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CARDIOVASCULAR ANESTHESIA

Intrathecal Morphine Reduces Infarct Size in a Rat Model of Ischemia-Reperfusion Injury

From the Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina

Address correspondence and reprint requests to Leanne Groban, MD, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157–1009. Address email to lgroban{at}wfubmc.edu

	Abstract

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Systemically-administered morphine reduces infarct size in rat models of myocardial ischemia-reperfusion. We sought to determine whether much smaller doses of spinally-administered morphine offer a similar cardioprotective benefit. Barbiturate-anesthetized, open-chested, Wistar rats with chronic indwelling thoracic intrathecal catheters were instrumented for hemodynamic measurements and subjected to 30 min of coronary occlusion and 90 min of reperfusion. Myocardial infarct size was determined using triphenyl-tetrazolium staining. Rats were randomly assigned to receive intrathecal (IT) 0.9% saline (vehicle), IV morphine (0.3 mg/kg) plus IT saline, small-dose IT morphine (0.3 µg/kg), or large-dose IT morphine (3 µg/kg) 20 min before occlusion. IV and both doses of IT morphine reduced infarct size, defined as area of necrosis expressed as a percentage of area at risk (%AN/AAR), as compared with vehicle. The %AN/AAR group means were as follows: IV (n = 7), 30% ± 6%; IT_small-dose (n = 9), 30% ± 5%; IT_large-dose (n = 9), 18% ± 4%; and vehicle (n = 10), 47% ± 5%. There were no significant differences in infarct size among the morphine-pretreated rats. During ischemia-reperfusion, heart rate was unchanged from baseline in the IT_large-dose group, whereas in the IT_small-dose, IV and vehicle groups, significant declines in heart rate occurred. Changes in arterial blood pressure were similar among groups. These results indicate that IT morphine reduces infarct size in rats, and this benefit is as great as that provided by IV morphine administration.

IMPLICATIONS: Our findings suggest that spinally-administered morphine provides a previously unrecognized cardioprotective benefit. In anesthetized rats subjected to ischemia-reperfusion injury, we show that very small doses of intrathecal morphine reduce infarct size in rats, and this benefit is as great as that provided by much larger doses of IV morphine.

	Introduction

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Systemically-administered opioids in large doses supplemented by inhaled or IV drugs have long been popular to provide general anesthesia to high-risk patients undergoing cardiac surgery. The "large-dose opioid" technique reduces the neuroendocrine stress response, easily maintains stable intraoperative hemodynamic values, and provides intense analgesia control in the immediate postoperative period. The "large-dose opioid" technique has been associated with reduced incidence and severity of perioperative ischemia (1) and reduced morbidity and mortality (2), presumably through reductions in myocardial oxygen consumption. Animal data suggest that some opioids also possess direct cardiac protective properties. IV morphine reduces infarct size in rat models of ischemia-reperfusion injury (3,4) via a mechanism that appears to be independent of any opioid hemodynamic effects. A -opioid receptor-K⁺_ATP channel interaction within the myocardium is one presumed mode of cardioprotection (3,4), and this interaction may be further facilitated by adenosine (5) and protein kinase C (6).

Since the mid-1990s, however, the use of large-dose opioid anesthesia for cardiac surgery has fallen into disfavor because of an association with extended duration of ventilator dependence and intensive care length of stay (7,8). Some clinicians have substituted intrathecal opioids (0.25 mg to 2.0 mg) for IV opioids in the hope of facilitating earlier tracheal extubation (9,10). Intrathecal (IT) dosing reduces the total amount of opioid required (11,12). Even though opioid receptor subtypes have been identified within the spinal cord and that spinal injection of opioids activates inhibitory pathways that can modulate neuronal trafficking from nociceptive stimuli (13), opioids administered spinally before an ischemia-reperfusion event may or may not afford the same degree of cardioprotection that is observed with systemic opioid "pretreatment." Given that morphine is highly ionized and hydrophilic, and that doses as small as 1/1000th those used IV are effective in modifying pain behavior in rats (14), studies have shown much smaller plasma concentrations of morphine after IT administration as compared with the plasma levels achieved after IV morphine (15,16). Likewise, IT injections of morphine produce larger concentrations of the opioid in the cerebral spinal fluid and brain than are measured after systemic administration (17). Accordingly, this study tests the hypotheses that small doses of IT morphine reduce infarct size in rats and that this benefit is as significant as that provided by much larger doses of IV morphine.

