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Anesth Analg 2003;97:1776-1783
© 2003 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Kappa-Opioid Receptor Selectivity for Ischemic Neuroprotection with BRL 52537 in Rats

Zhizheng Zhang, MD*, Tsung-Ying Chen, MD{dagger}, Jeffrey R. Kirsch, MD*, Thomas J. K. Toung, MD{dagger}, Richard J. Traystman, PhD*, Raymond C. Koehler, PhD{dagger}, Patricia D. Hurn, PhD*, and Anish Bhardwaj, MD{dagger},{ddagger}

*Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon; and Departments of {dagger}Anesthesiology/Critical Care Medicine and {ddagger}Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Address correspondence and reprint requests to Anish Bhardwaj, MD, Neuroscience Critical Care Division, Meyer 8-140, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287. Address e-mail to abhardwa{at}jhmi.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
{kappa}-Opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(±)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1) saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2) saline 15 min before reperfusion followed by BRL 52537 (1 mg · kg-1 · h-1) at reperfusion for 22 h, 3) saline 15 min before reperfusion followed by nor-BNI (1 mg · kg-1 · h-1) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mg · kg-1 · h-1) and nor-BNI (1 mg · kg-1 · h-1) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% ± 4.3%; caudoputamen [CP], 23.8% ± 6.7%) (mean ± SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% ± 4.9%; CP, 53.3% ± 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% ± 5.3%; CP, 40.9% ± 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke.

IMPLICATIONS: The neuroprotective effect of selective {kappa}-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The opioidergic system in the brain is important in the pathophysiology of cerebral ischemia (1). All three receptor subtypes that have been identified—µ, {kappa}, and {delta}—demonstrate antinociceptive effects (2). In addition, systemic administration of {kappa}-opioid receptor (KOR) agonists confers neuroprotection in animal models of global and focal cerebral ischemia. For example, dynorphin A (3) and other selective nonpeptide KOR agonists (U-62,066E and U-50,488H) reduce mortality and ameliorate hippocampal CA1 neuronal injury after transient global ischemia (4,5). In permanent focal ischemia, GR89696 and CI-977 reduce cortical damage in rodents and in cats (2,6–8). Furthermore, KOR agonists facilitate postischemic recovery of complex neurobehavior after transient global ischemia that correlates with hippocampal CA1 neuronal protection (9–12).

Several pre- and postsynaptic antiexcitotoxic mechanisms of ischemic neuroprotection conferred by KOR agonists have been postulated. For example, KOR agonists modulate glutamate excitotoxicity by inhibiting presynaptic glutamate release in vitro (13–17), via closure of N-type Ca2+ channels (18) and restriction of Ca2+ entry into presynaptic terminals. KOR agonists also inhibit excitatory postsynaptic potentials through similar presynaptic mechanisms involving reduced glutamate release (13,16,17) and attenuate ischemia-evoked nitric oxide (NO) production (19).

Most previous work concerning neuroprotection with KOR agonists has been performed in models of global ischemia or permanent focal ischemia. Less work has investigated the effects of KOR agonists and antagonists in transient focal ischemia to determine the role of KOR during the reperfusion period. In this study, we tested the hypotheses that 1) a highly selective KOR agonist, BRL 52537 hydrochloride [(±)-1-(3,4-dichloro-phenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine] (20–23), reduces infarct volume and improves functional outcome in a well characterized model of transient middle cerebral artery occlusion (MCAO) when given at reperfusion after 2 h of ischemia and b) that neuroprotection conferred by BRL 52537 is prevented by the addition of the prototypical KOR antagonist nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol] (24–26).


