The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s

Research Report

The selective mu opioid receptor antagonist, alvimopan, improves delayed GI transit of postoperative ileus in rats Hiroyuki Fukuda a , Kiyotaka Suenaga a , Daisuke Tsuchida a , Christopher R. Mantyh a , Theodore N. Pappas a , Gareth A. Hicks b , Diane L. DeHaven-Hudkins c , Toku Takahashi a,⁎ a

Department of Surgery, Duke University Medical Center, Surgical Service 112, VA Medical Center, 508 Fulton Street, Durham, NC 27705, USA b Neurology and GI CEDD, GlaxoSmithKline, Essex, UK c Department of Pharmacology, Adolor Corporation, Exton, PA 19341, USA

A R T I C LE I N FO

AB S T R A C T

Article history:

Postoperative ileus (POI) is often exacerbated by opioid analgesic use during and following

Accepted 24 February 2006

surgery, since mu opioid receptor activation results in a further delay of gastrointestinal (GI)

Available online 22 June 2006

transit. The effects of alvimopan, a novel, selective, and peripherally acting mu opioid receptor antagonist, and the reference compound methylnaltrexone, upon POI were

Keywords:

investigated in rats. Under isoflurane anesthesia, POI was induced by laparotomy with

Alvimopan

intestinal manipulation. Immediately after the surgery, the rats received

Blood–brain barrier

Three hours after the surgery, the rats were sacrificed and GI transit was estimated using the

51

Cr by gavage.

51

Enteric nervous system

geometric center (GC) of

Gastrointestinal

were administered by gavage either before or after the surgery, with or without morphine

Ileus

administration (1 mg/kg). GI transit was delayed by intestinal manipulation

Methylnaltrexone

(GC = 2.92 ± 0.17). Alvimopan (1 and 3 mg/kg) significantly reversed this delayed GI transit

Cr. Alvimopan (0.1–3 mg/kg) or methylnaltrexone (100 mg/kg)

when administered 45 min prior to surgery. However, the effects of alvimopan were less Abbreviations:

pronounced when administered following surgery. Morphine administration further

BBB, blood–brain barrier

delayed GI transit induced by intestinal manipulation (GC = 1.97 ± 0.11). Under these

CRF, corticotropin-releasing factor

conditions, alvimopan (1 and 3 mg/kg) also significantly improved delayed GI transit when

CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-

administered before surgery. Methylnaltrexone was inactive under all experimental

Thr-Pen-Thr-NH2

conditions. These data suggest that mu opioid receptors play a role in the pathogenesis of

DMSO, dimethyl sulfoxide

POI, and that the clinical benefit reported to be afforded by alvimopan may be in part

GC, geometric center

mediated via inhibition of an endogenous opioid release as well as blockade of the

GI, gastrointestinal

unwanted GI actions of analgesic agents.

POI, postoperative ileus

© 2006 Elsevier B.V. All rights reserved.

s.c., subcutaneous

1.

Introduction

Postoperative ileus (POI) is usually attributable to abdominal surgical procedures. POI causes various symptoms, prolonged

hospitalization, and increased medical costs (Livingston and Passaro, 1990). The pathogenesis of POI is multifactorial. Several mechanisms have been proposed, such as an inflammatory response (Kalff et al., 2000, 2003) and a neural reflex

⁎ Corresponding author. Fax: +1 919 286 1140. E-mail address: [email protected] (T. Takahashi). 0006-8993/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2006.02.092

