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Long-term feed intake regulation in sheep is mediated by opioid receptors¹

F. Y. Obese^*, B. K. Whitlock^*, B. P. Steele^*, F. C. Buonomo and J. L. Sartin^*,2

^* Anatomy, Physiology, & Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849; and and Monsanto Company, St. Louis, MO 63198

	Abstract

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These experiments were conducted to determine if 1) syndyphalin-33 (SD33), a µ-opioid receptor ligand, affects feed intake; 2) SD33 effects on feed intake are mediated by actions on opioid receptors; and 3) its activity can counteract the reduction in feed intake associated with administration of bacterial endotoxin. In Exp. 1, 5 mixed-breed, castrate male sheep were housed indoors in individual pens. Animals had ad libitum access to water and concentrate feed. Saline (SAL; 0.9% NaCl) or SD33 (0.05 or 0.1 µmol/kg of BW) was injected i.v., and feed intake was determined at 2, 4, 6, 8, 24, and 48 h after the i.v. injections. Both doses of SD33 increased (at least P < 0.01) feed intake at 48 h relative to saline. In Exp. 2, SAL + SAL, SAL + SD33 (0.1 µmol/kg of BW), naloxone (NAL; 1 mg/kg of BW) + SAL, and NAL + SD33 were injected i.v. Food intake was determined as in Exp. 1. The SAL + SD33 treatment increased (P = 0.022) feed intake at 48 h relative to SAL + SAL. The NAL + SAL treatment reduced (at least P < 0.01) feed intake at 4, 6, 8, 24, and 48 h, whereas the combination of NAL and SD33 did not reduce feed intake at 24 (P = 0.969) or 48 h (P = 0.076) relative to the saline-treated sheep. In Exp. 3, sheep received 1 of 4 treatments: SAL + SAL, SAL + 0.1 µmol of SD33/kg of BW, 0.1 µg of lipopolysaccharide (LPS)/kg of BW + SAL, or LPS + SD33, and feed intake was monitored as in Exp. 1. Lipopolysaccharide suppressed cumulative feed intake for 48 h (P < 0.01) relative to saline control, but SD33 failed to reverse the reduction in feed intake during this period. These data indicate that SD33 increases feed intake in sheep after i.v. injection, and its effects are mediated via opioid receptors. However, the LPS-induced suppression in feed intake cannot be overcome by the opioid receptor ligand, SD33.

Key Words: appetite • endotoxin • feed intake • opioid receptor • sheep • syndyphalin-33

	INTRODUCTION

Top Abstract INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Opioid receptors have been implicated in the regulation of feed intake (Glass et al., 1999; Bodnar and Klein, 2005). The opioid agonists stimulate, whereas opioid antagonists attenuate, feed intake (Bodnar, 2004). Opioids may influence feed intake by regulating orosensory feed reward, meal selection, or quantity of feed ingested (Glass et al., 1999). Syndyphalin-33 (SD33; Tyr-DMet (o)-Gly-methylphenylethylamide) is a tripeptide mu opioid receptor agonist capable of exhibiting prolonged analgesic activity in mice (Kiso et al., 1981). Moreover, its peripheral administration produced an acute elevation in GH concentrations in rats, sheep, and swine through actions at the hypothalamus (Buonomo et al., 1991).

Because SD33 crosses the blood brain barrier, its injection may provide a novel approach for administration of an opioid receptor agonist to increase feed intake along with activation of the GH system to promote anabolic responses. This would provide a unique molecule for application in agriculture and veterinary medicine.

The objectives of the current study were to determine: (1) if SD33 would increase feed intake; (2) if SD33 effects on feed intake were mediated by opioid receptors and; (3) if SD33 could reverse the inhibition of feed intake in endotoxemic sheep.

	MATERIALS AND METHODS

Top Abstract INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Animals, Feeding, and Management
All procedures involving animals were approved by the Institutional Animal Care and Use committee at Auburn University.

