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Anesth Analg 2001;93:581-586
© 2001 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Resensitization of Blood Pressure Response to µ-Opioid Peptide Agonists After Acute Desensitization

Hazel H. Szeto, MD, PhD, Yi Soong, MD, Dunli Wu, MD, and Joseph Fasolo, BS

Department of Pharmacology, Weill Medical College of Cornell University, New York, New York

Address correspondence and reprint requests to Hazel H. Szeto, MD, PhD, Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Address e-mail to hhszeto{at}mail.med.cornell.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
IV administration of µ-opioid peptide agonists (DAMGO, DALDA, and [Dmt1]DALDA) results in a transient, naloxone-sensitive, increase in blood pressure in awake sheep. Despite significant differences in pharmacokinetics, these blood pressure responses all last <15 min. The lack of correlation between half-life and duration of action suggested rapid desensitization. When a second dose of the same agonist was repeated 30 min later, the response was completely abolished. An increase in blood pressure and rapid desensitization was also observed with the {kappa}-opioid agonist (U50488H), whereas {delta}-agonists (DPDPE and DELT) had no effect on blood pressure. The response to DAMGO was abolished after prior exposure to DAMGO or DALDA, but there was no evidence of cross-desensitization between µ and {delta}, or µ and {kappa}, opioid agonists. Full resensitization of the blood pressure response occurred by 4 h for DAMGO (t1/2 = 15 min) and by 48 h for [Dmt1]DALDA (t1/2 = 1.8 h). These data support our hypothesis that the transient nature of the blood pressure response to µ-opioid agonists is caused by rapid desensitization and suggest that the rate of resensitization is dependent on the pharmacokinetics of the agonist.

IMPLICATIONS: This report suggests that rapid desensitization accounts for the transient increase in blood pressure observed after IV administration of µ-opioid agonists, and that the rate of resensitization is a function of the elimination half-life of the agonist.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Morphine is recommended for use in acute myocardial infarction to relieve pain and to reduce the increased sympathetic tone caused by cardiac ischemia and anxiety (1). Systemic morphine is generally associated with hypotension, especially in volume-depleted patients or when morphine is administered concomitantly with other anesthetic drugs. In contrast, systemic morphine administration has been reported to produce an initial brief increase in blood pressure in unanesthetized cats and dogs (2,3). A transient increase in mean arterial pressure, accompanied by an increase in heart rate and oxygen consumption, was recently reported when morphine was given as the sole medication in healthy humans (4). This cardiovascular stimulation was not observed with oxycodone. An increase in myocardial oxygen consumption might be harmful to patients with compromised myocardial function. The mechanism of the transient cardiovascular stimulation by morphine is not clear.

An immediate, but transient, increase in blood pressure was also reported after IV administration of highly selective µ-opioid peptide agonists in unanesthetized sheep (5–7). This increase in blood pressure was immediate in onset and was observed after IV administration of DAMGO (H-Tyr-D-Ala-Gly-NMePhe-Gly-ol), DALDA (H-Tyr-D-Arg-Phe-Lys-NH2), and [Dmt1]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2',6'-dimethyltyrosine). DALDA and [Dmt1]DALDA are dermorphin analogs with extraordinary selectivity for the µ-opioid receptor (see Table 1) (8,9). In contrast, selective {delta}-opioid agonists had no effect on blood pressure (6). Available evidence suggests that this brief increase in blood pressure is mediated by activation of peripheral µ-opioid receptors (7). The responses to all three µ-opioid peptide agonists were short-lived (<15 min) despite elimination half-lives that ranged from 0.25 to 1.8 h (10).


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  		Table 1. In Vitro Opioid Activity Profiles of DAMGO, DALDA, and [Dmt1]DALDA
 
The lack of correlation between elimination half-life and duration of drug action suggested that the duration of response might be limited by rapid desensitization of the µ-opioid receptor. Rapid homologous desensitization has been demonstrated in cell cultures expressing the µ-opioid receptor, and receptor phosphorylation and internalization may be responsible for the observed desensitization (11–13). Agonist exposure for as little as 3 min led to desensitization of the µ-opioid receptor expressed in Xenopus oocytes, with increased phosphorylation of the receptor observed by 5 min (11). With short periods of agonist exposure, resensitization of the µ-opioid receptor could be observed after 10 min of washing with agonist-free medium. The relevance of this desensitization phenomenon in the intact organism has not been demonstrated.

