Anesth Analg 2004;98:1712-1717
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000113550.47942.47
ANESTHETIC PHARMACOLOGY
Insulin Decreases Isoflurane Minimum Alveolar Anesthetic Concentration in Rats Independently of an Effect on the Spinal Cord
Yilei Xing, MD*,
Jim Sonner, MD*,
Michael J. Laster, DVM*,
Wella Abaigar, BS*,
Valerie B. Caraiscos, MSc
,
Beverley Orser, MD, and
Edmond I Eger, II, MD*
*Department of Anesthesia and Perioperative Care, University of California, San Francisco, California; and
Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
Address correspondence and reprint requests to Edmond I Eger II, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu
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Abstract
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The observation that insulin supplies an element of analgesia suggests that insulin administration might decrease the concentration of inhaled anesthetic required to produce MAC (the minimum alveolar anesthetic concentration required to eliminate movement in response to noxious stimulation in 50% of subjects). We hypothesized that insulin decreases MAC by directly affecting the nervous system, by decreasing blood glucose, or both. To test these hypotheses, we infused increasing doses of insulin either intrathecally or IV in rats anesthetized with isoflurane and determined the resulting MAC change (assessing forelimb and hindlimb movement separately). Infusion of insulin produced a dose-related decrease in MAC that did not differ among groups. That is, the IV and intrathecal infusions caused similar decreases in MAC at a given infusion rate. Blood glucose concentrations were larger in the rats given insulin with 5% dextrose. However, the percentage change in MAC determined from forelimb versus hindlimb movement did not differ. For a given insulin infusion rate, MAC changes and glucose levels did not correlate with each other, except, possibly, for the most rapid infusion rate, for which smaller glucose concentrations were associated with a marginally larger decrease in MAC. Intrathecal infusions of insulin did not produce spinal cord injury. In summary, we found that insulin decreases isoflurane MAC in a dose-related manner independently of its effects on the blood concentration of glucose. The sites at which insulin acts to decrease MAC appear to be supraspinal rather than spinal. The effect may be due to a capacity of insulin to produce analgesia through an action on one or more neurotransmitter receptors.
IMPLICATIONS: Intrathecal and IV insulin administration equally decrease isoflurane MAC in rats, regardless of the concentration of blood sugar. These findings indicate that although insulin decreases MAC, the decrease is not mediated by actions on the spinal cord.
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Introduction
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Several reports suggest that insulin supplies an element of analgesia and may therefore decrease the concentration of inhaled anesthetic required to produce MAC (the minimum alveolar anesthetic concentration required to eliminate movement in response to noxious stimulation in 50% of subjects). Insulin-induced hypoglycemia potentiates the antinociceptive action of morphine (1,2) and salicylates (3). The findings of Simon and Dewey (4) indirectly imply that this effect might be consequent to hypoglycemia. They reported that hyperglycemia decreases the antinociceptive potency of morphine, phenazocine, and levorphanol (but not methadone, propoxyphene, and meperidine), as determined by the tail-flick test. Insulin administration restores the sensitivity to morphine-induced antinociception to control values (4,5). Furthermore, insulin treatment relieves long-term hyperalgesia (6). Takeshita and Yamaguchi (7) found that insulin attenuates responses to noxious stimulation in a dose-dependent manner in diabetic animal models—more so in mice rendered diabetic by the administration of streptozotocin than in diabetic db/db mice. Several investigators have demonstrated that although both streptozotocin-induced mice and db/db mice are hyperglycemic, the former are hypoinsulinemic, whereas the latter are hyperinsulinemic (8–11).
