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-opioids in conscious lambs
1 Department of Physiology & Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Abstract |
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-opioid receptor agonist U-50488H at two stages of postnatal maturation under physiological conditions. Experiments were carried out firstly to define systemic and renal haemodynamic responses to -opioid receptor activation and, secondly, to determine whether these effects are altered during postnatal maturation. To investigate whether the responses to U-50488H resulted from receptor-dependent effects, responses to U-50488H were also tested in the presence of the specific -opioid receptor antagonist 5'-guanidinonaltrindole (GNTI). Experiments were carried out in two groups of conscious, chronically instrumented lambs aged 
1 and 6 weeks. Mean arterial pressure, mean venous pressure and renal blood flow (RBF) were measured for 30 min before and 90 min after i.v. injection of U-50488H or vehicle. Heart rate increased in both age groups of lambs within 10 min of U-50488H administration. Mean arterial pressure decreased for 50 min following U-50488H administration at 1 week but, in contrast, increased transiently at 10 min in 6-week-old lambs, returning to control levels by 20 min. In both age groups, there was a sustained decrease in RBF following U-50488H. The aforementioned responses to U-50488H were abolished by pretreatment with GNTI. These data provide the first measurements of systemic and renal haemodynamic responses to -opioid receptor activation during postnatal maturation.
(Received 7 February 2006;
accepted after revision 2 March 2006; first published online 25 May 2006)
Corresponding author F. G. Smith: Department of Physiology & Biophysics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada. Email: fsmith{at}ucalgary.ca
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Introduction |
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), mu (µ) and delta (
), respectively. Opioids are involved in a variety of processes, including fluid and electrolyte homeostasis, feeding, pain, substance abuse, traumatic brain injury and haemorrhagic shock.
Although µ and receptors are implicated in many of the aforementioned responses, a role for receptors in influencing cardiovascular homeostasis has previously been recognized following its localization to discrete brain regions involved in cardiorespiratory control (Mansour et al. 1996). For example, all opioid receptor subtypes have been localized to midbrain and brainstem regions involved in cardiovascular integration (Goldstein, 1976; Pfeiffer et al. 1981; Mansour et al. 1988; Rutherford & Gundlach, 1993), yet -binding sites predominate in the preoptic area, and in several hypothalamic regions of the rat brain, including the supraoptic and paraventricular nuclei, notably the magnocellular and parvocellular regions (Mansour et al. 1996).
During the perinatal period, endogenous opioid peptides appear to be upregulated. Elevated levels of enzymes such as enkephalin convertase (which forms enkephalin) around the time of birth in rats predict a heightened opioid activation in the newborn (Strittmatter et al. 1986). Furthermore, Zhang & Moss (1995) demonstrated age-related changes in the content of ß-endorphin and methionine-enkephalin, as well as dynorphin A and B within the tractus solitarii, ambigualis, gigantoreticularis and parabrachialis medialis nuclei in piglets, brain regions that normally influence cardiorespiratory control. In the ovine brain, maximum opioid receptor binding is present in the pons and medulla by term of gestation, with opiate receptor binding remaining high in newborn lambs and decreasing with postnatal maturation (Villiger et al. 1982). In addition, gene expression of endorphin precursors, proenkephalin A and B, is detectable in the kidney of newborn rat pups but not adult rats (Keshet et al. 1989) and newborn piglets but not adult pigs (Pittius et al. 1987; Keshet et al. 1989; Kew & Kilpatrick, 1990). Therefore, it seems likely that -opioid peptides may modulate systemic and/or renal haemodynamic effects during the perinatal period, perhaps also exhibiting age-dependent effects.
The present study was carried out to test the hypothesis that activation of -opioid receptors modulates systemic and renal haemodynamics in an age-dependent manner. To test this hypothesis, cardiovascular effects of the -opioid receptor agonist U-50488H were measured at two stages of postnatal maturation under physiological conditions in order: (a) to define systemic and renal haemodynamic responses to -opioid receptor activation; and (b) to determine whether these effects are altered during postnatal maturation. To investigate whether the responses to U-50488H resulted from direct activation of -opioid receptors (and to rule out any non-receptor or secondary effects of U-50488H), experiments were also carried out in the presence of the specific -opioid receptor antagonist 5'-guanidinonaltrindole (GNTI).