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All experimental protocols were approved by the Johns Hopkins University Animal Care and Use Committee and conformed to the National Institutes of Health guidelines for the care and use of animals in research. All techniques were as previously described (27–29). In brief, adult male Wistar rats (250–300 g) that were fasted from food overnight were anesthetized with halothane (1.0%–2.0%) in oxygen-enriched air (inspiratory oxygen concentration, 25%–30%) and allowed to breathe spontaneously. With use of aseptic surgical techniques, the right femoral artery was cannulated to monitor arterial blood pressure and arterial blood gases, and the femoral vein was cannulated for IV drug administration. After cannulation, the venous catheter was tunneled subcutaneously and exteriorized through a swivel that was sutured over the posterior midthorax and allowed the rat to move freely in its cage after emergence from anesthesia. Rectal and temporalis muscle temperatures were maintained with a heating lamp throughout surgical procedures, during MCAO, and during early reperfusion.

Cortical perfusion was measured by using laser Doppler flowmetry (LDF) as previously described (27–29) (Model MBF3D; Moor Instruments Ltd., Devon, UK). Briefly, the skull was thinned with a high-speed drill over the right parietal cortex (coordinates: 2 mm posterior and 6 mm lateral to the bregma) for placement of the LDF probe. To allow continuous monitoring of LDF, the headpiece of a specially designed cradle was modified to allow for free rotation around the longitudinal axis of the rat and was equipped with a snout mask for spontaneous ventilation and with a holder for the LDF probe. The probe was then positioned over an area devoid of large cortical blood vessels, and its position was not changed throughout the experiment. The LDF signal was allowed to stabilize over a 30-min period before baseline measurements were recorded.

Transient focal ischemia (2 h) was produced by MCAO by using an intraluminal suture technique as previously described (27), with modifications (28,29). Briefly, the right common carotid artery was exposed through a paramidline incision, and the external carotid artery was ligated. The occipital artery branch of the external carotid artery was coagulated, and the internal carotid artery (ICA) was separated from the vagus nerve. The pterygopalatine artery was ligated with a 4-O silk suture close to its origin. Ischemia was produced by advancing a 4-O monofilament nylon suture, with its distal tip rounded by application of heat, into the ICA through a puncture in the common carotid artery until the LDF signal displayed a significant reduction. After placement, the intraluminal suture was secured with a 4-O silk suture tied around the ICA. Reperfusion was produced by withdrawal of the intraluminal suture; this was associated with rapid restoration of the LDF signal. We have previously demonstrated that a reduction to <=40% of the baseline LDF signal is critical in producing consistent infarction volume in our model of MCAO (28). Rats that did not demonstrate 1) reduction of the LDF signal to <=40% of the baseline during MCAO or 2) rapid restoration of the LDF signal during reperfusion were excluded from the study. LDF measurements were averaged over 5-min periods at 5, 15, 30, 60, 90, and 120 min of MCAO and at 15 min of reperfusion. The femoral artery catheter was removed and the artery ligated at 15 min of reperfusion.

All experiments were performed in a blinded randomized fashion. In the first set of experiments, rats were divided to receive the following treatments: 1) saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h (saline/saline) (n = 15), 2) saline 15 min before reperfusion followed by the KOR agonist BRL 52537 (1 mg · kg-1 · h-1) for 22 h (saline/BRL 52537) (n = 10), 3) saline 15 min before reperfusion followed at reperfusion by the selective KOR antagonist nor-BNI (1 mg · kg-1 · h-1) for 22 h (saline/nor-BNI) (n = 11), or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed at reperfusion by BRL 52537 (1 mg · kg-1 · h-1) and nor-BNI (1 mg · kg-1 · h-1) for 22 h (nor-BNI/BRL 52537 + nor-BNI) (n = 8). All infusions were at 0.3 mL/h. In all experiments, rats were allowed to emerge from anesthesia at 15 min of reperfusion, housed in separate cages, and provided with free access to food and water. On completion of treatments at 22 h of reperfusion, the femoral venous catheter was carefully ligated and was removed under brief halothane anesthesia. Rats were housed in separate cages at room temperature (22°C–24°C) during emergence from anesthesia and thereafter until they were killed. Neurologic examination (30,31) with modifications was performed daily to assess for Neurological Deficit Score (NDS) (Table 1). A maximum NDS of 17 indicates poor neurologic status. Daily body weights were recorded.