	Methods

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All experimental procedures and protocols used in this study were reviewed and approved by the Animal Care and Use Committee of Wake Forest University School of Medicine (Winston-Salem, NC).

Surgical Preparation
After male Wistar rats (250–350 g) were anesthetized with 2.5% halothane (Halocarbon Laboratories, River Edge, NJ), in a room air-oxygen mixture (1:1). Thoracic IT catheters were inserted using a modification of Yaksh and Rudy’s technique (18). Briefly, the polyethylene catheter (Intramedic, PE-10) was inserted, under direct vision, 4 cm caudally through the cisternal membrane into the IT space leaving the catheter near the origin of the upper thoracic nerve roots. Animals recovered for a minimum of 3 days thereafter. Rats with forelimb or hindlimb motor deficits after recovery were euthanized.

No sooner than the third postimplantation day, rats were instrumented for the acute ischemia-reperfusion experiment. Anesthesia was induced by intraperitoneal administration of thiobutabarbital sodium diluted in saline (Sigma Research Biochemicals Incorporated, Natick, MA) (100 mg/kg) followed by additional IV injections of thiobutabarbital (50–100 mg/kg) to maintain an anesthetic depth sufficient to eliminate both corneal response to touch and withdrawal to paw pinch. A tracheostomy tube was inserted, and each rat was artificially ventilated (rodent ventilator model 806; New England Medical Instruments Inc., Medway, Mass) with a room air-oxygen mixture (1:1). Blood samples for arterial blood gas determination were monitored at regular intervals and ventilation was adjusted to keep PaCO₂ between 25 and 40 mm Hg, and PaO₂ was kept between 90 and 150 mm Hg throughout the experimental protocol. Body temperature was monitored with a rectal temperature probe and maintained at 37°C with a heating pad. The right internal jugular vein was cannulated with a 0.9% saline-filled polyethylene tube (Intramedic, PE-50) for IV drug administration. The left common carotid artery was cannulated with a 20-gauge, 2-cm angiocatheter attached to a 0.9% saline/heparin-filled pressure transducer (1 U/mL) for arterial blood pressure recording and blood sampling.

A left thoracotomy was performed at the fifth intercostal space. The pericardium was opened, and the left coronary artery and vein were identified just under the left atrial appendage. A 6–0 polypropylene ligature was placed around the left descending coronary artery close to its origin and the ends of the suture were threaded through a propylene tube to form a snare.

After a 15-min stabilization period, rats were randomly assigned to receive IV morphine (Abbott Laboratories, Chicago, IL) (300 µg/kg) plus IT vehicle (10 µL normal saline), IT vehicle (10 µL normal saline), IT small-dose morphine (0.3 µg/kg 0.1 µg), or IT large-dose morphine (3 µg/kg 1.0 µg). Morphine was diluted in normal saline. The IT morphine injected volume was 10 µL. Another 10 µL of saline was injected after each morphine injection to clear the catheter dead space. IT and IV drugs were administered over a period of 2 min 20 min before coronary occlusion. All rats were subjected to 30 min of coronary occlusion followed by 90 min of reperfusion. Coronary artery occlusion was produced by clamping the snare onto the epicardial surface of the heart with a hemostat and was verified by epicardial cyanosis accompanied in some cases by ventricular arrhythmias. Reperfusion was achieved by unclamping the hemostat and loosening the snare and was verified by observing an epicardial hyperemic response.

A schematic illustration of the experimental design is illustrated in Figure 1. Systemic arterial pressures and heart rate (HR) were continuously monitored on an oscilloscope. Recorded hemodynamics were acquired during a 6-s period using a computer (Dell OptiPlex GXMT 5133 pentium, Dell Computer, Austin, TX) interfaced with an analog-to-digital converter (model DT 2821; Data Translation Devices, Marlborough, MA). The average of three acquisitions of data was obtained with the coronary circulation intact at basal anesthetized conditions (Baseline 1), and 20 min after IT or IV drug pretreatment, just before coronary occlusion (Baseline 2), at min 30 of coronary occlusion (Ischemia), and at 15, 45, and 90 min of reperfusion.

View larger version (14K): [in this window] [in a new window]   Figure 1. Schematic illustration of experimental protocol. Data were obtained at the following time points: 15 min after instrumentation and stabilization, representing baseline 1 (Base 1); 20 min after IV or intrathecal (IT) morphine administration, representing baseline 2 (Base 2); 30 min of coronary occlusion (occlusion); and at 15, 45, and 90 min of reperfusion.