Five mixed-breed, castrate male sheep were housed indoors in individual pens, with 2 sheep per room, in a temperature- and light- (12-h light and 12-h dark cycle) controlled facility. Sheep had a BW range of 53.6 to 75 kg at the onset of the experiments. The sheep had ad libitum access to water and were provided concentrate feed (as-fed basis), which contained 12% CP and was calculated to meet 100% of the daily requirements (NRC, 1985). Body weights were measured weekly.

Exp. 1
To determine a dose of SD33 that would elicit feed intake for use in subsequent experiments, 5 sheep were randomly selected to receive 1 of 3 treatments: 0.9% saline vehicle (SAL) as a control, or 0.05 or 0.1 µmol of SD33 (Peninsula Laboratories Inc., San Carlos, CA; purity > 99%) per kg of BW injected via jugular catheters (catheters were placed in the sheep on the day before an experiment). The order of treatments was randomized. On the morning of an experiment, the sheep were offered a known weight of fresh feed at –2 h (pretreatment, to insure the sheep were feed satiated). Feed was weighed at 0, 2, 4, 6, 8, 24, and 48 h (time 0 represents administration of the respective treatments) after treatments were administered and replaced with fresh feed. Feed intake was expressed as a percentage of BW and presented as cumulative feed intake. Each treatment was administered to each sheep with at least a 1-wk interval between treatments. Feed intake was monitored daily to ensure that feed intake had stabilized before a subsequent treatment.

Exp. 2
This experiment was designed to determine whether the effect of SD33 on feed intake was a receptor-dependent event. The role of opioid receptors (due to SD33) on feed intake was determined in the presence or absence of the opioid receptor antagonist, naloxone (NAL). Five sheep were randomly assigned to 1 of 4 treatments: SAL + SAL as control, SAL + 0.1 µmol of SD33/kg of BW, 1 mg of NAL (Sigma-Aldrich Co, St. Louis, MO)/kg of BW + SAL, or NAL + SD33. Doses for NAL were based on previously published experiments on feed intake (Alavi et al., 1991) and on experiments using GH or LH as an end point (Estienne et al., 1990; Schall et al., 1991).

The treatments were designed such that the opioid antagonist, NAL, was administered 5 min before the opioid receptor agonist (SD33). The other groups represented the appropriate controls for the experiment (such that the first i.v. injection within each treatment combination was followed 5 min later with a second i.v. injection). Fresh feed was presented 2 h before the initiation of the experiment to ensure that animals were satiated. Feed intake was monitored at 2, 4, 6, 8, 24, and 48 h after the second i.v. injection. Opioid agonists may alter body temperature in animals (Adler et al., 1988; Spencer et al., 1988; Colman and Miller, 2002); therefore, rectal temperature was monitored at 0 and at 8, 24, and 48 h after i.v. injection. Each treatment was administered to each sheep with at least a 1-wk interval between treatments, and the order of the treatments was randomized. Daily feed intake was also measured between treatments to ensure that intake had stabilized before the initiation of each subsequent treatment.

Exp. 3
This experiment was designed to determine whether SD33 could alter the depression in feed intake associated with the proinflammatory stress as modeled with low level endotoxin challenge. Five sheep were randomly selected to receive 1 of 4 treatments intravenously: SAL + SAL as a control, SAL + 0.1 µmol of SD33/kg of BW, 0.1 µg of lipopolysaccharide (LPS; from Escherichia coli O55:B5; Sigma-Aldrich)/kg of BW + SAL, or LPS + SD33. The first i.v. injection within each treatment combination was given 5 min before the second injection. The same sheep were used as in Exp. 2; feed intake was monitored at 2, 4, 6, 8, 24, and 48 h, and rectal temperature at 0, 8, 24, and 48 h after i.v. injections. The order of the treatments was randomized. Each treatment was administered to each sheep with at least a 2-wk interval between treatments to avoid tolerance to LPS (Demling et al., 1986; Whyte et al., 1989). Daily feed intake was monitored to ensure that intake had stabilized before the initiation of each subsequent treatment.