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  		Table 1. Neurological Deficit Scoring After Two Hours of Middle Cerebral Artery Occlusion
 
In a second set of experiments, rats were treated with IV infusions of saline/saline (n = 6) or saline/BRL 52537 (1 mg · kg-1 · h-1) (n = 6). Second infusions were started at the onset of reperfusion and continued until 22 h of reperfusion. Rectal temperatures were recorded hourly for the first 6 h after reperfusion and then at the end of treatment (22 h of reperfusion).

In both sets of experiments, on Day 4 of reperfusion, rats were deeply anesthetized with 5% halothane and decapitated. The brain was harvested and sliced into 7 2-mm-thick coronal sections for staining with 1% triphenyltetrazolium chloride in saline at 37°C for 30 min as previously described (29,30). Infarct volume was measured with digital imaging (Digital Camera 40; Eastman Kodak Co., Rochester, NY) and image analysis software (SigmaScan Pro; Jandel, San Rafael, CA). The infarcted area was numerically integrated across each section and over the entire ipsilateral hemisphere. Infarct volumes were measured separately in the cerebral cortex and caudoputamen (CP), expressed as a percentage of the ipsilateral structure volume, and corrected for swelling as previously described (32). BRL 52537 hydrochloride and nor-BNI were obtained from Research Biochemical International (Natick, MA).

Physiological variables, mean LDF measurements, and body weight among groups were subjected to repeated-measures analysis of variance. Differences in infarct volume were determined by one-way analysis of variance. Post hoc analysis comparisons were made with the Newman-Keuls test. Data are presented as mean ± SEM. The NDS score is presented as median (with 25% and 75% quartiles) and was analyzed by the nonparametric Mann-Whitney U-test. A value of P < 0.05 was considered significant.


   Results
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 Introduction
 Methods
 Results
Discussion
 References
 
Mean arterial blood pressure, partial pressure of arterial carbon dioxide (PaCO2) and oxygen (PaO2), pH, and rectal temperature were within normal physiological ranges in all animals at baseline, during MCAO, and during early reperfusion (Table 2). Cerebral perfusion, as determined by LDF signal, was not different in various treatment groups (Fig. 1). In the second set of experiments, mean arterial blood pressure, PaCO2, and PaO2 were within normal ranges (data not shown), and the LDF signal was not different in the two treatment groups at baseline, during MCAO, and during early reperfusion. Rectal temperature during the first 6 h of reperfusion was not different in rats treated with saline/saline (37.1°C ± 0.4°C) compared with saline/BRL 52537 (36.7°C ± 0.5°C). Similarly, there were no differences in rectal temperature in the two experimental groups at 22 h of reperfusion (saline/saline, 37.1°C ± 0.3°C; saline/BRL 52537, 36.5°C ± 0.3°C).


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  		Table 2. Physiological Variables at Baseline (Preischemia), During Ischemia, and at 15 Minutes of Reperfusion (Postischemia)
 


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  		Figure 1. Residual laser Doppler flowmetry (LDF signal) after middle cerebral artery occlusion (MCAO), expressed as a percentage of the preischemic baseline signal in various treatment groups (mean ± SEM).

 
In the first set of experiments, the mortality rate before completion of the experimental protocol was as follows: 1 in 10 with saline/BRL 52537 with subarachnoid hemorrhage (SAH), 3 in 11 with saline/nor-BNI (1 with SAH and 1 with focal hemorrhage in infarct), and 7 in 15 (2 with SAH) in saline/saline treatment died before completion of the experimental protocol. One rat in the in the nor-BNI/BRL 52537 + nor-BNI treated group was excluded because it did not have adequate reduction in ischemic LDF. One rat treated with saline/BRL 52537 was excluded because of a hematoma in the subarachnoid space. One rat treated with saline/BRL 52537 sustained a SAH and was not included in the final analysis. Thus, eight rats per treatment group satisfactorily completed the experimental protocol except in nor-BNI/BRL 52537 + nor-BNI, in which seven rats were included in the final analysis.