Insulin regulates the function of both voltage-gated and ligand-gated ion channels. It activates potassium channels, thus causing inhibition in hippocampal and hypothalamic neurons (12,13). Insulin also enhances the function of N-methyl-D-aspartic (NMDA) receptors (14) and gamma-aminobutyric acid (GABA)A receptors (15). In contrast, insulin depresses 
-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor-mediated excitatory neurotransmission in hippocampal neurons (16). Insulin upregulates glycine receptor function in spinal neurons (17). Also, insulin stimulates the release of Ca2+ at the distal tips of neurites, the supposed location of secreted neuropeptide; that is, insulin may regulate a unique neuronal Ca2+ pool that contributes to neuropeptide secretion (18). Moreover, insulin may have neuroprotective and neurotoxic effects that are mediated, at least in part, by NMDA receptors (19). Insulin receptors are present in lateral lamina V and lamina X of the spinal cord and, to an even greater extent, in dorsal root ganglia (20). These findings suggest that insulin may play a role in sensory pathways involved in nociceptive function.
From the evidence cited previously, we hypothesized that insulin may decrease the inhaled anesthetic requirement by directly affecting neurotransmission, by decreasing blood glucose, or both. Consistent with this hypothesis, insulin administration restores the lessened effect of clonidine on MAC caused by streptozotocin-induced diabetes (21). However, streptozotocin-induced diabetes itself decreases MAC, and insulin administration restores MAC to normal values (21,22). In this study, we sought to distinguish between a global effect of insulin on the central nervous system and one primarily on the lumbar spinal cord. Our focus on the spinal cord results from the studies of Rampil et al. (23), Rampil (24), Antognini and Schwartz (25), and Antognini (26), who showed that the spinal cord is the primary mediator of the immobility (MAC) caused by inhaled anesthetics. To accomplish these goals, we infused ascending doses of insulin intrathecally or IV in rats anesthetized with isoflurane and determined the resulting change in MAC.
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Methods
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Methods followed those described by Zhang et al. (27). With approval of the Committee on Animal Research of the University of California, San Francisco, we studied 2- to 3-mo-old male specific-pathogen-free Sprague-Dawley rats [Crl:CD®(SD)Br] obtained from Charles River Laboratories (Hollister, CA). Each animal was used in only one experiment. Intrathecal or IV catheters were inserted under isoflurane anesthesia by methods described by Yaksh and Rudy (28) and Zhang et al. (27). Rats were allowed to recover from anesthesia and surgery for at least 24 h before study.
The MAC was determined in groups of 8 rats before and after infusion of the drug or of the vehicle control. Each rat was placed in a clear plastic cylinder. A rectal temperature probe was inserted to allow control of body temperature (37°C–38°C) by using a heat lamp or application of ice to the plastic chambers as needed.
During the determination of the initial (control) MAC (MAC0), we infused artificial cerebrospinal fluid (aCSF) through the intrathecal catheter at 1 µL/min. The aCSF was made up daily from stock solutions. The final composition of the aCSF was 154.7 mM Na+, 0.82 mM Mg2+, 2.9 mM K+, 132.49 mM Cl–, 1.1 mM Ca2+, and 5.9 mM glucose, at a pH of 7.4.
Isoflurane was introduced at a partial pressure of approximately 1.0% of an atmosphere. Isoflurane partial pressures were continuously monitored with an infrared analyzer (Datascope, Helsinki, Finland). However, the concentration used to determine MAC was obtained by using gas chromatography (which we considered more accurate). After a 30-min equilibration period, a tail clamp was applied to the proximal portion of the tail and oscillated 45° at approximately 1 Hz for 1 min or until the animal moved (whichever came first). All control animals moved at this partial pressure. The isoflurane partial pressure was then increased in 0.1% to 0.2% atmosphere steps (30 min per step) until the isoflurane partial pressures bracketing movement and lack of movement during application of the tail-clamp stimulus were determined.