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Methods |
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1 (n
= 13) and 6 weeks (n
= 15). Animals were obtained from a local source (Woolfitt Acres, Olds, Alberta, Canada) and housed with their mothers in individual pens in the vivarium of the Health Sciences Centre except during surgery and experiments. All surgical and experimental procedures were carried out in accordance with the Guide to the Care and Use of Experimental Animals provided by the Canadian Council on Animal Care, and with the approval of the Animal Care Committee of the University of Calgary. Surgical procedures
Using aseptic techniques and previously detailed methods (Smith & Abraham, 1995; de Wildt & Smith, 1997), surgery was performed on newborn lambs at least 2 days after birth and on older lambs at least 4 days before the start of experiments.
Briefly, anaesthesia was induced with a mask and halothane (3–4%) in oxygen, the trachea was intubated and anaesthesia was maintained by ventilating the lungs with halothane (1–1.5%) in a mixture of nitrous oxide and oxygen (3:2). Under sterile conditions, polyethylene catheters (i.d. 1.19 mm, o.d. 1.70 mm; Intramedic) were inserted into right and left femoral vessels and advanced to the abdominal aorta and inferior vena cava, for pressure measurements, intravenous (i.v.) infusions and drug injections during experiments. Catheters were tunnelled subcutaneously to exit the lamb on the left and right flanks.
Through a left flank incision, the left kidney was approached, the renal artery dissected free of tissue, and a precalibrated ultrasonic flow transducer placed around the left renal artery (3–4S, Transonics Instruments Inc., Ithaca, NY, USA) as previously described (de Wildt & Smith, 1997) for later measurement of renal blood flow (RBF). Upon closure of incisions, all catheters and the flow transducer cable were secured in a body jacket (Lomir Inc., Montreal, Quebec, Canada) for safe storage between experiments. Antibiotics (5.0 mg kg–1 enrofloxacin, Baytril) were administered intramuscularly at the time of surgery and at 12 h intervals thereafter, for 48 h. Lambs were allowed to recover from the effects of surgery and anaesthesia in a critical care unit for small animals (Shor-Line, Kansas City, KS, USA), with adjustable oxygen supply. All lambs were able to stand within 60 min of completion of surgery, upon which they were returned to the vivarium.
Experiments were not begun until a minimum of 3 days had elapsed after the day of surgery. During this time, animals were trained to rest comfortably in a supportive sling in the laboratory environment for 1–2 h daily to allow them to become accustomed to their surroundings before the start of experiments.
Experimental procedures
On the day of an experiment, each lamb was removed from the vivarium and placed in the same supportive sling in the laboratory environment for at least 60 min before the experiment started. During this time and throughout the experiment, 5% dextrose in 0.9% sodium chloride was infused i.v. (4.17 ml kg–1 h–1), to assist in maintaining fluid balance. Arterial and venous catheters were connected to pressure transducers (P23XL, Statham, West Warwick, RI, USA) for measurement of mean arterial pressure (MAP) and mean venous pressure (MVP); the flow transducer cable was connected to a flowmeter (Transonics Systems Inc., Ithaca, NY, USA) for measurement of RBF. Mean arterial pressure, MVP and RBF were recorded continuously onto a polygraph (model 7, Grass Instruments, West Warwick, RI, USA) and digitized at 200 Hz using the acquisition and analysis software PolyVIEW® (Astro-Medical Inc., Grass Instrument Division, West Warwick, RI, USA).
At the end of each experiment, lambs were returned to the ewe, where they were housed until the next study day. After all experiments, lambs were killed with sodium pentobarbitone by I.V. Placement of catheters and the ultrasonic flow transducer was confirmed by post mortem inspection, and the zero offset of the flow transducer was determined; both kidneys were removed and immediately weighed.
Protocol I.
Experiments consisted of measurement of arterial pressure for 30 min before and 90 min after i.v. bolus injection of the specific -opioid receptor agonist U-50488H. In each animal, at intervals of 24–48 h and in random order, one of the following doses of U-50488H was tested: 0, 0.1, 0.50, 1.0 and 5.0 mg kg–1, until a maximum of three doses had been tested in each lamb. The volume of each injection was 0.35 ml kg–1. Heart rate was determined from the systolic peak of the arterial pressure waveform. In both age groups, the U-50488H dose versus peak HR response curve was constructed and the EC100 dose (minimum inhibitory concentration) was determined for use in protocols II and III.