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Fig. 1 – Geometric center of 51Cr in rats that underwent intestinal manipulation. Alvimopan (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 3 mg/kg), methylnaltrexone (100 mg/kg), or vehicle was administered before the surgery (n = 6–10, **P < 0.01 compared with vehicle, ANOVA followed by Dunnett). (Barquist et al., 1996; Holzer et al., 1992). We have recently shown that abdominal surgery delays gastrointestinal (GI) transit via an activation of the somato-sympathetic pathway (Uemura et al., 2004). In addition, POI is often exacerbated by opiate analgesic use during and following surgery. Opioid receptors are commonly activated in postoperative patients, because morphine and other opiate analgesic agents are often used for pain treatment after surgery and the surgical stress stimulates the release of endogenous opioids (Brix-Christensen et al., 1997). Such mu receptor activation arising from both exogenous and endogenous sources results in an unwanted impairment of gastric emptying and transit through both small and large intestine (Schmidt, 2001). Alvimopan, [[2(S)-[[4(R)-(3-hydroxyphenyl)-3(R),4-dimethyl1-piperidinyl]methyl]-1-oxo-3-phenylpropyl]-amino]-acetic acid dihydrate, is a novel, peripherally acting and selective mu opioid receptor antagonist with low and variable systemic absorption, and limited oral bioavailability (Camilleri, 2005; Schmidt, 2001). Following parenteral and oral administration,

alvimopan acts on peripheral mu opioid receptors. Thus, alvimopan has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders (Zimmerman et al., 1994). Clinical studies demonstrated that alvimopan reversed the morphine-induced inhibition of GI transit in humans without affecting analgesia (Liu et al., 2001). Alvimopan normalized bowel function in patients who underwent abdominal surgery (Schmidt, 2001; Taguchi et al., 2001; Wolff et al., 2004). In the present study, we investigated the effects of the selective, peripheral mu opioid receptor antagonist alvimopan in a rat model of ileus. These results demonstrate that mu antagonists improve POI induced by intestinal manipulation, with and without concomitant morphine administration, and suggest an important role of endogenous opioids in the pathogenesis of POI in the rat. The effect of alvimopan was compared with methylnaltrexone, which is a non-selective opioid antagonist that does not cross the blood–brain barrier (BBB) (Kotake et al., 1989; Yuan and Foss, 2000).

Fig. 2 – Geometric center of 51Cr in rats that underwent intestinal manipulation. Alvimopan (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 3 mg/kg), methylnaltrexone (100 mg/kg), or vehicle was administered after the surgery (n = 6–7, **P < 0.01 compared with vehicle, ANOVA followed by Dunnett).

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Fig. 3 – Geometric center of 51Cr in rats that underwent intestinal manipulation. Morphine (1 mg/kg s.c.) was administered 15 min before the surgery. Alvimopan (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 3 mg/kg), methylnaltrexone (100 mg/kg), or vehicle was administered before the surgery (n = 6, *P < 0.05, **P < 0.01 compared with vehicle, ANOVA followed by Dunnett).

Our data demonstrate the expected delay in GI transit following intestinal manipulation, in the presence or absence of administered morphine. The delayed GI transit was partially prevented by alvimopan, but not methylnaltrexone, when administered prior to surgery, with a smaller reversal observed with postoperative dosing. These data suggest that mu opioid receptors play a role in the pathogenesis of POI induced by intestinal manipulation in rats, and that mu antagonists such as alvimopan may provide benefit in the clinical POI setting by blocking part of the pathophysiological process in addition to blockade of the unwanted GI effects of administered opiate analgesic agents.

by laparotomy plus intestinal manipulation. Alvimopan was efficacious at doses of 1 and 3 mg/kg, with the maximum effect observed at the 3 mg/kg dose (n = 9, GC = 4.48 ± 0.21, P < 0.01). Methylnaltrexone did not improve delayed GI transit (n = 6, GC = 2.85 ± 0.89) when administered 15 min prior to surgery (Fig. 1).

2.2.

Postsurgical treatment with antagonists

2.

Results

When alvimopan was administered 45 min after surgery, the stimulatory effect of alvimopan was only observed at the highest dose (3 mg/kg) (n = 6, GC = 4.43 ± 0.41, P < 0.01). Methylnaltrexone administered after surgery did not improve the delayed GI transit (n = 6, GC = 3.01 ± 0.26) (Fig. 2).