Baseline body weight was similar in all treatment groups before randomization to various treatments. Total weight loss on Day 4 of reperfusion was less with saline/BRL 52537 treatment as compared with saline/saline, saline/nor BNI, and nor-BNI/BRL 52537 + nor-BNI (Table 3). Median NDS was significantly better with saline/BRL 52537 treatment as compared with saline/saline, saline/nor-BNI, and nor-BNI/BRL 52537 + nor-BNI (Table 3). In the second experiment, no mortality occurred before completion of the experimental protocol, and no rats were excluded on the basis of the LDF criterion.


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  		Table 3. Daily Weight Loss and Neurological Deficit Score (NDS)
 
Triphenyltetrazolium chloride-determined infarct volume in survivors at 4 days of reperfusion was significantly attenuated with saline/BRL 52537 compared with saline/saline treatment. Infarct volume in rats treated with saline/nor-BNI was not different from those treated with saline/saline. Addition of nor-BNI to BRL 52537 completely prevented the neuroprotection conferred by BRL 52537 (Fig. 2). In the second set of experiments, infarct volume was also significantly attenuated in the saline/BRL 52537-treated rats as compared with saline/saline treatment in the cortex (saline/saline, 31.2% ± 5.0%; saline/BRL 52537, 10.1% ± 3.0%), CP complex (saline/saline, 69.2% ± 7.0%; saline/BRL 52537, 32.0% ± 7.1%), and total hemisphere (saline/saline, 15.8% ± 2.1%; saline/BRL 52537, 4.6% ± 1.7%).



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  		Figure 2. Triphenyltetrazolium chloride-determined infarct volume at 4 days of reperfusion in the ipsilateral hemisphere, cerebral cortex, and caudoputamen complex in various treatment groups (n = 8 in all groups except n = 7 in the nor-BNI/nor-BNI + BRL 52537 treatment group) (mean ± SEM). *P < 0.05 versus saline/saline.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrates two important findings. First, IV administration of a selective KOR agonist, BRL 52537, improves functional and histological outcomes when administered at the onset of reperfusion after two hours of transient focal ischemia that is not mediated by a decrease in core body temperature. Second, the conferred neuroprotection by BRL 52537 is prevented with the addition of the KOR antagonist nor-BNI. Thus, neuroprotective effects of a selective KOR agonist appear to be mediated at the level of the KOR or its downstream consequences.

Pharmacologically defined subtypes for the opioid receptors are well established and are based on the relative affinity and rank order of agonist potencies (33,34). Autoradiographic studies have shown two functionally distinct KORs ({kappa}1 and {kappa}2) in rat brain (33,34), and both full-length and truncated KOR messenger RNA transcripts have been characterized in the brain (35). Receptor subtype-specific KOR agonists or antagonists are not readily available. We used a water-soluble agent, BRL 52537 hydrochloride (20–23), which is highly specific for the {kappa} receptor (e.g., Ki {kappa}, 0.24 nM; Ki µ, 1560 nM) and has 16 times the potency of standard KOR ligands such as U-60,488. To further test the receptor specificity of ischemic neuroprotection with BRL 52537, we used the standard KOR antagonist, nor-BNI (Ki {kappa}, 0.28 nM; selectivity ratio {kappa}/µ, 22; {kappa}/{delta}, 17) (24–26). BRL 52537’s and nor-BNI’s relative {kappa}1/{kappa}2 affinities are not established. IV administration of BRL 52537 and nor-BNI or their combination did not have any significant effects on the physiological variables during ischemia and early reperfusion. In several preliminary experiments, we ascertained that IV infusion of 1 mg · kg-1 · h-1 of BRL 52537 for 4 days in naïve (nonischemic) rats did not alter sensorium or level of activity as compared with vehicle controls and did not produce any gross evidence of neuronal death, myelin injury, or gliosis on histopathology. The rationale for using the dose of nor-BNI was based on our preliminary dose-escalation experiments (data not shown) in naïve nonischemic rats that demonstrated significant sedation produced by the dose used in this study (1 mg · kg-1 · h-1).

