ONE of the most basic defense mechanisms is generation of a vigorous response to a noxious stimulus. This is no more evident than the response to surgical intervention, whereby patients can move violently, and did so all too commonly before the introduction of anesthesia more than 150 yr ago. Therefore, immobility is an essential anesthetic goal, and the achievement of this anesthetic endpoint was used by Eger et al.  1when they developed a standard of anesthetic potency. The minimum alveolar concentration (MAC) is the concentration that prevents gross and purposeful movement in 50% of subjects when a supramaximal noxious stimulus is applied. It would seem obvious that such a stimulus, if applied to an awake animal or human, would evoke an immediate and vigorous response. In this issue of Anesthesiology, Mogil et al.  2report data in mice indicating that tail clamping, although supramaximal in terms of the isoflurane requirement to produce immobility, does not always produce an immediate motor response in the awake animal. What might be the reason for this apparent incongruity?

Mogil et al.  2determined isoflurane MAC in 11 genetically different mouse strains, reporting a significant MAC variation among the strains. They also examined the latency to move purposefully in response to application of the tail clamp in the absence of anesthesia. Surprisingly, they found that application of a 500-g tail clamp in the awake animal often elicited nocifensive behavioral responses only at surprisingly long latencies (range of means, 1–58.4 s), raising the issue of whether the clamp was truly supramaximal. For this reason, they repeated the experiment using a second tail clamp exerting greater force (2 kg). Not unexpectedly, MAC values were higher across strains using the stronger clamp (range, 0.99–1.59%) compared with the 500-g clamp (range, 0.86–1.2%). Furthermore, response latencies to the 2-kg clamp in the absence of anesthesia tended to be shorter for most strains, although they were actually longer in three mouse strains. Moreover, there was a significant negative correlation between MAC and nocifensive response latencies to both tail-clamp stimuli in the absence of anesthesia. These results indicate that baseline nociceptive sensitivity varies across strains and that this might influence anesthetic requirements such that animals exhibiting greater basal nociceptive sensitivity (i.e. , shorter response latencies) have higher MAC values.

What might account for these data? The observation that response latencies were not instantaneous in the absence of anesthesia and that, in some strains, the stronger clamp stimulus was less effective suggested the possibility that the clamp stimulus resulted in stress-induced analgesia. The authors therefore investigated the possibility that the tail clamp elicited an opioid-sensitive form of stress-induced analgesia. They found that in the absence of anesthesia, the opiate antagonist, naloxone, decreased latencies for noxious stimulus-evoked nocifensive responses to both the 500-g and the 2-kg tail-clamp stimuli in all strains. Even in the presence of naloxone, however, the response latencies were not instantaneous, suggesting that additional factors, such as nonopioid stress-induced analgesia, may influence basal nociception. Importantly, the magnitude of naloxone’s antianalgesic effect was negatively correlated with the MAC, i.e. , the more naloxone reduced the latency to respond while the mouse was awake, the lower the MAC was. This suggests that, depending on the genetic makeup, endogenous opiates might play a role in MAC. However, there have been several studies that showed that naloxone does not alter MAC.3–6The data from Mogil et al.  2showing a negative correlation between the extent of stress-induced analgesia and MAC makes us wonder whether this issue has been adequately addressed. Perhaps the aforementioned studies on naloxone and MAC used animals that tended to have low levels of opioid-sensitive stress-induced analgesia, and hence one would not expect naloxone to significantly alter MAC. This prompts us to suggest that a follow-up study be performed wherein the mouse strains studied by Mogil et al.  2be given naloxone followed by MAC determination to address a possible MAC-sparing action of endogenous opioids. Indeed, Dahan et al.  7reported that 129/SV-C57BL/6 mice exhibited a modest increased MAC after naloxone administration.

The mechanism by which stress-induced analgesia occurs is not completely understood, but it likely involves brainstem and spinal cord antinociceptive circuitry that has been intensely investigated during the past four decades.8Electrical stimulation in the midbrain periaqueductal gray was originally reported to prevent nocifensive responses during laparotomy in awake rats.8In humans, stimulation of the periaqueductal gray decreases anesthetic requirements 30%.9If the periaqueductal gray is involved in stress-induced analgesia in humans, it might be expected that stress may influence anesthetic requirements, but this has not been extensively investigated. There is little doubt that humans exhibit stress-induced analgesia, as suggested by reports that more than one third of patients admitted to a hospital for severe injuries did not experience any pain at the time of injury.10Furthermore, humans exhibit diffuse noxious inhibitory controls, whereby acute pain elicited by a noxious stimulus can be reduced by a preceding painful stimulus.11In general, the extent to which stress and anxiety modulate endogenous antinociceptive systems to thereby influence anesthetic requirements has not received much attention and, based on the study of Mogil et al. ,2seems to be a worthwhile topic of further study.