Our objectives were to determine whether desensitization occurs to the blood pressure response with µ-opioid peptide agonists, whether there is cross-desensitization among µ-, {delta}- and {kappa}-opioid agonists, and whether the time-course of resensitization is agonist-dependent.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Drugs and Chemicals
[Dmt1]DALDA was synthesized by Dr. Peter W. Schiller (Clinical Research Institute of Montreal, Montreal, Quebec, Canada). All other drugs were provided by the National Institute on Drug Abuse. DAMGO (0.3 mg/kg), DALDA (0.6 mg/kg), [Dmt1]DALDA (0.006 mg/kg), DPDPE (H-Tyr-D-Pen-Gly-Gly-D-Pen-OH; 0.3 mg/kg), and U50488H ([trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide]; 1.5 mg/kg) were dissolved in sterile saline for IV administration to animals. DELT (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2; 0.3 mg/kg) was first dissolved in 10 drops of dimethyl sulfoxide and then diluted in sterile saline just before use.

Chronic indwelling catheters were surgically implanted in the descending aorta and inferior vena cava of adult female sheep under "single shot" epidural anesthesia according to guidelines approved by the Institution for the Care and Use of Animals at Weill Medical College of Cornell University. Sixteen sheep were used for this study, and the weight of the animals ranged between 50 to 58 kg. Five or more days were allowed for recovery from surgery before experimental studies. Continuous recording of blood pressure and heart rate were obtained with a Gould 2800S analog recorder (Gould, Valley View, OH) and appropriate amplifiers.

Studies on Desensitization with µ-Opioid Agonists
After a 2-h control period, each animal received either two doses of the same µ-opioid agonist (DAMGO-DAMGO, DALDA-DALDA, [Dmt1]DALDA-[Dmt1]DALDA), or two different µ-opioid agonists (DALDA-DAMGO), given IV 30 min apart.

Studies on Desensitization with the {kappa}-Opioid Agonist U50488H
After a 2-h control period, each animal received two IV doses of U50488H 30 min apart.

Studies on Cross-Desensitization Among µ-, {delta}-, and {kappa}-Opioid Agonists
After a 2-h control period, each animal received one of the following two drug combinations given IV separated by 30 min: vehicle-DAMGO, DAMGO-DAMGO, DPDPE-DAMGO, DELT-DAMGO, vehicle-U50488H, U50488H-U50488H, U50488H-DAMGO, or DAMGO-U50488H.

Studies on Resensitization of Response to µ-Opioid Agonists
The time course of resensitization was studied using two drugs, DAMGO and [Dmt1]DALDA, because of their similar potency but very different elimination half-lives (0.25 and 1.8 h, respectively). For DAMGO, the second dose was administered 0.5, 1, 2, or 4 h after the first dose. For [Dmt1]DALDA, the second dose was administered 0.5, 4, 24, and 48 h after the first dose. For each drug, the four different times of pretreatment were conducted in the same animal on 4 different days, with at least 2 days between studies.

Blood pressure and heart rate were analyzed by using 1-min intervals, and control values were determined over 5 min before drug administration. Mean blood pressure was calculated as diastolic pressure + 1/3 pulse pressure. Data were presented as mean ± SE. The effect of each drug on mean blood pressure, and the effects of various pretreatments on the response to DAMGO, were analyzed by using one-way analysis of variance. Post hoc analyses were performed with the Dunnett’s test.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Studies on Desensitization with µ-Opioid Agonists
There was no significant difference in mean arterial blood pressure or heart rate before drug treatment in the different groups. Mean arterial blood pressure was 74.8 ± 1.6, 74.5 ± 4.0, and 70.7 ± 2.8 mm Hg before the administration of DAMGO, DALDA, and [Dmt1]DALDA, respectively. Control heart rate was 75.6 ± 2.7, 79.5 ± 4.1, and 72.7 ± 7.8 bpm, respectively. The administration of the first dose of each of the three µ-opioid agonists all produced significant increases in blood pressure (P < 0.001) (Fig. 1). The doses were selected based on previous studies to produce a 20%–40% increase in blood pressure. There was no significant change in heart rate after any of the three µ-opioid agonists (data not shown). When a second dose of the same µ-opioid agonist was repeated 30 min later, there was no change in blood pressure for DAMGO, DALDA, or [Dmt1]DALDA (Fig. 1).