Animals were excluded from data analysis if 1) coronary artery occlusion did not produce severe ischemia, i.e., area-at-risk (AAR) expressed as a percentage of the LV was 20%, or 2) if either ventricular fibrillation or severe hypotension (mean arterial blood pressure [MAP] below 40 mm Hg) were observed, or 3) inadequate IT drug administration was evident after intrathecal dye injection and cord extrusion.

Infarct Size Determination
After the heart was excised, a second investigator unaware of the randomization determined infarct size. The LV was isolated and sliced into 5 cross-sectional pieces. The unstained region of the myocardium (the AAR) was separated from the blue, nonischemic zone using a dissecting microscope. The AAR was incubated for 15 min in a 1% solution of triphenyltetrazolium chloride (TTC) in 100 mM phosphate buffer (pH 7.4) at 37°C. In the presence of intact dehydrogenase enzyme systems or NAD+/NADH, TTC dye forms red precipitates that identify non-necrotic tissue. Necrotic tissue, lacking these enzyme systems, remains a pale color. After TTC incubation, tissue samples were refrigerated overnight in a 10% solution of buffered formalin. The AAR was subdivided into non-necrotic (TTC-positive, red) and necrotic areas (AN) (TTC negative, pale) the next day using a dissecting microscope. The AAR and AN were determined gravimetrically. Areas of necrosis were expressed as a percentage of the AAR (AN/AAR).

Power calculations for infarct size were based on the two-sample Student’s t-test with standard deviation of 7.5%. Power analyses showed that 10 animals per treatment group would be sufficient to detect a 15% reduction in infarct size with a power of 90%.

Statistical Analysis
Statistical analyses were performed with PC SAS (SAS Institute, Cary, NC). Time-related differences and group-time interactions were analyzed by two-way analysis of variance for repeated measures adjusted for baseline values. One-way analysis of variance was used to determine the effects of treatment on gravimetric values of LV regions of risk and necrosis. Post hoc comparisons were performed with Student-Newman-Keuls test. Analysis of covariance was used to determine the effects of treatment on AN/AAR with covariate adjustments for LV and values for the "adjusted" AN/AAR are reported as least square means ± SE. All other values are reported as mean ± SEM. Statistical significance was defined as P < 0.05.

	Results

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Forty animals completed the study. One animal in the systemic morphine group was excluded because of an inadequate ischemic burden (%AAR/LV = 20) and 2 others were excluded because of intractable ventricular fibrillation. In the IT morphine groups, one animal in each of the "small" and "large" dose groups was excluded as a result of severe hypotension (IT_small animal, MAP = 38 mm Hg during early reperfusion; IT_large animal, MAP = 20 mm Hg during ischemia). No animals were excluded for failed IT drug administration.

Figure 2 shows the HR and MAP at baseline, after 20 min of either IV or IT morphine or saline (vehicle) pretreatment (Baseline 2), after 30 min of coronary occlusion, and at 15, 45, and 90 min of reperfusion. HR and MAP were not different among groups at baseline. Twenty min after IT (both doses) and IV morphine, 5% to 8% reductions from baseline HR were observed. During ischemia-reperfusion, heart rate was unchanged from baseline conditions (baseline 1 and 2) in the "large" dose IT morphine group whereas in the "small" dose IT morphine, IV morphine, and vehicle groups, significant declines in HR from Baseline 1 were observed. In the vehicle and "small" dose IT groups, significant declines in HR from Baseline 2 were also noted. MAP declined 14% from Baseline 1 after both IV and IT morphine treatments (Baseline 2) (P < 0.05). During coronary occlusion and reperfusion MAP further declined 27 to 41% from Baseline 1 (P < 0.05) and 11 to 34% from Baseline 2 (P < 0.05). These responses in MAP were not different among morphine treatments or saline.

View larger version (24K): [in this window] [in a new window]   Figure 2. Effect of IV and intrathecal (IT) morphine on heart rate and mean arterial blood pressure at baseline (Base 1), after drug pretreatment (Base 2), coronary occlusion or ischemia (isch), and at 15, 45 and 90 min of reperfusion (Rep15, Rep45, Rep90, respectively). VEH = vehicle group; IT Small = intrathecal small-dose morphine group; IT Large = intrathecal large-dose morphine group; IV = IV morphine group. *P < 0.05 significantly different from Base 1; #P < 0.05 significantly different from Base 2; P < 0.05 significantly different from IV, IT small, VEH responses.

