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From the *Department of Anaesthetics and Intensive Care, Faculty of Medicine, Imperial College; and Magill Department of Anaesthesia, Intensive Care and Pain Management, Chelsea and Westminster Hospital, Chelsea and Westminster Healthcare NHS Trust, London, UK.
Address correspondence and reprint requests to Mervyn Maze, MB ChB, FRCP, FRCA, FMedSci, Sir Ivan Magill Professor of Anaesthetics, Imperial College, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Address e-mail to m.maze{at}ic.ac.uk.
Translational research is now the cornerstone of the medical research ethos with major advances facilitated by the cooperative interaction of bench and bedside workers. Even though the provision of anesthetic care for a surgical intervention is remarkably safe, further advances in the specialty need to build on translational style research that addresses clinical problems in the still risky perioperative period (1). Designing appropriate clinical studies depends on good, robust, and reproducible preclinical data to support the investment in prospective studies large enough to be adequately powered to reveal an effect that can change clinical practice. However, some advances may not be suitable for investigation by prospective, randomized, controlled trials because of their rarity; therefore, even though a condition has serious implications on an individual basis, logistical considerations may prevent prospective study at a population level.
In this issue of Anesthesia & Analgesia there is an excellent example of translational research, Kakinohana et al. (2) have diligently pursued the clinically significant problem of paraplegia that complicates 3%–16% of thoracic and thoracoabdominal aneurysm repair and is associated with a significant increase in mortality and reduction in quality of life (3). By implementing an experimental paradigm in which to delineate the pathogenesis Kakinohana et al. (4) have identified targets for potential therapies. Prompted by a case of paraparesis secondary to a combination of transient spinal cord ischemia and neuraxial morphine after thoracoabdominal aortic aneurysm repair, the authors undertook a series of preclinical studies to elucidate the contributing factors. Earlier, they reported that µ and 
opioid receptor agonists are the offending ligands and proposed that these facilitate the release of the excitatory neurotransmitter, glutamate that triggers excitotoxic cell death via stimulation of N-methyl d-aspartate receptors on inhibitory interneurons in the ventral horn of the spinal cord, thereby causing spastic paraparesis (5).
Opioid-induced neurotoxicity will be difficult to establish in the clinical environment because of significant concerns over withholding opioids in any possible control group; yet, there is accumulating scientific evidence that opioids may induce injury in the nervous and immune systems (6,7) although this view is far from unanimous (8). The toxicity is dose- and time-dependent, and expresses itself as an apoptotic injury after chronic morphine dosing; how transferable these studies are to the critical care environment in which prolonged mechanical ventilation is facilitated by sedative regimens, which include opioids, is not apparent. Acute opioid-induced toxicity, thought to be due to disinhibition of vulnerable areas, occurs predominatly but not exclusively in the limbic system (9,10). Activation of opiate receptors located on 
-aminobutyric acidergic interneurons leads to their quiescence resulting in loss of inhibitory tone (11) with subsequent increase in metabolic rate, epileptiform electroencephalogram activity (12) and excitotoxicity. Therefore, concerns over the effects of high-dose opioid therapy, even for short periods, have been raised.
Of potentially greater significance is opioid enhancement of ischemic injury that Kakinohana et al. have observed, as opioids in the anesthetic regimen may represent a modifiable risk factor in settings where ischemia is an expected occurrence during the course of cardiac, vascular and neurosurgery. Opioid agonists have been shown to exacerbate ischemic brain injury in animal models (13), whereas opioid antagonists have been proposed as a possible treatment for stroke (14) and spinal cord ischemia to prevent toxicity from the endogenous opiates. The original case, referred to by Kakinohana et al., involved a patient with spinal cord ischemia that resolved with naloxone therapy; yet, reversal of the analgesia provided by opioids precludes the routine use of naloxone for neuroprotection in this setting. Therefore, any potential reduction in perioperative opioid use, while maintaining effective analgesia, may be beneficial.
To identify a potential therapy, the group used the 
2 adrenoceptor agonist, dexmedetomidine, based on its putative ability to reduce excitatory neurotransmitter release (15) and provide neuroprotection (16–19). Using both histopathological and functional end-points, Kakinohana et al. (2) demonstrated that dexmedetomidine's neuroprotective effects extend to the prevention of morphine-enhanced ischemic injury in a dose-dependent manner when administered after the injury. The authors did not explore by what mechanism dexmedetomidine transduces its neuroprotective effect, although previous studies in other acute neurological injury paradigms have revealed a dependence on the 2A adrenoceptor (17,19). Dexmedetomidine exerts both antiexcitotoxic and antiapoptotic effects (18), and it is of interest that morphine toxicity has been shown to be prevented by cAMP and protein kinase A inhibition (20), downstream effects of 2A adrenoceptor coupling. Thus, there appears to be considerable scientific basis for their findings.
Yet, the time may not be ripe to exploit Kakinohana et al.'s finding into clinical scenarios. The outcome that was observed was identified at 72 h, and it is not certain that this will result in a long-term benefit. Furthermore, a lack of a sedative control group may confound the interpretation, and thus one cannot conclude confidently that this is a specific effect of 2 adrenoceptor agonists, especially as reductions in -aminobutyric acidergic and glycinergic signaling have been hypothesized to contribute to this injury. We advocate future studies which both probe the mechanism and investigate additional clinical applications. For example, as therapeutic hypothermia has been successfully used in some settings of acute neurological injury (21,22), it will be important to determine the interaction of this intervention with dexmedetomidine.
The 2 adrenoceptor agonists exhibit important sedative, analgesic, and organ-protective properties (18). Because of their opioid-sparing effects, the 2 agonists may reduce opioid-induced side effects, including the reported neurotoxicity and immune dysfunction. Furthermore, their use for analgesia after thoracic surgery has been described with an additional salubrious effect of protecting the kidney (23). The 2 adrenoceptor agonists are also cardioprotective (24) and may prevent postoperative delirium (25), an effect that may be related to either their neuroprotective properties, or possibly because of the qualitative and neurobiological similarity between the sedative state produced by 2 adrenoceptor agonists and nonrapid eye movement sleep (26).
Our specialty has been challenged to halt the "intellectual malaise" surrounding our clinical discipline to successfully compete for research funds (1,27). Because of the data-rich environment in which we practice, we are uniquely positioned to prosecute translational research; in this manner, we can clinically exploit basic discoveries in the anesthesiology-related arena both for the benefit of our patients and to restore the standing of our specialty.
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