2.1.

Presurgical treatment with antagonists

2.3.

Alvimopan (1 mg/kg and 3 mg/kg) administered 45 min before the surgery significantly improved delayed GI transit induced

Presurgical treatment with antagonists and morphine

When morphine (1 mg/kg s.c.) was administered 15 min before the surgery, the GC induced by manipulation was reduced to

Fig. 4 – Geometric center of 51Cr in rats that underwent intestinal manipulation. Morphine (1 mg/kg s.c.) was administered 15 min before surgery. Alvimopan (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 3 mg/kg), methylnaltrexone (100 mg/kg), or vehicle control was administered 45 min after the surgery (n = 6).

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Fig. 5 – Geometric center of 51Cr in rats that underwent intestinal manipulation. Morphine (1 mg/kg s.c.) was administered 75 min after the surgery. Alvimopan (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 3 mg/kg), methylnaltrexone (100 mg/kg) or vehicle control was administered 45 min after the surgery (n = 6).

1.97 ± 0.11 (n = 6). Alvimopan (1 mg/kg and 3 mg/kg) administered 45 min prior to surgery improved the delayed GI transit and GC was significantly increased to 3.23 ± 0.35 (n = 6, P < 0.05) and 3.29 ± 0.27 (n = 6, P < 0.01) by 1 mg/kg and 3 mg/kg of alvimopan, respectively. However, methylnaltrexone administered 15 min before surgery was without effect (Fig. 3).

2.4. Postsurgical treatment with antagonists + presurgical treatment with morphine Alvimopan (1 mg/kg and 3 mg/kg) administered 45 min following surgery slightly improved delayed GI transit induced by morphine and intestinal manipulation. However, neither this effect, nor that of methylnaltrexone, was statistically significant (n = 6) (Fig. 4).

2.5. Postsurgical treatment with antagonists and morphine When morphine was administered 75 min following surgery and alvimopan was administered 45 min after surgery, the highest dose of alvimopan (3 mg/kg) produced a slight improvement in delayed GI transit (n = 6, GC = 3.95 ± 0.34), but the effect was not statistically significant (n = 6) (Fig. 5).

2.6. Pretreatment of alvimopan before the surgery of laparotomy only As previously reported (Uemura et al., 2004), laparotomy alone produced a significant delay in GI transit as measured by geometric center (GC = 5.3), compared to anesthesia only

Fig. 6 – Geometric center of 51Cr in rats that underwent laparotomy only and intestinal manipulation. As shown in Fig. 1, alvimopan significantly improved delayed GI transit induced by laparotomy plus intestinal manipulation. In contrast, alvimopan failed to improve delayed GI transit induced by laparotomy only (GC = 5.08 ± 0.54 in alvimopan treated rats, GC = 5.18 ± 0.43 in vehicle treated rats, **P < 0.01, n = 6).

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(GC = 9.5). Moreover, when laparotomy and manipulation were performed, GI transit was further delayed (GC = 2.9) (Uemura et al., 2004) (Fig. 6). As shown in Fig. 1, alvimopan significantly improved delayed GI transit induced by laparotomy plus intestinal manipulation. In contrast, alvimopan failed to improve delayed GI transit induced by laparotomy only (GC = 5.08 ± 0.54 in alvimopan treated rats, GC = 5.18 ± 0.43 in vehicle treated rats, n = 6).

3.

