Endothelin ETA receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice

Endothelin ETA receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice

European Journal of Pharmacology 543 (2006) 48 – 53 www.elsevier.com/locate/ejphar Endothelin ETA receptor blockade potentiates morphine analgesia bu...

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European Journal of Pharmacology 543 (2006) 48 – 53 www.elsevier.com/locate/ejphar

Endothelin ETA receptor blockade potentiates morphine analgesia but does not affect gastrointestinal transit in mice George A. Matwyshyn a , Shaifali Bhalla a,1 , Anil Gulati a,b,⁎ a

b

Department of Biopharmaceutical Sciences (M/C 865), University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA Department of Bioengineering and Neurology and Rehabilitation Medicine, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA Received 26 January 2006; received in revised form 27 April 2006; accepted 19 May 2006 Available online 26 May 2006

Abstract Development of analgesic tolerance and constipation remain a major clinical concern during long-term administration of morphine in pain management. Central endothelin mechanisms are involved in morphine analgesia and tolerance. The present study was conducted to investigate the effect of intracerebroventricular (i.c.v.) and peripheral administration of endothelin ETA receptor antagonist, BMS182874, and endothelin ETB receptor agonist, IRL1620, on morphine analgesia and changes in gastrointestinal transit in male Swiss Webster mice. Results indicate that morphine (6 mg/kg, s.c.) produced a significant increase in tail flick latency compared to control group. Pretreatment with BMS182874 (50 μg, i.c.v.) significantly enhanced morphine-induced analgesia, while IRL1620 (30 μg, i.c.v.) pretreatment did not affect tail-flick latency values. Changes in gastrointestinal transit were measured by percent of distance traveled by charcoal in the small intestine of gastrointestinal tract. Percent distance traveled in morphine (6 mg/kg, s.c.) treated mice (48.45 ± 5.65%) was significantly lower (P < 0.05) compared to control group (85.07 ± 1.82%). Administration of BMS182874 centrally (50 μg, i.c.v.) or peripherally (10 mg/kg, i.p.) did not affect morphine-induced inhibition of gastrointestinal transit. Pretreatment with IRL1620 (30 μg, i.c.v., or 10 mg/kg, i.v.) also did not affect morphine-induced inhibition of gastrointestinal transit. This study demonstrates that endothelin ETA receptor antagonists delivered to the CNS enhance morphine analgesia without affecting gastrointestinal transit. © 2006 Elsevier B.V. All rights reserved. Keywords: IRL1620 {Suc-[Glu9,Ala11,Ala15]ET-1-(8–21)]}; BMS182874 (5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyd)-1-Naphthalenesulfonamide); Morphine; Analgesia; Gastrointestinal transit; Central nervous system; Endothelin; (Mice)

1. Introduction The management of pain experienced by patients recovering from surgical procedures or suffering from terminal illnesses has been a widespread health concern (Nakamura et al., 2002). At the present time, morphine is one of the most effective antinociceptive agents used to manage pain. However, chronic pain management with morphine leads to severe adverse effects such as nausea, vomiting, dysuria, development of tolerance, ⁎ Corresponding author. Department of Biopharmaceutical Sciences (M/C 865), The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA. Tel.: +1 312 996 0826; fax: +1 312 413 1948. E-mail address: [email protected] (A. Gulati). 1 Current affiliation: Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA. 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2006.05.032

physical dependence, impairment of consciousness, and severe constipation (Dowling et al., 1997). Various treatment regimens have been unable to establish a favorable balance between analgesia and adverse effects of analgesics used to relieve acute and chronic pain. Clinical strategies to manage and prevent these adverse effects include treatment regimens involving the substitution of opioids, varying the routes of administration and/or formulation of opioids, and concurrent administration of multiple agents that may interact with opioid receptors. Reports indicate an interaction between different opioid receptor subtypes, and several cellular and molecular targets. Mechanisms implicated in development of tolerance and dependence due to chronic administration of opiates are complex; often linking alterations in opiate transduction and interaction between opiate and nonopiate systems (Vaccarino and Kastin, 2000). Non-opiate systems that participate in the action of opiates include nitric

