Caffeine accelerates recovery from general anesthesia via multiple pathways

J Neurophysiol. 2017 Sep 1;118(3):1591-1597. doi: 10.1152/jn.00393.2017. Epub 2017 Jun 28.


Various studies have explored different ways to speed emergence from anesthesia. Previously, we have shown that three drugs that elevate intracellular cAMP (forskolin, theophylline, and caffeine) accelerate emergence from anesthesia in rats. However, our earlier studies left two main questions unanswered. First, were cAMP-elevating drugs effective at all anesthetic concentrations? Second, given that caffeine was the most effective of the drugs tested, why was caffeine more effective than forskolin since both drugs elevate cAMP? In our current study, emergence time from anesthesia was measured in adult rats exposed to 3% isoflurane for 60 min. Caffeine dramatically accelerated emergence from anesthesia, even at the high level of anesthetic employed. Caffeine has multiple actions including blockade of adenosine receptors. We show that the selective A2a adenosine receptor antagonist preladenant or the intracellular cAMP ([cAMP]i)-elevating drug forskolin, accelerated recovery from anesthesia. When preladenant and forskolin were tested together, the effect on anesthesia recovery time was additive indicating that these drugs operate via different pathways. Furthermore, the combination of preladenant and forskolin was about as effective as caffeine suggesting that both A2A receptor blockade and [cAMP]i elevation play a role in caffeine's ability to accelerate emergence from anesthesia. Because anesthesia in rodents is thought to be similar to that in humans, these results suggest that caffeine might allow for rapid and uniform emergence from general anesthesia in humans at all anesthetic concentrations and that both the elevation of [cAMP]i and adenosine receptor blockade play a role in this response.NEW & NOTEWORTHY Currently, there is no method to accelerate emergence from anesthesia. Patients "wake" when they clear the anesthetic from their systems. Previously, we have shown that caffeine can accelerate emergence from anesthesia. In this study, we show that caffeine is effective even at high levels of anesthetic. We also show that caffeine operates by both elevating intracellular cAMP levels and by blocking adenosine receptors. This complicated pharmacology makes caffeine especially effective in accelerating emergence from anesthesia.

Keywords: adenosine receptors; cAMP-elevating drugs; caffeine; emergence from anesthesia; isoflurane.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine A2 Receptor Antagonists / administration & dosage
  • Adenosine A2 Receptor Antagonists / pharmacology*
  • Adenosine A2 Receptor Antagonists / therapeutic use
  • Anesthesia, General / methods*
  • Anesthetics, General / pharmacology
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Caffeine / administration & dosage
  • Caffeine / pharmacology*
  • Caffeine / therapeutic use
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology*
  • Central Nervous System Stimulants / therapeutic use
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Delayed Emergence from Anesthesia / drug therapy
  • Delayed Emergence from Anesthesia / prevention & control*
  • Isoflurane / pharmacology
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Triazoles / pharmacology


  • Adenosine A2 Receptor Antagonists
  • Anesthetics, General
  • Central Nervous System Stimulants
  • Pyrimidines
  • Triazoles
  • Colforsin
  • Caffeine
  • 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine
  • Isoflurane
  • Cyclic AMP