To determine MACi (during infusion of insulin), we then infused the study drug at 1 µL/min through the intrathecal catheter or at 10–100 µL/min through the IV catheter (for the units of insulin infused per minute, see Table 1). We used the 1 µL/min rate for intrathecal infusion to confine the infusate to the lumbosacral region of the cord (see below); we used the higher IV infusion rates to supply a sufficient quantity of glucose without infusing a hyperosmotic solution. For these determinations, the initial target isoflurane partial pressure was lower than that used for the control studies, and this lower concentration always permitted movement in response to the tail clamp. As with the control studies, the isoflurane concentration was increased by 0.1% to 0.2% atmospheres until the isoflurane partial pressures bracketing lack of movement and movement during the tail-clamp stimulus were determined.
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Table 1. Percentage Changes in Minimum Alveolar Anesthetic Concentration (MAC) Resulting from Insulin in Artificial Cerebrospinal Fluid (aCSF), 5% Dextrose (dex), or Normal Saline (sal) Administered Intrathecally (IT) or IV
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MAC values were determined by a single crossover, the mean of the least partial pressure that caused immobility and the most partial pressure that allowed movement. Change in MAC was calculated as the percentage change relative to MAC0. That is, for MACi, the percentage change in MAC equaled 100 x (MACi – MAC0)/MAC0. For IV and intrathecal infusions, movement of the head or forelimbs (MACif) or movement of the hindlimbs (MACih) was considered separately as a positive response.
Rats given the large dose of insulin (100 mU/min) had access to a 5% glucose solution after determination of MACi. In pilot studies, we found that in the absence of such access, the rats often died of hypoglycemia. On the second day after determination of MACi for the rats given insulin intrathecally, we re-determined MAC (recovery MAC, or MACr). The percentage change in MAC equaled 100 x (MACr – MAC0)/MAC0.
In the rats given insulin IV, blood samples were taken immediately from the abdominal aorta after the rats failed to respond to the tail clamp stimulus. The blood samples were analyzed for their glucose content.
We used intrathecal infusion rates (1 µL/min) that confine drug delivery to the lumbothoracic cord of rats. In previous studies that used this infusion rate and duration of study, postmortem examination established that aCSF containing methylene blue did not spread beyond the lumbothoracic cord region (29).
Insulin (Humulin R; Eli Lilly, Indianapolis, IN) containing 100 U/mL (100 mU/µL) was diluted in aCSF to 100 mU/µL (no dilution), 10 mU/µL, 1 mU/µL, or 0.1 mU/µL for intrathecal infusion (see Table 1 for insulin units infused per minute). As noted previously, the infusion rate in all the intrathecal groups was 1 µL/min. For the IV infusion groups, the insulin was diluted in saline or 5% dextrose to different concentrations and infused at different rates. For the 100 mU/min group, the concentration was 1 mU/µL and the infusion rate was 100 µL/min; for the 10 mU/min group, the concentration was 0.1 mU/µL and the infusion rate was 100 µL/min; for the 1 mU/min group, the concentration was 0.1 mU/µL and the infusion rate was 10 µL/min; and for the 0.1 mU/min group, the concentration was 0.01 mU/µL and the infusion rate was 10 µL/min. Infusions continued for approximately 2 h, the time needed to determine MAC.
Differences in the potency of isoflurane among the experimental groups were compared with two-sample paired or unpaired Student’s t-tests. P < 0.05 was considered statistically significant. The effect of insulin dose, the route of insulin administration (intrathecal versus IV), and the limb from which MAC was determined (front versus hind) on the percentage change in the isoflurane MAC determined was evaluated in a three-way analysis of variance. The effect of insulin and glucose concentration on MAC change was determined by using multiple regression. Median effective doses (ED50) were calculated by using nonlinear regression to a sigmoid curve. The maximal decrease in MAC from intrathecal and IV infusion of insulin and MACr versus MACi were compared by using a Student’s t-test.
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Results
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The percentage change in the isoflurane MAC determined from forelimb movement (MACif) did not differ significantly from the MAC determined from hindlimb movement (MACih) (Fig. 1). We used the average of the percentage change of the forelimbs (MACif) and hindlimbs (MACih) for individual rats.