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  		Figure 1. Comparison of the blood pressure response to the first and second dose of DAMGO (0.3 mg/kg, top panel, n = 5), DALDA (0.6 mg/kg, middle panel, n = 5) and [Dmt1]DALDA (0.006 mg/kg, bottom panel, n = 4). The second dose was given 30 min after the first dose. The arrows indicate time of peptide administration. Data were presented as percent change in blood pressure from control values.

 
Studies on Desensitization with the {kappa}-Opioid Agonist U50488H
Mean arterial blood pressure was 71.2 ± 5.1 mm Hg before U50488H administration. Blood pressure increased significantly after the first dose of U50488H (P < 0.001), with a peak increase of 51.4% ± 9.7% at 5 min after drug administration. Heart rate increased from 81.8 ± 7.4 bpm to 130.4 ± 16.5 bpm at 2 min. The increase in blood pressure after U50488H was significantly longer compared with the µ-opioid agonists. Repeat administration of the same dose of U50488H 30 min later produced no significant change in arterial blood pressure (Fig. 2) or heart rate (data not shown).



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  		Figure 2. Comparison of the blood pressure response to the first and second dose of U50,488H. The two doses of U50,488H (1.5 mg/kg) were given IV 30 min apart (n = 5). The arrows indicate time of peptide administration. Data were presented as percent change in blood pressure from control values.

 
Studies on Cross-Desensitization Among µ, {delta}, and {kappa}-Opioid Agonists
Prior exposure to one µ-opioid agonist resulted in complete desensitization to a different µ-opioid agonist given 30 min later (Fig. 3). The response to DAMGO was abolished after pretreatment with either DAMGO or DALDA (P < 0.05). IV administration of the {delta}-opioid agonists (DPDPE or DELT) alone had no effect on blood pressure or heart rate (data not shown), and prior exposure to DPDPE or DELT had no effect on the blood pressure response to DAMGO 30 min later (Fig. 3). In contrast, prior exposure to U50488H significantly decreased the response to DAMGO (P < 0.05), but pretreatment with DAMGO did not significantly alter the response to U50488H (Fig. 4).



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  		Figure 3. Effects of DAMGO (0.3 mg/kg) given 30 min after pretreatment with vehicle (VEH) (n = 5), DAMGO (0.3 mg/kg, n = 5), DALDA (0.6 mg/kg, n = 5), DPDPE (0.3 mg/kg, n = 4), or DELT (0.3 mg/kg, n = 4). Data were presented as maximal percent change in blood pressure after DAMGO from control values. *P < 0.05 compared with VEH pretreatment.

 


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  		Figure 4. Top panel, Effects of DAMGO (0.3 mg/kg) given 30 min after pretreatment with vehicle (VEH) (n = 5), DAMGO (0.3 mg/kg, n = 5), or U50,488H (1.5 mg/kg, n = 4). Bottom panel, Effects of U50,488H (1.5 mg · kg) given 30 min after pretreatment with VEH (n = 5), U50,488H (1.5 mg/kg, n = 5), or DAMGO (0.3 mg/kg, n = 4). Data were presented as maximal percent change in blood pressure after DAMGO from control values. *P < 0.05 compared with VEH pretreatment.

 
Studies on Resensitization of Response to µ-Opioid Agonists
To determine the time course of resensitization, the second dose of DAMGO was given at various times after the first dose. Figure 5 (top panel) shows 50% recovery of the response to DAMGO if the second dose of DAMGO was given 1 h after the first dose. By 4 h, the response to DAMGO was completely recovered. In contrast, the resensitization of the response to [Dmt1]DALDA was much slower, with only 60% recovery by 24 h, and full recovery was not observed until 48 h after the first dose.