Protocol II. Mean arterial pressure, MVP and RBF were measured for 30 min before and 90 min after i.v. injection of U-50488H (EC100 dose selected from protocol I) (experiment one) and vehicle (0.35 ml kg–1 0.9% sodium chloride; experiment two). The two experiments were carried out in random order at intervals of 24–48 h.
Protocol III.
To determine the role of -opioid receptors in eliciting the cardiovascular responses to U-50488H measured in protocol II, and to determine the duration of its inhibitory effect, responses to U-50488H were also measured 24 h before and 1, 24, 48 and 72 h after i.v. injection of the specific -opioid receptor antagonist GNTI, at a dose of 0.25 mg kg–1 in 1-week-old lambs and 0.5 mg kg–1 in 6-week-old lambs. These doses of GNTI were selected as the EC100 from preliminary experiments over the range of doses 0–5.0 mg kg–1 in the two age groups.
Details of drug selection and preparation
U-50488H.
[(+/–)-Trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzene-acetamide methane sulphonate salt] (U-50488H; Sigma-Aldrich, St Louis, MO, USA) was selected because it is a highly selective -opioid receptor agonist (Lahti et al. 1982; Vonvoigtlander et al. 1983) and relatively inactive at the µ-receptor. U-50488H was dissolved in 0.9% sodium chloride to make a stock solution of 20 mg ml–1. Different doses of U-50488H were prepared by serial dilution and stored in aliquots at –20°C until later use.
GNTI.
5'-Guanidinyl-17-(cyclopropylmethyl)-6,7-dehydro-4,5
-epoxy-3,14-dihydroxy-6,7-2',3'-indolomorphinian dihydrochloride (GNTI; Tocris, Ellisville, MO, USA) is a potent -opioid receptor antagonist displaying 208- and 799-fold selectivity over µ and receptors, respectively, a greater antagonist potency than the prototypical -opioid receptor antagonist, norbinaltorphimine (nor-BNI) and with a considerably shorter half-life (Jones & Portoghese, 2000; Jewett et al. 2001). GNTI was dissolved in sterile water to make a stock solution of 10 mg ml–1; doses were prepared by dilution on the morning of the experiment.
Computations
Using PolyVIEW®, 1 min files were extracted for all cardiovascular variables and data were exported to a spreadsheet (Excel, Microsoft Office) where they were averaged over consecutive 10 min intervals. Renal vascular resistance (RVR) was calculated as follows: (MAP – MVP)/RBF, where RBF was normalized per gram kidney weight.
Statistical analyses
Since values obtained during the three consecutive control 10 min periods were similar, these were averaged to one value (Control). For protocol I, dose-dependent effects of U-50488H on HR were evaluated using one-way ANOVA. For protocol II, ANOVA procedures for repeated measures over time were applied to the measured variables, factors being age (1 and 6 weeks) and treatment (U-50488H and vehicle); where the F value was significant, a Dunnett's pairwise multiple comparison procedure was applied to determine significant differences from Control. For protocol III, one-way ANOVA was applied to determine the effects of GNTI on the responses to U-50488H in each age group. Where the F value was significant, a Holm's Sidak multiple comparison procedure was applied to determine where the significant difference(s) occurred. Significance was accepted at the 95% confidence interval. All values in the text, including data in figures and tables, are presented as means ± s.d.
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Results |
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For protocol I, nine animals aged 9.3 ± 1.9 days (body weight, 7.8 ± 1.3 kg) and 11 animals aged 40.4 ± 4.0 days (body weight, 12.7 ± 2.6 kg) were studied. Figure 1 illustrates the U-50488H dose versus peak HR response in both age groups. The EC100 dose was 0.5 mg kg–1 at 1 week and 1.0 mg kg–1 at 6 weeks; these doses were applied in protocols II and III.
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For protocol II, seven animals aged 9.4 ± 1.7 days (body weight, 8.2 ± 1.4 kg) and 10 animals aged 38.9 ± 2.2 days (body weight, 12.4 ± 2.9 kg) were studied. There were no differences between vehicle- and U-50488H-treated animals measured during control conditions in both age groups of lambs (Table 1). HR and RVR were decreased and RBF and MVP were increased at 6 compared to 1 week of age.