Infusion of insulin produced a dose-related decrease in MAC that did not differ among groups (Table 1, Fig. 2). Thus, the decrease with intrathecal infusion did not differ from the decrease obtained with either of the IV infusions, and the decrease with the IV infusions did not differ, although, as would be expected, the blood glucose concentrations were larger in the rats given insulin with 5% dextrose. At the 10 and 100 mU/min infusion rates, blood glucose concentrations differed significantly (69 ± 21 mg/dL versus 39 ± 16 mg/dL, P < 0.05; and 46 ± 14 mg/dL versus 14 ± 3 mg/dL, P < 0.001) (Table 1).
With a three-way analysis of variance, there was a significant effect of insulin dose but no effect of route of insulin administration or limb from which MAC was determined, nor were there any significant two- or three-way interactions among these variables on the percentage decrease in the isoflurane MAC. The effects of route and limb are shown in Figure 1. In subsequent analyses, the forelimb and hindlimb MAC values were pooled.
The effect of insulin and glucose concentration on MAC change was evaluated with multiple regression. Regardless of the order of entry of the variables or the method of variable selection (stepwise, forward, or backward), there was a statistically significant effect of log insulin but not of glucose concentration or log glucose concentration. The final regression model was equation
where a0 = 37.1 ± 3.2 (P < 0.001) and a1 = 7.6 ± 2.2 (P < 0.002). The relation between the MAC changes predicted from this regression model and the observed MAC changes at each insulin dose are shown in Figure 3.
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Figure 3. The predicted minimum alveolar anesthetic concentration (MAC) in this figure was calculated from a linear regression model (described in Results) in which MAC is expressed as a function only of insulin dose. This is plotted against the observed MAC for each insulin infusion rate. The insulin infusion rate by itself is a good predictor of the observed MAC. At no infusion rate does the predicted MAC significantly differ from the observed MAC.
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Neither the ED50 for insulin infusion nor the maximal decrease in MAC differed on the basis of the route of insulin administration. The ED50 for intrathecal infusion of insulin on MAC change was 0.65 ± 0.45 mU/min. For IV infusion, the ED50 was 1.9 ± 0.8 mU/min. The maximum effect of IV infusion, achieved at the highest infusion rate for insulin, was a MAC decrease of 29.9% ± 2.8% (mean ± SE; n = 16), whereas for intrathecal infusion the maximum decrease was 27.0% ± 2.7% (mean ± SE; n = 8).
Although, as noted previously, there was no significant effect of glucose on MAC, we noted that the MAC decrease at the most rapid IV infusion rate of insulin decreased MAC approximately 5% more than we would have predicted from the 3 small doses of insulin (Fig. 4). This suggested that, in addition to the effect of insulin on MAC, in the animals given the largest dose of insulin there may have been an effect of hypoglycemia on MAC. This difference did not reach significance (P = 0.10). However, given the number of animals studied at this insulin dose, the size of the MAC difference, and the variability in the data, it is not surprising that this secondary measure did not reach significance, because this study had a probability (power) of only 0.21 for detecting a significant difference in this measurement. Study of more animals (at least 30) would be required to have a power of at least 0.8 for detecting this difference.
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Figure 4. Minimum alveolar anesthetic concentration (MAC) changes as a function of glucose concentration. The four points shown represent the average MAC change and glucose concentration at each of the 4 IV insulin infusion rates studied. There is a discrepancy of approximately 5% (MAC fraction of 5%) in the MAC predicted at the smallest glucose concentration based on a regression line drawn through the three points obtained with the larger glucose concentrations. This suggests the possibility that severe hypoglycemia may have an effect independent of insulin in decreasing MAC, although this discrepancy did not reach significance (P = 0.1).
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We found no evidence that intrathecal infusions of insulin produced spinal cord injury. Motor activity appeared grossly to be normal, and isoflurane MACr measured in animals 24 h after recovery from intrathecal insulin administration did not differ from MAC0 (Table 1, Fig. 2).