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  		Figure 5. Time course of resensitization of the blood pressure response to DAMGO (top panel) and [Dmt1]DALDA (bottom panel). The second dose of DAMGO was given 0.5, 1, 2, or 4 h after the first dose. The second dose of [Dmt1]DALDA was given 0.5, 4, 24, and 48 h after the first dose. Only two doses of the same drug were given in any one experiment. Data were presented as maximal percent change in blood pressure after DAMGO from control values (n = 4–5 for each experiment).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
As previously reported, these highly selective µ-opioid agonists produced a transient increase in blood pressure in awake sheep (5–7). This increase in blood pressure is similar to the transient increase in blood pressure reported after IV administration of morphine to healthy human subjects (4). The apparent difference in potency of the three peptide analogs is attributed, in part, to differences in their pharmacokinetics and in their affinity and in vitro potency at the µ-opioid receptor. The plasma clearance of DALDA and [Dmt1]DALDA are 10-fold lower compared with DAMGO in sheep (10), which would make DALDA 20-fold less potent than DAMGO, and [Dmt1]DALDA fivefold more potent than DAMGO. These relative potencies are consistent with the relative potency of DALDA and [Dmt1]DALDA in the guinea pig ileum assay (see Table 1) (9). The mechanism of this blood pressure response is not clear, but there is evidence that it is mediated by peripheral opioid receptors (7). This blood pressure response is not associated with any change in heart rate, and these µ-opioid agonists inhibited baroreflex-mediated bradycardia to norepinephrine (7,14,15).

The duration of blood pressure response to the three µ-opioid agonists was similar despite significant differences in their elimination half-lives. The elimination half-lives of DAMGO, DALDA, and [Dmt1]DALDA were recently determined in sheep and found to be 0.25, 1.5, and 1.8 hours, respectively (10). The results of the present study support our hypothesis that the transient nature of the blood pressure response to µ-opioid agonists is caused by rapid desensitization or tachyphylaxis. When the same dose of µ-opioid agonist was repeated 30 minutes later, the response was completely abolished. This loss of response to the second dose was observed for all three µ-opioid agonists, and there was cross-desensitization among the three µ-opioid agonists. These data suggest that the decline in response after the first dose reflects rapid and progressive onset of desensitization rather than elimination of the agonist, and it would explain the lack of correlation between duration of response and elimination half-life of the agonist.

Desensitization has been observed in cell systems containing native µ-opioid receptors or transfected with the cloned µ-opioid receptor. Prior exposure to DAMGO attenuates the inhibition of adenylyl cyclase activity (13,16,17) and activation of potassium channels (11) by DAMGO. Furthermore, desensitization seems to develop very rapidly for the µ-opioid receptor. With µ-opioid receptors expressed in Xenopus oocytes, a reduction in current was found within three minutes of exposure and maximal desensitization occurred within 20 minutes of agonist exposure (11). The magnitude of desensitization was dependent on both exposure time and concentration of the agonist, with maximal desensitization observed at 10 µM of DAMGO. Cross-desensitization has not been studied in cell systems.

The present results also show acute desensitization to the response induced by the {kappa}-opioid agonist U50488H. Desensitization of the {kappa}-opioid receptor has been demonstrated in cell culture studies with reduction in the ability of U50488H to inhibit forskolin-stimulated adenylyl cyclase and increase GTP{gamma}S binding have been reported after pretreatment with U50488H (18,19). The longer duration of the response to U50488H suggests a slower onset of desensitization with the {kappa}-opioid receptor. Desensitization of the {kappa}-opioid receptor in cellular systems is also slower and less robust compared with the µ-opioid receptor (18–20).