Statistical Analysis
The effects of treatment, animal, and time on cumulative feed intake in Exp. 1, 2, and 3 were determined using GLM procedures for repeated measures (SAS Inst. Inc., Cary, NC). Mean separation was performed by using the least squares means/PDIFF statements of SAS. Data were expressed as cumulative feed intake on a percentage of BW basis. Values of P < 0.05 were considered significant.

	RESULTS

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Exp. 1
Figure 1 summarizes the effect of i.v. administration of 2 doses of SD33 (0.05 or 0.1 µmol/kg of BW) on cumulative feed intake in sheep. The i.v. injection of SD33 at a dose of 0.05 or 0.1 µmol/kg of BW resulted in differences in cumulative feed intake at 24 (P = 0.008) and 48 h (P < 0.001) compared with saline. The analysis of the individual treatments vs. saline control indicated that SD33 at a dose of 0.1 µmol/kg of BW increased feed intake at 24 (P = 0.002) and 48 h (P < 0.001), whereas the 0.05 µmol/kg of BW dose of SD33 increased feed intake at 48 h (P = 0.008) relative to saline. The increase in cumulative feed intake by the 0.05 and 0.1 µmol/kg doses by 48 h were 7.4 and 14.7%, respectively. Food intake of sheep treated with the low (0.05 µmol/kg of BW) or high (0.1 µmol/kg of BW) dose SD33 did not differ (P > 0.05) from saline-treated sheep for the first 8 h after i.v. injection. There was a difference in cumulative feed intake between the 2 doses of SD33 at 24 (P = 0.038) and 48 h (P = 0.01).

View larger version (16K): [in this window] [in a new window]   Figure 1. Effect of i.v. injection of saline (SAL) or syndyphalin-33 (SD33, an opioid agonist; 0.05 or 0.1 µmol/kg of BW; n = 5) on cumulative feed intake in sheep. Data are least squares means (±SEM). (A) 24 h after i.v. injection. a,bMeans denoted by different letters differ (P < 0.05). (B) 48 h after i.v. injection. a–cMeans denoted by different letters differ: a,cP < 0.001; b,cP < 0.01; and a,bP < 0.01.

View larger version (25K): [in this window] [in a new window]   Figure 2. Effect of i.v. injection of saline (SAL) + SAL, SAL + syndyphalin-33 (SD33, an opioid agonist; 0.1 µmol/kg of BW), naloxone (NAL; an opioid antagonist; 1 mg/kg of BW) + SAL, and NAL + SD33 on cumulative feed intake in sheep. Data are least squares means (±SEM). (A) Cumulative feed intake to 48 h after i.v. injection (n = 5). SAL + SD33 increased feed intake above SAL + SAL at 48 h (P = 0.022). NAL + SAL differed from SAL + SAL at 4, 6, 8, 24, and 48 h (P < 0.006). NAL + SD33 differed from SAL + SAL at 6 and 8 h (P < 0.01), but not at 24 or 48 h. (B) Cumulative feed intake at 48 h. Data are from Figure 2A but are graphed separately for clarity. Means denoted by different letters differ: a,bP < 0.05; b,cP < 0.001; and b,dP < 0.05. (C) Daily feed intake before, during, and after SAL, NAL, SD33, and NAL + SD33 treatments. See panels A and B for statistical differences. Arrow indicates injection of treatments.

View larger version (14K): [in this window] [in a new window]   Figure 3. Effect of syndyphalin-33 (SD33) on the inhibition of cumulative feed intake by lipopolysaccharide (LPS), an endotoxin. Treatment with SD33 increased feed intake at 48 h (P < 0.04). Lipopolysaccharide inhibited feed intake (P < 0.001), but SD33 did not alter LPS effects. Data are expressed as cumulative feed intake (means ± SEM).