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Discussion
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Confirming our hypothesis, the results suggest that insulin decreases MAC by acting at loci other than the spinal cord. Dose (insulin)-response (MAC) curves did not differ for IV versus intrathecal insulin administration. This suggests that the effect of intrathecal infusion likely resulted from systemic absorption and actions on higher centers. Intrathecal infusion of insulin did not decrease MAC by the production of neurological injury, because animals recovered well (without obvious motor impairment) and because MACr did not differ from control (Fig. 2). Consistent with an absence of injury, the estimates of change in isoflurane MAC values for hindlimbs and forelimbs did not differ (Fig. 1).
Our results are consistent with the finding that insulin administration restores the lessened effect of clonidine on MAC caused by streptozotocin-induced diabetes (21). However, our results would appear to conflict with the finding by others that streptozotocin-induced diabetes itself decreases MAC and that insulin administration restores MAC to normal values (21,22). We suggest that this apparent discrepancy may result, in part, from the doses of insulin used in the respective studies. For example, Brian et al. (22) gave 7 U of extended insulin zinc suspension per day, or 0.3 U/h (average), a dose sufficient to treat the diabetes caused by streptozotocin injection. Because our studies provided an infusion that extended over two to three hours, a comparable dose in our studies would be an infusion of 0.1–1.0 mU/min. As seen in Figure 2, such an infusion would produce a change that might be too small to measure. An alternative explanation is that injection of the 7 U of insulin in the diabetic animals merely restores the insulin levels to normal and thus does not represent an analgesic dose. In addition, we would argue that the diabetic animal is not normal and that restoration of normality by insulin administration would not be predicted to decrease MAC.
The percentage decrease of MAC by infusing insulin could be predicted from the infusion rate of the insulin (Fig. 3). The results showed that there was no difference in MAC change between the intrathecal, IV with saline, and IV with 5% dextrose groups when insulin was infused at the same dose per minute, yet blood glucose levels differed between the IV with saline and IV with 5% dextrose groups (Table 1, Fig. 2). These results suggest that insulin decreases MAC by a mechanism that is independent of blood glucose. However, surely a sufficiently small blood glucose concentration must affect MAC, and this is suggested by the findings illustrated in Figure 4.
Insulin may have regulatory effects on NMDA, GABAA, and -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors (30–36). Results from our previous studies suggest that GABA, glycine, and NMDA receptors may contribute directly or indirectly to the immobility produced by inhaled anesthetics (27,29,37,38). Insulin may partially mediate the decreases in MAC through actions on one or more of these receptors.
In summary, we found that insulin decreases isoflurane MAC in a dose-related manner independently of its effects on the blood concentration of glucose. The sites at which insulin acts to decrease MAC appear to be supraspinal rather than spinal. The effect may be due to a capacity of insulin to produce analgesia through an action on one or more neurotransmitter receptors.
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Acknowledgments
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Supported by National Institutes of Health Grant GM47818; Baxter Healthcare Corp. donated the isoflurane used in these studies.
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Footnotes
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Dr. Eger is a paid consultant to Baxter Healthcare Corp.
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Accepted for publication December 3, 2003.
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Top
Abstract
Introduction
) and IV (
) insulin administration equally affects movement of the hindlimbs and forelimbs. The data are taken from rats given various doses of insulin, ranging from those that caused little or no change in minimum alveolar anesthetic concentration (MAC) to those that produced change. The finding that hindlimbs and forelimbs are equally affected indicates that the decreases in MAC probably are not the result of spinal cord injury, because injury likely would affect hindlimb movement more than forelimb movement. MACi = MAC during infusion of insulin.
), and IV with 5% dextrose (
) administration of the same doses of insulin equally affect movement. The recovery minimum alveolar anesthetic concentration (MAC) (
) does not differ from the control MAC. The asterisks indicate significant differences from control MAC (MAC0): *P < 0.05; **P < 0.01; and ***P < 0.001. MACi = MAC during infusion of insulin.