This desensitization seems to be receptor-specific in that exposure to one µ-opioid agonist resulted in cross-desensitization to a different µ-opioid agonist, but prior exposure to {delta}-opioid agonists did not diminish the response to DAMGO. It is notable that pretreatment with U50488H partially attenuated the response to a subsequent dose of DAMGO. This may be explained by the fact that the (+)-(1R,2R)-U50488H isomer possesses weak µ-opioid activity (21) and the use of the racemate compound in this study resulted in partial desensitization of the µ-opioid receptor. This is supported by the finding that pretreatment with DAMGO did not significantly attenuate the response to U50488H. Together, these data support homologous, but not heterologous, desensitization of the response to µ- and {kappa}-opioid agonists.

The significantly different time course for resensitization to DAMGO and [Dmt1]DALDA also supports the notion that this is not a nonspecific functional desensitization because the duration of the response was similar for both agonists. The response to DAMGO was completely resensitized after four hours whereas resensitization to [Dmt1]DALDA took as long as two days. The time course of resensitization correlates with the elimination half-life of the two agonists, with the half-life of [Dmt1]DALDA being 7–8 times longer compared with DAMGO. These data suggest that the rate of recovery from desensitization is agonist dependent and is a function of the duration of agonist exposure. Desensitization was reversible in Xenopus oocytes within three minutes after agonist washout (11). It has also been reported that {delta}-opioid receptors in NG108 cells can be resensitized with a time constant of 6.7 minutes (22). Unlike these in vitrostudies, the rate of agonist removal in the intact animal is not immediate but is a function of the pharmacokinetics of the agonist.

Several mechanisms have been implicated in decreased responsiveness to opioid agonists with repeated or continuous exposure in cell systems, including receptor phosphorylation, uncoupling of the receptor from G proteins, and reduction in receptor number as a result of receptor internalization. Increased phosphorylation of the µ-opioid receptor protein was demonstrated after as little as five minutes of exposure to DAMGO in Xenopus oocytes (11). The rank order for various opioid agonists in desensitization generally paralleled the rank order for phosphorylation of the µ-opioid receptor in Chinese hamster ovary (CHO) cells (12). Several studies have suggested the involvement of protein kinases (PKC) in opioid receptor desensitization. Activation of PKC reduced the responsiveness of µ-opioid receptors in Xenopus oocytes (23), and another study demonstrated the involvement of PKC in the functional uncoupling of {delta}-opioid receptors from G-proteins (24). The rapid onset and reversal of desensitization is supportive of receptor phosphorylation as the major underlying mechanism of desensitization (11,12). Down-regulation of the µ receptor has been demonstrated after DAMGO exposure in CHO and human embryonic kidney cells (13,25,26), and there is evidence that the reduced receptor number was caused by rapid internalization of the µ-opioid receptor (25,26). Reduction in 3H]DAMGO binding was observed within 5 minutes of DAMGO exposure in CHO cells with maximal decrease (58%) reached within 30 minutes of continuous agonist treatment (25).

In summary, these results provide evidence of rapid desensitization to the cardiovascular actions of µ-opioid agonists in vivo. The rapid onset of desensitization accounts for the transient nature of the response to selective µ-opioid agonists, and the rate of resensitization is dependent on the pharmacokinetics of the agonist. In addition, these results demonstrate homologous desensitization to both µ- and {kappa}-opioid receptors and there is no evidence to suggest heterologous desensitization among µ-, {delta}-, and {kappa}-opioid receptors. Rapid desensitization might explain why significant hypertension is usually not seen with systemic morphine in humans. In addition, rapid desensitization would limit any potential increase in myocardial oxygen demand when µ-opioid agonists are administered to patients with compromised myocardial function. In addition to being a very potent and long-acting analgesic when given intrathecally (27), we have recently found that [Dmt1]DALDA also produces a long-lasting antinociceptive response after subcutaneous administration in mice and it seems to have cardioprotective actions against ischemia-reperfusion injury in the isolated guinea pig heart (unpublished data). Such potent, long-acting, highly selective µ-opioid agonists with minimal cardiovascular effects may be particularly useful for pain relief after acute myocardial infarction.


   Acknowledgments
 
This work was supported, in part, by a multi-center program project grant from the National Institute on Drug Abuse (5PO1 DA08924).

We thank Abimbola Omoniyi and Michelle Arndt for their technical assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 2, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press