	DISCUSSION

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Complex interactions exist between the opioid system and feed intake regulating neurotransmitter systems (Olsen et al., 1998). Information regarding the possible interaction between NPY, orexin, or AgRP and opioid peptides in feeding regulation have been described. Neuropeptide Y and AgRP have their neurons colocalized in the medial portion of the arcuate nucleus of the hypothalamus (Hahn et al., 1998; Henry, 2003). The central administration of NPY or AgRP induces a powerful increase in feed intake in many species (Parrot et al., 1986; Jewett et al., 1992; Hagan et al., 2000) including sheep (Miner et al., 1989; McMahon et al., 1999; Wagner et al., 2004a). Opioid receptors have been suggested to play a key role in mediating this potent orexigenic effect of NPY and AgRP on feed intake. This is evidenced by the fact that an opioid antagonist can block NPY-induced feed intake (Kotz et al., 1993; Rudski et al., 1996; Pomonis et al., 1997), and also recently, the combined inhibition of - and µ-opioid receptors blocked AgRP-induced feeding (Hagan et al., 2001; Brugman et al., 2002). In other studies, orexin activation of feed intake could also be prevented by opioid receptor antagonists (Sweet et al., 2004). This inhibitory effect of opioid receptor antagonists on orexin-stimulated feeding did not occur when antagonists were chosen that could not access the central nervous system. Thus, it is not surprising that an opioid receptor ligand should have an effect on feed intake regulation. However, it is interesting to note that most of these neurotransmitters have rapid effects on feed intake, whereas activation of opioid receptors by SD33 required 24 h for activation of feed intake.

Interestingly, the effects of SD33 on GH release were rapid, in terms of minutes (Buonomo et al., 1991). By contrast, the effects of SD33 on feed intake were slower to develop, requiring at least 8 h to become manifest. This is consistent with other studies indicating that the endocrine system is a rapidly responding system, whereas appetite control requires more time to become fully activated (McMahon et al., 1999).

Experiment 2 determined whether SD33 effects on feed intake were specific actions mediated by opioid receptors. The effects of SD33 on GH regulation in rats were also blocked by NAL (Buonomo et al., 1991). Naloxone has the greatest affinity for µ-receptors but at greater concentrations also blocks the other opioid receptor types (Mancev et al., 2000). Naloxone has also been shown to reduce feed intake effects of opioid agonists in sheep (Baile et al., 1981a; Della-Fera et al., 1984). The i.v. injection of 0.125 mg/kg of NAL blocked the increase in feed intake elicited by intracerebroventricular injection of the µ-receptor opiate agonist, D-ala²-met enkalphlinamide (Baile et al., 1981a). Naloxone has also been suggested to suppress feed intake by reducing the palatability of feed (Drewnowski et al., 1992; Giraudo et al., 1993; Glass et al., 1996).

The i.v. injection of NAL (the nonspecific opioid antagonist) alone suppressed feed intake for 48 h. This confirms the feeding reductions in response to i.v. injections of NAL in other studies with sheep (Baile et al., 1981a; Alavi et al., 1991) and cattle (Burgwald-Balstad et al., 1995). Although the pharmacokinetics of NAL has not been characterized in ruminants, it is known to be a short-acting opiate antagonist with a half-life approximating 40 min in rats (Tepperman et al., 1983) and 1 h in humans (Nagi et al., 1976). The ease with which NAL enters the brain after i.v. administration, coupled with its rapid redistribution, elimination, and consequent fall in brain concentrations has been suggested to account for its relatively short action (Berkowitz, 1976). In the study by Baile et al. (1981a), i.v. injections of NAL at doses of 0.062 and 0.125 mg/kg of BW decreased feed intake for 2 h in short-term (4 h) fasted sheep. In another study, NAL at a dose of 1 mg/kg of BW reduced the 4- and 8-h feed intake by 40 and 30%, respectively, in 16-h fasted lean sheep relative to saline-treated controls. However, the 24-h feed intakes were not different (Alavi et al., 1991). The percentage decrease in feed intake at 4 and 8 h were similar to that obtained in our study. The differences in the duration of NAL reduced feed intake in our study and that of Alavi et al. (1991) might be due to differences in the physiological condition of sheep used. The sheep in the study by Alavi et al. (1991) were fasted 16 h, whereas sheep in this study were satiated as well as being larger (36 vs. 80 kg). The hunger drive might have been greater for the 16-h fasted sheep used in the study by Alavi et al. (1991) and would therefore minimize the effects of NAL. In addition, the ad libitum fed sheep in this report were rapidly adding body fat, which may have altered the pharmacokinetic profile for NAL. In any event, cumulative feed intake was inhibited through 48 h. Interestingly, a similar long-term pattern of feed intake stimulation was observed with SD33.