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50 min, whereas there was only a transient increase in MAP observed at 6 weeks (Fig. 2). There were effects of treatment (P < 0.001) and time (P < 0.001), as well as an interaction between treatment and time (P < 0.001), on the HR response to U-50488H (Fig. 2). That is, in both age groups of animals, HR increased in response to U-50488H but not vehicle. There were no effects of U-50488H or vehicle on MVP.
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For protocol III, four animals aged 16.1 ± 2.5 days (body weight, 8.7 ± 1.3 kg) and four animals aged 46.1 ± 6.0 days (body weight, 14.7 ± 1.9 kg) were studied. There were no effects of GNTI on any of the measured or calculated variables in either age group (Table 2). Effects of U-50488H on the measured variables were, however, abolished by pretreatment with GNTI after 1 h at 1 week and after 24 h at 6 weeks of age (Fig. 4); these inhibitory effects were sustained for 72 h (Fig. 4).
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Discussion |
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-opioid receptors were measured under physiological conditions in conscious, chronically instrumented lambs at two postnatal ages. Novel findings of our study are that administration of the specific -opioid receptor agonist U-50488H to conscious lambs was associated with a small but sustained decrease in MAP in 1-week-old lambs whereas, in contrast, there was a small but transient increase in MAP at 6 weeks. In both age groups of lambs, there was a sustained increase in HR following administration of U-50488H and a sustained decrease in RBF. These haemodynamic responses to U-50448H were abolished by pretreatment with the selective -opioid receptor antagonist GNTI. Our findings demonstrate that -opioids appear to modulate both systemic and renal haemodynamics during the newborn period.
Previous studies in adult mammals have explored the role of -opioid receptors centrally in modulating cardiovascular homeostasis. For example, dynorphin, the endogenous -opioid receptor ligand, when microinjected into the preoptic medialis nucleus of anaesthetized rats, resulted in a decrease in both MAP and HR (Feuerstein & Faden, 1984). Also, Carter & Lightman (1985) showed in urethane-anaesthetized rats, that microinjection of U-50488H into the nucleus tractus solitarius (NTS) elicited a dose-dependent increase in MAP and a small decrease in HR, both of which were blocked by the selective antagonist MR2266BS and were similar to that observed following injection of the -opioid receptor ligand dynorphin. Recently, Gottlieb et al. (2005) showed also in anaesthetized rats, that U-50488H microinjected into the parvocellular paraventricular nucleus was associated with an immediate pressor response along with a baroreflex-evoked bradycardia.
While the CNS effects of -agonists are clearly opioid receptor mediated, the actions of these compounds in the peripheral circulation are not completely understood (Pugsley, 2004). Previous studies investigating systemic cardiovascular effects of -opioid receptor activation in adult animals have provided variable and often conflicting results. For example, i.v. administration of three -opioid receptor agonists (bremazocine, tifluaodom and U-50488H) to urethane-anaesthetized Sprague–Dawley rats was associated with a decrease in MAP (Gulati & Bhargava, 1988). In pentobarbitone-anaesthetized mongrel dogs (Hall et al. 1988), U-50488H produced a dose-related depression in MAP, left ventricular systolic pressure, left ventricular dP/dt and HR. These effects were reversed by the non-selective opioid receptor antagonist naloxone. A second -opioid receptor agonist, spiradoline mesylate, also produced a naloxone-reversible cardiovascular depression (Hall et al. 1988). In chloralose-anaesthetized cats, spiradoline mesylate did not decrease MAP, whereas in baroreceptor-denervated cats, there was a dose-related hypotensive effect. From these observations, it was concluded that the cardiovascular effects of -opioid receptor agonists are peripherally mediated (Hall et al. 1988). In humans, a single 30 min i.v. infusion of a 2 mg dose of the -opioid receptor agonist niravoline to healthy volunteers induced a slight, but significant, increase in blood pressure by 30 min, which disappeared within 120 min, with no change in HR (Connell et al. 1987). In conscious adult ewes, Szeto et al. (1996) showed that i.v. administration of U-50488H increased MAP in addition to HR. This last observation in adult sheep was similar to our present observations in lambs aged 6 weeks.