Discussion

The pathogenesis of POI is still controversial and several mechanisms have been proposed. Kalff et al. (2000, 2003) demonstrated that the inflammatory response of the gut wall plays an important role for postoperative GI dysmotility. Tache and her colleagues suggested that endogenous corticotropin releasing factor (CRF) inhibits the gastric motor function after surgical stress (Barquist et al., 1996; Luckey et al., 2003; Tache et al., 1999). Others showed the role of inhibitory adrenergic pathways in POI (Boeckxstaens et al., 1999; De Jonge et al., 2003; De Winter et al., 1997). However, one common factor contributing to the GI dysregulation that results from surgery is the use of opioids for pain management during the perioperative and postoperative periods (Kurz and Sessler, 2003). POI is often exacerbated by opiate analgesic use during and following surgery (Kurz and Sessler, 2003), due to the wide distribution of opioid receptors in the GI tract (Bagnol et al., 1997) and their role in the modulation of gut motility and secretion (Kurz and Sessler, 2003). Mu receptors predominate in the submucosal and mucosal layers and are located on both nerve terminals and somatodendritic synaptic elements. Numerous mu receptorimmunoreactive cells are also localized in the region of myenteric plexus (Bagnol et al., 1997). Functionally, mu receptors inhibit the release of acetylcholine from the myenteric plexus in gut (Kromer, 1988; Yokotani and Osumi, 1998). The activation of mu receptors by morphine results in decreased intestinal myoelectric activity and impaired smooth muscle contractions (Weisbrodt et al., 1980). Morphine also inhibits the propulsive migrating motor activity of the small intestine (Burleigh et al., 1981; Ferraz et al., 1995; Porreca et al., 1984) and the colon (Frantzides et al., 1990; Jacoby et al., 1987), and increases non-propulsive contractions in the colon (Ferraz et al., 1995; Frantzides et al., 1990). Gastric motility and emptying are also attenuated by morphine (Gutstein and Akil, 2006). Opioid agonists can act on multiple regions of the GI tract to cause slowing of transit and reduced secretion, and can exacerbate the ileus arising from surgical procedures. In the present study, we investigated the effects of the selective, peripheral mu opioid receptor antagonist alvimopan and the reference peripheral opioid receptor antagonist, methylnaltrexone, in a rat model of ileus. The reversal of ileus with alvimopan in the absence of morphine supports a role for endogenous opioid peptides in the generation of POI in a rat model. Alvimopan also improved POI accompanied by morphine administration, when given prior to the surgery or analgesic. This was in agreement with previous clinical studies, where alvimopan improved recovery of bowel function and shortened the duration of hospitalization (Schmidt,

67

2001; Taguchi et al., 2001; Wolff et al., 2004), and was well tolerated without reversing morphine analgesia (Liu et al., 2001; Schmidt, 2001). Differences in the efficacy of alvimopan were observed between pre- and postoperative dosing. Alvimopan improved POI accompanied by morphine administration, when given prior to the surgery or analgesic. This was in agreement with previous clinical studies (Schmidt, 2001; Taguchi et al., 2001; Wolff et al., 2004). The GI transit was significantly improved when alvimopan was administered before surgery, but only a trend toward significance was achieved when alvimopan was administered after surgery. The advantage of preoperative administration is clear from these data. Alvimopan is able to antagonize opioid receptors located in the GI tract and improve delayed GI transit with or without exogenous opioid administration. To our knowledge, our finding that alvimopan improved the delayed GI transit resulting from intestinal manipulation, in the absence of administration of morphine, is the first demonstration in an animal model of POI that mu opioid receptor antagonists can improve GI transit, even if exogenous opiate drugs are not administered. It has been suggested that endogenous opioids participate in the control of GI motility (Brown et al., 1993; Bueno and Fioramonti, 1988; Kaufman et al., 1988) and have been proposed to play a role in POI (Kurz and Sessler, 2003). However, although a role for endogenous opioid peptide release in POI has been suggested previously (Kromer, 1988; Patierno et al., 2004; Yoshida et al., 2000), direct evidence from preclinical studies of ileus using mu-selective peripheral opioid antagonists is lacking. Our data suggest that not only exogenous but also endogenous opioids play a role in the pathogenesis of POI. However small, the part played by endogenous opioids in the pathophysiology of POI is an important one, and deserves further study in other models, performed in other species, and indeed in man. Alvimopan failed to improve delayed GI transit induced by laparotomy only, while alvimopan significantly improved delayed GI transit induced by laparotomy plus manipulation. This suggests that intestinal manipulation up-regulates endogenous opioid pathways, and it is conceivable that endogenous opioids are increased by intestinal manipulation and stimulate opioid receptors of the GI tract, resulting in impaired GI transit. Recent evidence suggests that mu opioid receptors internalize almost immediately after abdominal surgery. Patierno et al. (2004) showed that mu opioid receptor internalization was associated with the laparotomy rather than with the mechanical manipulation of the intestine, and the stimulus responsible for endogenous opioid release was hypothesized to be the noxious challenge of surgery and not intestinal manipulation. Although this group (Patierno et al., 2004) was able to demonstrate prevention of mu opioid receptor internalization by pretreatment with the mu receptor antagonist CTOP, CTOP pretreatment was not able to prevent the effect on transit induced by either laparotomy or manipulation. We also failed to observe an effect of alvimopan on the delay in transit induced by laparotomy. As discussed in the Patierno work (2004), it is unknown whether central or peripheral opioid pathways mediate release of endogenous opioids and the resultant receptor internalization observed in the laparotomy/ileus model. It is also unknown how the