View larger version (17K): [in this window] [in a new window]   Figure 3. Effect of IV and intrathecal (IT) morphine on myocardial infarct size. Graph shows area of necrosis (AN) expressed as a percentage of the area at risk (AAR) (AN/AAR). Circles represent individual subjects; and bars represent mean responses for the group. VEH = vehicle group; IT small = IT small-dose morphine group; IT Large = intrathecal large-dose morphine group; IV = IV morphine group. *P < 0.05 significantly different from VEH.

	Discussion

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Neuroaxial opioids produce antinociception in humans and have become an important technique in the management of postoperative pain. IT morphine administered to cardiac surgical patients at doses ranging between 0.25 mg and 2.0 mg produces more intense and prolonged postoperative analgesia than systemically-administered morphine and generally facilitates earlier extubation (5–10 hours) (9,11). In patients with medically intractable angina pectoris, small-dose IT morphine (0.6 mcg to 1.0 mg) can relieve anginal pain with minimal circulatory or respiratory side effects (19).

In rats, IT morphine produces antinociception (20) and reduces postoperative pain behaviors (14). Although effective doses depend on the specific nociceptive tests used, the minimum IT morphine doses reported to modify pain behavior in rats range between 0.3 and 2.0 µg (14). Because there is no recognized IT morphine dose for cardiogenic pain in rats subjected to experimental ischemia-reperfusion injury, we extrapolated our IT morphine dose from other models of nociceptive, visceral, and postoperative pain (14,20,21). In the present study we used the smallest neuraxial morphine dose that modified pain responses in these other models because our rats were also receiving general anesthesia. The IT morphine doses, 0.1 (0.3 µg/kg) and 1.0 µg (3 µg/kg), effective in our study were 1000-fold and 100-fold smaller than the cardioprotective, systemic morphine dose, 300 µg/kg, used by others (3,4) and ourselves. Interestingly, the IT morphine doses required to modify pain behavior in rats subjected to noxious, nociceptive stimuli have also been approximately 1000-fold smaller than the effective systemic morphine dose (14). In humans, the therapeutic ratio for single doses of systemic morphine and IT morphine that produce antinociception and postoperative pain relief is approximately 10:1. Specifically, with regard to analgesic potential in humans, 0.05–0.3 mg/kg IV morphine is comparable to 0.2–0.5 mg IT morphine. As a result of these markedly differing doses in both humans and rats, IT morphine results in much smaller plasma concentrations than IV morphine.

IT morphine can have activity through mechanisms other than relief of pain. Other potential mechanisms of cardioprotection from IT morphine include stress response attenuation and cardiac sympathectomy. Opioid receptor subtypes, predominately µ and , have been identified on pre- and postsynaptic neurons and in the spinal intermediolateral cell column where their activation can modulate autonomic responses to nociceptive stimuli (13). Opioids administered spinally activate bulbospinal inhibitory neurons, which can attenuate excitatory neuronal trafficking within the dorsal horn as well (13). In the anesthetized cat, neuraxial morphine decreased cardiac efferent sympathetic nerve activity presumably through direct inhibition of the sympathetic nervous system at the level of the brainstem and spinal cord (22). Interestingly, in anesthetized rats, IT µ agonists did not change resting HR and MAP but attenuated hemodynamic responses evoked by noxious thermal stimuli, suggesting that opioids attenuate the afferent limb of the pain-evoked autonomic reflex (23). In humans, spinal opioid receptor activation may attenuate increased sympathetic nerve activity elicited by myocardial ischemia; however, local anesthetics administered either spinally or epidurally possess greater efficacy at blocking sympathetic afferent and efferent fibers (24). Correspondingly, IT opioids may only partially attenuate the stress response in patients undergoing cardiac surgery (25). Additional studies will be required to determine which of these several mechanisms played a role in the cardioprotection observed in the current study.