Administration of bacterial endotoxin, LPS, a product found in the cell wall of gram-negative bacteria, results in fever and anorexia in sheep and cattle (Baile et al., 1981b; Coleman et al., 1993; Soliman et al., 2001) due to the release of proinflammatory cytokines including IL-1 ß (Kinsbergen et al., 1994; Ohtsuka et al., 1997) and tumor necrosis factor- (Coleman et al., 1993; Bieniek et al., 1998; Harris et al., 2000). Huang et al. (1999) demonstrated a reversal of LPS-induced anorexia in rats treated with a synthetic central melanocortin antagonist SHU-9119, and Wagner et al. (2004a) found similar results in sheep using AgRP. Also, the intracerebroventricular administration of NPY was found to restore appetite in endotoxic sheep (McMahon et al., 1999) indicating that NPY and the melanocortin system may mediate endotoxin-induced reduction in appetite. There is an indication that endogenous opioid peptides mediate some of the physiological consequences of LPS administration, including analgesic effects (Yirmiya et al., 1994). With the possible involvement of opioid peptides and their receptors as mediators of the NPY, orexin, and AgRP stimulatory action on feed intake, we hypothesized that the opioid receptor ligand SD33, which increases feed intake in normal sheep, should be able to reverse the reduction in feed intake associated with the administration of bacterial endotoxin. Moreover, the analgesic effects of SD33 plus the ability to elevate GH and potentially mobilize fat for energy should make SD33 a useful adjunct treatment in diseased animals. However, SD33 failed to alter the reduction in feed intake induced by LPS at any time point. This was unexpected, given that NPY and AgRP, acting via independent pathways, normalize feed intake in endotoxemic sheep and both neurotransmitters are reported to be dependent on opioid receptors. These data indicate that the inhibition of feed intake produced by endotoxin injection may utilize NPY receptor or MC4-R dependent processes but are independent of opioid receptors. As another explanation, Baile et al. (1981b) reported that elfazepam, a benzodiazepine and feed intake stimulant, did not override the anorexia associated with high fever when sheep were injected with 35 µg of bacterial endotoxin/kg^0.75 but did elicit feeding when the fever was prevented with dipyrone, an antipyretic agent. Elfazepam also stimulated intake in sheep, which were less febrile following a smaller dose of endotoxin (0.05 or 0.2 µg/kg^0.75). In this study, SD33 effects were not apparent until after the fever was normalized so that fever-associated effects on appetite should not have been a major factor. Another possibility that may account for these data would be an LPS downregulation of opioid receptors, rendering SD33 inactive in this model. Finally, SD33 did not influence LPS effects on feed intake, which indicates that a potent feed intake stimulus alone is insufficient to affect this particular disease model. Rather, specific pathways may be important in modulating disease suppression of appetite.

In conclusion, i.v. injection of SD33 activates long-term feed intake in sheep via the opioid receptor. The effects of SD33 were persistent, lasting between 24 and 48 h, indicating that SD33 may be of practical value for stimulation of appetite, though the effects of an opioid receptor agonist would require pharmacologic and residue studies prior to commercial use. These drugs might be more readily adapted to use in disease-associated inappetance or in body wasting diseases. However, SD33 failed to abolish or restore the decrease in feed intake induced by endotoxin, indicating that the effects of this disease model on appetite might not be mediated through µ-opioid receptor dependent pathways. However, opioid receptor agonists may be useful as a pharmacologic tool in diseases other than endotoxemia.

	Footnotes

 
¹ This project was supported by National Research Initiative Competitive Grant No. 2004-35206-14136 from the USDA Cooperative State Research, Education, and Extension Service.

² Corresponding author: sartijl{at}vetmed.auburn.edu

Received for publication June 26, 2006. Accepted for publication August 10, 2006.

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