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binding of a peripherally selective antagonist like alvimopan to gut opioid receptors prior to laparotomy or manipulation may affect subsequent receptor internalization or protect against GI dysfunction. Although methylnaltrexone is peripherally selective (Brown and Goldberg, 1985), it is a weaker antagonist at the mu opioid receptor than alvimopan (Cassel et al., 2005; Daubert et al., 2000) and is about 200-fold less potent than alvimopan to antagonize morphine-induced inhibition of GI transit in mice following oral administration (Little et al., 2001). In these studies, we tested both compounds at their respective ED50 values to antagonize morphine-induced inhibition of GI transit (Little et al., 2001; Zimmerman et al., 1994), and we believe that the lack of activity for methylnaltrexone was due to its lower affinity for the mu opioid receptor and its weaker potency in vivo. Adrenoceptors are located in the GI tract and regulate GI motility (Langer, 1997). The activation of alpha-2 adrenoceptors inhibits the release of acetylcholine from cholinergic nerve terminals and impairs smooth muscle contraction of the intestine (Fuder and Muscholl, 1995) and stomach (Yokotani et al., 1993). We have recently shown that abdominal surgery delays GI transit via an activation of the somato-sympathetic pathway (Uemura et al., 2004). Delayed GI transit induced by laparotomy was significantly improved by the pretreatment of guanethidine and yohimbine, an alpha-2 adrenoceptor antagonist (Uemura et al., 2004). This suggests that adrenoceptors are also involved in the pathogenesis of POI. It remains unclear whether mu opioid receptors act independently from adrenoceptors after the intestinal manipulation to cause delayed GI transit. In conclusion, mu opioid receptors play an important role in the pathogenesis of POI induced by intestinal manipulation. The benefit afforded by alvimopan in this condition may be in part mediated via inhibition of endogenous opioid actions in addition to blockade of the unwanted GI actions of analgesic agents.

4.

Experimental procedures

4.1.

GI transit after the surgery

The procedures were performed under protocols approved by the animal research committee of the Duke University Medical Center and the VA Medical Center. Male Sprague–Dawley rats (BW; 250–300 g) were fasted for 24 h with free access to water. Under an isoflurane (2%) anesthesia, the abdomen was opened by a 5 cm midline laparotomy. The terminal ileum (10 cm long) was exteriorized and gently compressed by fingers using moist gauze for 10 min. The surgery was completed in 25 min. No analgesic agent was used postoperatively. GI transit was estimated using the geometric center (GC) of 51 Cr, as previously described (Brown et al., 1993; Miller et al., 1981; Uemura et al., 2004). In preliminary control experiments with anesthesia only, orally administered 51Cr reached the rectum in 8 h, making the calculation of geometric center (GC) inaccurate. However, at 3 h, orally administered 51Cr stayed in the ileum–cecum and the calculated GC was approximately 10, while laparotomy plus intestinal manipulation significantly