We doubt that reduction in infarct size observed in the IT morphine groups was attributable to hemodynamic effects. The hemodynamic picture that accompanies acute myocardial ischemia is the result of a complex interaction between ischemic myocardium and excitatory and inhibitory reflexes arising from the heart. Occlusion of the left main coronary artery can produce LV dysfunction and dilation, conditions that provoke vagally-mediated reflexes. However, cardiac sympathetic afferents, activated with lesser degrees of ischemia or before maximal ventricular dilation, elicit dominant pressor sympathetic reflexes. In this study, occlusion and reperfusion of the left coronary artery elicited an inhibitory, depressor response similar to that reported by Sole et al. (26). However, in our rats treated with "large" dose IT morphine, HR was not decreased by coronary occlusion. Whether the "stable" heart rate response during ischemia and reperfusion influenced the reduced infarct size observed in this group is unclear. Opioid receptor stimulation induces multiple cardiovascular effects, including alterations in arterial tone, arterial blood pressure, HR, and contractility. In our model, these effects were further modulated by the underlying myocardial injury. It seems unreasonable to attribute a causal relationship between hemodynamics and ischemic injury because infarct size was also reduced in the IV and "small" dose IT morphine-treated rats (as compared with vehicle), despite similar declines in HR and blood pressure in these and the control animals.

The clinical implications of this study should be interpreted with caution. First, coronary occlusion of the main artery in the rat usually leaves the subendocardial and subepicardial muscle layers intact (27). In human infarcts, the subendocardial layers are often affected. Nonetheless, the rodent model has been extensively used to determine the role of systemic opioids and K⁺_ATP channel agonists in myocardial protection (3–6) and has been used to establish the role of spinally-administered opioids in limiting nociceptive and visceral pain responses (14,20,21). Second, the choice of basal anesthetic used may have influenced the ischemia-induced, cardio-cardiac reflexes or the hemodynamic picture that accompanied the acute myocardial ischemia. For instance, pentobarbital depresses the effect of morphine on the cardiac acceleration responses to somatic noxious stimulation and this morphine-pentobarbital interaction is presumed to occur at the supraspinal level (28). In the current study, thiobutabarbital sodium, a long-acting barbiturate, was used as the basal anesthetic because of its frequent use in other rat studies of myocardial preconditioning and because of its stable hemodynamic profile (3–6).

Additionally, it cannot be deduced from this study whether this central pathway of myocardial protection is exclusively opioid-mediated. Similar to the cardioprotective K⁺_ATP channel-opioid receptor interaction within the myocardium, it is reasonable to expect that there may also be opioid receptors activating K⁺_ATP channels in the central nervous system (CNS). The central administration of K⁺_ATP channel agonists, such as diazoxide, minoxidil, and lemakalim, has resulted in analgesia and antinociception in mice (29). This antinociceptive effect is blocked by both K⁺_ATP channel antagonists and opiate receptor antagonists. Correspondingly, IT morphine-induced antinociception is blocked by K⁺_ATP channel antagonists (29). Besides K⁺_ATP channels, adenosine and protein kinase C have been implicated in the signal transduction pathway of peripheral opioid-mediated cardioprotection (5,6). Although there is evidence to suggest that adenosine and opioid receptors are tightly coupled within the CNS (30), it remains unclear whether this interaction is involved in a central mechanism of cardioprotection. Accordingly, future studies using central and peripheral-acting, selective opioid receptor and adenosine receptor antagonists, K⁺_ATP channel blockers, and protein kinase C inhibitors will be required to determine the mechanism of cardioprotection by IT morphine. Also, it is not known whether IT morphine confers cardioprotection by limiting leu-kocyte activation at the injury site similar to that reported by Wang et al. (31) in morphine-preconditioned rats subjected to experimental myocardial infarction. Furthermore, the determination of plasma and cerebral spinal fluid concentrations of morphine may help distinguish whether the effect is independent of the route of opioid administration. Specifically, as the plasma concentrations from very small doses of IT morphine should be far smaller than that achieved from IV dosing (15,16), it is unlikely that IT dosing confers cardioprotection via a peripheral mechanism.

In summary, pretreatment with IT morphine protects the heart from subsequent ischemia-reperfusion injury by limiting the magnitude of infarction. The optimal dose, the maximal protective effect and the cellular mechanisms of IT opioid cardioprotection remain unknown. Our findings suggest that the CNS may serve as an alternative site of action for morphine-mediated cardioprotection. This could be singularly useful when intraoperative myocardial ischemia is expected, e.g., during off-pump coronary artery surgery.

	Acknowledgments

 
Supported, in part, by the Society of Cardiovascular Anesthesiologists, Ischemia Research and Education Foundation Starter Grant to Dr. Groban.

	Footnotes

 
Presented in part at the annual meeting of the American Society of Anesthesiologists, Orlando, Florida, October 13, 1998.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Groban, L. Articles by Butterworth, J. Search for Related Content PubMed PubMed Citation Articles by Groban, L. Articles by Butterworth, J. Related Collections Cardiovascular Heart Pain