclusions: Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action.