In various organs, including the brain, spinal cord and heart, -opioid receptor binding sites as well as receptor density increase gradually with postnatal development in the rat (Spain et al. 1985; Barg & Simantov, 1989; Barg et al. 1989; Zimlichman et al. 1996), guinea-pig (Barg et al. 1989; Barg & Simantov, 1989), mouse (Le Moine et al. 2002) and human (Pfeiffer et al. 1982). The identification of subtypes of -opioid receptors with distinct pharmacological and molecular properties in brain tissue in several species (Pfeiffer et al. 1982; Kornblum et al. 1987; Clark et al. 1989; Rothman et al. 1990; Wolleman et al. 1993; Nishi et al. 1993; Butelman et al. 1998) may implicate different subtypes in mediating different functional responses. It is therefore possible that the different MAP responses to U-50488H observed in the two age groups of animals reflect age-dependent changes in the expression of one or more specific -opioid receptor subtypes. We also observed that the sustained increase in HR in 6-week-old lambs occurred in the absence of any decrease in MAP, which one would expect to elicit a baroreflex-mediated response. This suggests that -opioids may in fact modulate the arterial baroreflex control of HR. Further experiments are needed in which the arterial baroreflex control of HR is directly assessed before and after administration of U-50488H in order to confirm this postulate.
Renal haemodynamic responses to U-50488H are not well characterized in adult animals, and no studies have previously measured renal haemodynamic responses to -opioid receptor agonists in young animals. Using Doppler flow, Bachelard & Pitre (1995) showed no effects on renal vascular tone following bilateral injection of U-50488 into the paraventricular nucleus of conscious, unrestrained adult Wistar Kyoto rats; this was recently confirmed in anaesthetized adult rats by Gottlieb et al. (2005). We measured a significant and sustained decrease in RBF in both age groups of conscious lambs following i.v. administration of U-50488H, resulting from an increase in RVR. Although the mechanism underlying this renal haemodynamic response to U-50488H is not known, it may reflect an increase in renal sympathetic nerve activity (Kapusta et al. 1989; Kapusta, 1995), although effects of local vasoactive factors cannot be ruled out at this time.
In addition to receptor-mediated cardiovascular effects of -opioid receptor agonists, receptor-independent effects have also been described. These include inhibitory effects of -opioid receptor agonists on gated ion channels, at least in rat cardiac muscle (Pugsley, 2004). To rule out receptor-independent effects of U-50488H (i.e. to demonstrate whether the observed responses to U-50488H were the result of direct receptor-induced effects), we tested its effects before and after administration of the highly selective -opioid receptor antagonist GNTI (Lahti et al. 1982; Vonvoigtlander et al. 1983). Until recently, the only available antagonist selective for the -opioid receptor was nor-BNI which produces reliable selective antagonism of -opioid receptors only after several hours, with non-selective antagonism being exhibited for both - and µ-agonists for 1–2 h after its administration (Endoh et al. 1992; Broadbear et al. 1994). Nor-BNI also has a relatively low potency in vivo after systemic administration, a slow onset and long duration of action, with effects persisting for many weeks. GNTI is a recently synthesized -opioid receptor antagonist which is 800 fold more selective for - than -opioid receptors, and two- to threefold more potent than nor-BNI (Jones & Portoghese, 2000; Stevens et al. 2000). In a schedule-controlled behavioural study in the rhesus monkey (Negus et al. 2002), GNTI exhibited antagonism of U-50488H-induced behavioural effects in a dose- and time-dependent manner. GNTI had a faster onset and shorter duration than nor-BNI, with a peak effect at 24 h after i.v. administration, with effects persisting for 4 days (Negus et al. 2002). Consistent with these findings, the effects of GNTI in inhibiting the cardiovascular responses to U-50488H in the present study in conscious lambs also persisted for several days, although the onset of the inhibitory effect of GNTI appeared to be age dependent, occurring earlier in the younger lambs (Fig. 4). Since the observed responses to administration of U-50488H were abolished by pretreatment with GNTI, it is possible to conclude that they result directly from activation of -opioid receptors, thus ruling out any receptor-independent effects on the measured variables.
In conclusion, the present study provides the first information regarding the role of -opioid receptor activation in influencing systemic and renal haemodynamics under physiological conditions during postnatal maturation. Also, since the observed cardiovascular responses to U-50488H were abolished by pretreatment with GNTI, we can conclude that they resulted from direct effects on the -opioid receptor.
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EC100.
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