The finding that BRL 52537 reduces damage from experimental stroke when infusion starts at reperfusion is consistent with our previous work (19), as well as that of other investigators. Baskin et al. (8) demonstrated ischemic neuroprotection in the cat with three different {kappa} agonists when drugs were started six hours after permanent vascular occlusion and continued with slow-release subcutaneous osmotic pumps for continuous drug delivery for seven days. In mice, opioid receptor binding studies in focal cerebral ischemia suggest that KOR binding is preserved for long time periods (12–48 hours), more so than {delta}- and µ-opioid receptors (36). The functional significance of these findings remains unclear. Modulation of excitatory neurotransmitter release by exogenous KOR agonists on preserved {kappa}-binding on presynaptic membranes has been postulated to be one mechanism for a potentially long therapeutic window with KOR agonists, suggesting a potentially long therapeutic window. In this study, addition of nor-BNI to BRL 52537 completely reversed the neuroprotection conferred with BRL 52537 treatment alone, confirming that the observed ischemic neuroprotection with BRL 52537 is specifically mediated via the KORs and is not a nonspecific action. BRL 52537 did not just provide histological neuroprotection in our study; in addition, BRL 52537-treated rats had less mortality, better NDS, and less weight loss as compared with controls in our study. Although weight loss is difficult to interpret in a catabolic state after stroke, it has been used as an indirect indicator of stroke severity (37,38).

With nor-BNI treatment alone, we did not see any worsening in injury volume or NDS compared with control treatment. This could be because two hours of focal ischemia resulted in severe or near-maximal injury in our model. Thus, it is plausible that one would see greater ischemic injury with nor-BNI treatment if lesser degrees and intensities of ischemia were used. Alternatively, the activity of endogenously released agonists for KOR may become relatively small during reperfusion after two hours of ischemia. Prolonged treatment with BRL 52537 (19) and nor-BNI (data not shown) at doses used in this study for four days does not produce gross evidence of neuronal death, myelin injury, or gliosis.

Temperature is a critical variable that modulates outcome and stroke size after focal ischemia, in that small differences in brain temperature during and after ischemia can have a profound influence on histopathologic outcome (39,40). In this study, we controlled rectal and temporalis muscle temperatures during ischemia and early reperfusion. Furthermore, we observed no changes in core body (rectal) temperatures for the entire duration of treatment. Although others have demonstrated a hypothermic response to KOR agonists (41), we conclude that the observed ischemic neuroprotection in our study was not due to changes in body temperature.

Although the purpose of our study was not to discern mechanisms of ischemic neuroprotection by BRL 52537, several antiexcitotoxic mechanisms have been postulated. For example, in vitro (13–16) KOR agonists modulate glutamate toxicity by attenuating presynaptic glutamate release, possibly by closing N-type Ca2+ channels (17). KOR agonists may also inhibit excitatory postsynaptic potentials by attenuating presynaptic Ca2+ influx and consequent glutamate release (13–16), as well as by modulating N-methyl-D-aspartate-induced dopamine release (33). Repeated injections of a KOR agonist, U-50,488H, into mice under nonischemic conditions increase regional NO synthase activity in brain (42). Recently, we demonstrated that BRL 52537 attenuates ischemia-evoked NO production in vivo (19) and postulated that the conferred neuroprotection may be due to attenuation of the excitotoxic effects of NO from neuronal sources. Other alternative neuroprotective mechanisms include amelioration of cerebral edema by KOR agonists (5). Our study demonstrates that BRL 52537 confers significant histological neuroprotection when corrected for cerebral swelling at the end point used in this study (four days). Furthermore, we have previously shown that maximal edema occurs at 48 hours after 2 hours of MCAO in our model (43).

In conclusion, these data demonstrate and confirm that KORs are important in experimental ischemic brain injury and that they may provide a therapeutic strategy for neuroprotection in ischemic stroke.


   Acknowledgments
 
Supported in part by US Public Health Service/National Institutes of Health Grants NS20020 and NS33668. AB is supported in part by the Established Investigator Grant from the American Heart Association.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 7, 2003.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press