reduced GC to around 3. Therefore, the 3-h time point was chosen for subsequent studies. Immediately after the operation, rats received radiochromium (0.25 ml, 0.5 μCi; Na51CrO4 in saline) by oral gavage. Three hours after the surgery, rats were sacrificed by terminal anesthesia with pentobarbital sodium (200 mg/kg, IP), the abdomen opened, and the stomach, small intestine, cecum, and colon removed. As previously described (Uemura et al., 2004), the stomach was numbered as segment 1 and the small intestine was divided into 10 equal segments (segment 2–11). The cecum was numbered 12 and the colon was divided into 3 equal segments (segment 13–15). The feces were numbered as segment 16. Each segment was placed into a vial and the radioactivity was counted by a gamma counter for 1 min. The geometric center (GC; the center of the distribution of 51Cr) within the GI tract and feces was calculated using the following equation, as previously described (Mizuta et al., 1999; Uemura et al., 2004). GC ¼ Rð fraction of

4.2.

51

Cr per segment  segment numberÞ:

Alvimopan study protocols

The ability of alvimopan or methylnaltrexone to prevent or reverse the effect of intestinal manipulation upon GI transit, in the presence or absence of morphine, was investigated using the following study designs (Studies 1–6). Study 1: Presurgical treatment with antagonists. Alvimopan (0.1, 0.3, 1, and 3 mg/kg) or vehicle [10% dimethyl sulfoxide (DMSO] was administered by oral gavage 45 min before surgery. Methylnaltrexone (100 mg/kg) was administered by oral gavage 15 min before surgery. Study 2: Postsurgical treatment with antagonists. Alvimopan (0.1, 0.3, 1, and 3 mg/kg), methylnaltrexone (100 mg/kg) or vehicle was administered by oral gavage 45 min after the surgery. Study 3: Presurgical treatment with antagonists + morphine. Alvimopan (0.1, 0.3, 1, and 3 mg/kg) or vehicle was administered by oral gavage 45 min before surgery. Methylnaltrexone (100 mg/kg) was administered by oral gavage 15 min before surgery. Morphine (1 mg/kg) was administered (s.c.) 15 min before surgery. Study 4: Postsurgical treatment with antagonists + presurgical treatment with morphine. Morphine (1 mg/kg) was administered (s.c.) 15 min before surgery. Alvimopan (0.1, 0.3, 1, and 3 mg/kg), methylnaltrexone (100 mg/kg) or vehicle was administered by oral gavage 45 min after surgery. Study 5: Postsurgical treatment with antagonists and morphine. Alvimopan (0.1, 0.3, 1, and 3 mg/kg), methylnaltrexone (100 mg/kg), or vehicle was administered by oral gavage 45 min after surgery. Morphine (1 mg/kg) was administered (s.c.) 75 min after surgery. Study 6: Presurgical treatment with alvimopan versus laparotomy only. We have recently shown that laparotomy itself delayed GI transit, compared to the effects of anesthesia only. Laparotomy plus intestinal manipulation further delayed GI transit (Uemura et al., 2004). To investigate whether alvimopan improves delayed GI transit induced by laparotomy without manipulation, alvimopan (1 mg/kg) or vehicle was administered by oral gavage 45 min before the laparotomy.

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4.3.

Materials

Alvimopan was a gift from GlaxoSmithKline (Harlow, UK). Methylnaltrexone was provided from Adolor Corporation (Exton, PA). Alvimopan was dissolved in 10% DMSO. DMSO, morphine was obtained from Sigma (St. Louis, MO).

4.4.

Statistical analysis

Results were expressed as means ± SE. Statistical analysis was performed by one-way analysis of variance. Dunnett's post hoc analysis was used to determine significant differences between the control and treatment groups. P values <0.05 were considered as significant.

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