To standardize MAC determination, Eger et al.  1used a supramaximal stimulus. Noxious stimuli were applied to several sites, including the tail, paw, mucous membrane of the mouth, and trachea. Among these, they determined that clamping the tail of an animal seemed to be supramaximal, in that the other stimuli required lesser concentrations of anesthetic to prevent movement. Subsequently, most investigators have used tail clamping, although most parts of the body have been used, including the ears, paws, and dew claws. Likewise, in humans, a variety of stimuli have been applied at various sites. Zbinden et al.  12used electrical stimulation, deep muscle pinching, and intubation. The recurring theme has always been whether the stimulus is “supramaximal.” A supramaximal stimulus was originally based on the premise that increasing the intensity would not increase anesthetic requirements. Although application of more than one supramaximal noxious stimulus does not seem to increase anesthetic requirements,1it is unknown whether application of two or more submaximal noxious stimuli require more anesthesia compared with when either one is applied separately. Surgical patients are subjected to a wide variety of noxious stimuli, some that would be considered supramaximal and others that are likely submaximal. Although noxious stimuli can be applied with increasing intensity and time and across more and more dermatomes, the motor response achieves a maximum: One can withdraw one’s arm or leg only so quickly with a finite amount of force. Hence, when the motor response reaches a maximum, increasing the stimulus intensity does not elicit further movement.

One limitation of the MAC concept is its “all-or-none” nature. However, movement resulting from noxious stimulation can be variable in its quality and quantity. When a clamp is applied to the tail of an anesthetized animal, it might move immediately, and continue to move if the clamp is left on, or it might not move until 59 s later. In both situations, however, the movement would be considered positive. At equipotent sub-MAC concentrations, we have observed less movement with halothane than with isoflurane, suggesting that anesthetics might differ in the manner in which they depress movement.13,14In addition, determining MAC is subjective: It requires the investigator to state that the animal (or human) either did or did not display “gross and purposeful movement.”

For more than four decades, anesthetic potency has been measured using MAC. This is a remarkable record for a concept that has some limitations. Nonetheless, we remain committed to the MAC concept as it measures a clinically relevant phenomenon. We have all had patients who moved vigorously during surgery, and although the anesthetic concentration is likely to be sufficient to produce unconsciousness and amnesia, either rightly or wrongly, to the other healthcare workers in the operating room, this movement is the sine qua non  of an inadequate anesthetic. In addition, patient movement can sometimes be disastrous, depending on the nature of the surgery. The data from Mogil et al.  demonstrate that there are likely to be genetic factors that influence anesthetic requirements and that pain modulation systems might be involved in responses to the “supramaximal” stimuli normally used to determine MAC.2Understanding these genetic factors, pain modulation systems, and how anesthetics produce immobility will go a long way to developing safer anesthetics.

*Department of Anesthesiology and Pain Medicine and Section of Neurobiology, Physiology and Behavior, †Section of Neurobiology, Physiology and Behavior, University of California, Davis, California.

Eger EI, Saidman LJ, Brandstater B: Minimum alveolar anesthetic concentration:A standard of anesthetic potency. Anesthesiology 1965; 26:756–63
Mogil JS, Smith SB, O’Reilly MK, Plourde G: Influence of nociception and stress-induced antinociception on genetic variation in isoflurane anesthetic potency among mouse strains. Anesthesiology 2005; 103:751–8
Levine LL, Winter PM, Nemoto EM, Uram M, Lin MR: Naloxone does not antagonize the analgesic effects of inhalation anesthetics. Anesth Analg 1986; 65:330–2
Pace NL, Wong KC: Failure of naloxone and naltrexone to antagonize halothane anesthesia in the dog. Anesth Analg 1979; 58:36–9
Harper MH, Winter PM, Johnson BH, Eger EI: Naloxone does not antagonize general anesthesia in the rat. Anesthesiology 1978; 49:3–5
Roy RC, Stullken EH: Electroencephalographic evidence of arousal in dogs from halothane after doxapram, physostigmine, or naloxone. Anesthesiology 1981; 55:392–7
Dahan A, Sarton E, Teppema L, Olievier C, Nieuwenhuijs D, Matthes HW, Kieffer BL: Anesthetic potency and influence of morphine and sevoflurane on respiration in μ-opioid receptor knockout mice. Anesthesiology 2001; 94:824–32
Reynolds DV: Surgery in the rat during electrical analgesia induced by focal brain stimulation. Science 1969; 164:444–5
Roizen MF, Newfield P, Eger EI, Hosobuchi Y, Adams JE, Lamb S: Reduced anesthetic requirement after electrical stimulation of periaqueductal gray matter. Anesthesiology 1985; 62:120–3
Melzack R, Wall PD, Ty TC: Acute pain in an emergency clinic: latency of onset and descriptor patterns related to different injuries. Pain 1982; 14:33–43
Willer JC, De Broucker T, Le Bars D: Encoding of nociceptive thermal stimuli by diffuse noxious inhibitory controls in humans. J Neurophysiol 1989; 62:1028–38
Zbinden AM, Maggiorini M, Petersen-Felix S, Lauber R, Thomson DA, Minder CE: Anesthetic depth defined using multiple noxious stimuli during isoflurane/oxygen anesthesia: I. Motor reactions. Anesthesiology 1994; 80:253–60
Jinks SL, Antognini JF, Carstens E: Spectral analysis of movement patterns during anesthesia. Anesth Analg 2004; 98:698–702
Jinks SL, Martin JT, Carstens E, Jung SW, Antognini JF: Peri-MAC depression of a nociceptive withdrawal reflex is accompanied by reduced dorsal horn activity with halothane but not isoflurane. Anesthesiology 2003; 98:1128–38