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oxide (NO), N-methyl-D-aspartate (NMDA), gamma amino butyric acid (GABA), dopamine, adrenergic, 5-hydroxytryptamine (5-HT), cholecystokinin, adenosine, glutamate, and Neuropeptide FF. However, there is no approved and effective strategy to manage the problem of tolerance and physical dependence on opioid analgesics (Williams et al., 2001). More recently, the role of endothelin receptors in pain and their interaction with opioids has been demonstrated. Endothelin ETA receptor antagonists, BQ123 and BMS182874, have been demonstrated to have an effect on analgesia and on development of opiate tolerance (Bhalla et al., 2002, 2003). It has been shown that stimulation of endothelin ETB receptors in keratinocytes releases beta-endorphins leading to analgesia (Khodorova et al., 2003). However, in the central nervous system (CNS), it was found that activation of endothelin ETB receptors does not modulate morphine induced analgesia (Bhalla et al., 2004). Analgesic tolerance and physical dependence are clinically important adverse effects observed during pain management with opioid analgesics. Another frequent and persistent side effect in the course of opioid treatment is constipation. Opioid action on the gut appears to be mediated mainly by receptors in the gastrointestinal tract as well as those in the CNS. Opioids also have a direct local effect on the bowel (Manara et al., 1986). Exogenously administered opioids act within the CNS to alter autonomic outflow to the gut, affecting intestinal motility (Bueno and Fioramonti, 1988; Galligan and Burks, 1982a,b; Shook et al., 1987). The route of administration of morphine does not seem to affect the incidence of opioidinduced constipation (Schwarzer et al., 2004). The gut is an organ where many neuroactive drugs such as opioid analgesics have an adverse effect on gastrointestinal function, because many of the transmitters and transmitter receptors present in the brain are also found in the enteric nervous system. Conventional treatment measures are often ineffective in managing constipation and alternative approaches are needed. Opioid antagonists (naloxone, naltrexone, and nalmefene) have been studied as a means of antagonizing the peripheral effects of opioids, but these agents can enter the CNS and reverse opioid analgesia or cause withdrawal symptoms (Foss, 2001). Quaternary derivatives of naltrexone and naloxone, naltrexone methylbromide and naloxone methylbromide, respectively, reverse morphine-induced acute gastrointestinal transit inhibition, without affecting the chronic effects of morphine (Russell et al., 1982). We have shown that endothelin ETA receptor antagonists potentiate morphine analgesia and prevent development of tolerance in rats (Bhalla et al., 2002, 2003). It is of interest to determine whether endothelin ETA antagonists potentiate only the analgesic action of morphine or if they also affect gastrointestinal motility. The present study was conducted to determine the effect of centrally and peripherally administered endothelin ETA receptor antagonist, BMS182874, and endothelin ETB receptor agonist, IRL1620, on morphine-induced analgesia and morphine-induced changes in gastrointestinal transit in mice.

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2. Materials and methods 2.1. Animals Male Swiss Webster mice weighing 25–30 g were obtained from Harlan Sprague–Dawley (Indianapolis, IN). The animals were housed five to a cage in a room maintained at a constant ambient temperature (23 ± 1 °C, humidity 50 ± 10%, 12 h light/ dark cycle (6:00 A.M.–6:00 P.M). Food and water were made available ad libitum. Experiments were carried out after the animals had been acclimated to the environment for at least 4 days. Study protocols were approved and studies were carried out according to the guidelines established by the Animal Care Committee of University of Illinois at Chicago. 2.2. Drugs BMS182874 hydrochloride (Tocris Cookson, Inc., Ellisville, MO, USA) was dissolved in 20% dimethylsulfoxide (DMSO) prepared in sterile saline and injected intracerebroventricularly (i.c.v.) for central studies, and intraperitoneally for peripheral studies. The dose and route of administration of BMS182874 were selected on the basis of previous studies (Ihara et al., 1992; Stein et al., 1994). IRL1620 (Sigma Chemical Company, St. Louis, MO, USA) was dissolved in sterile saline and injected intracerebroventricularly (i.c.v.) for central studies, and intravenously for peripheral studies. The dose and route of administration of IRL1620 were selected on the basis of previous studies (Palacios et al., 1998). Morphine sulfate (Mallinckrodt Chemical Co., St. Louis, MO, USA) was dissolved in distilled deionized pyrogen-free water and injected subcutaneously (s.c.). 2.3. Experimental procedure For intracerebroventricular injections, mice were hand-held by the loose skin behind the head and a midline drawn through the anterior base of the ears. The site of injection was 2 mm from either side of this midline. A 27 gauge sterile hypodermic needle with a guard attached to a 10 μl sterile Hamilton syringe was inserted perpendicularly to depth of 6.0 mm through the skull into the brain, and drugs were delivered to the ventricle of the mouse brain (DalBo et al., 2004; Galeotti et al., 2002; Haley and McCormick, 1957; Yokoyama et al., 2004). Vehicle (sterile saline), BMS182874 or IRL1620 were administered as described above. The volume of drug injection was 5.0 μl. At the end of each experiment, methylene blue dye was injected and the placement of the injection was confirmed by observing the site and extent of staining. Morphine sulfate (6 mg/kg, s.c.) was administered 30 min after administration of vehicle, BMS182874, or IRL1620. 2.3.1. Determination of analgesic latency The analgesic response to morphine was determined by the tail-flick latency method (Gulati and Bhargava, 1988, 1990). The tail-flick latencies to thermal stimulation (focused light) were determined before and at 30, 60, 90, 120, 180, 210, 240, 270, 300, and 360 min after morphine injection. The baseline

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and between groups were tested using analysis of variance (ANOVA). A level of P < 0.05 was considered significant. 3. Results Body weight was measured at baseline and there was no difference between the treatment groups. BMS182874 and IRL1620 pretreatment in combination with morphine (6 mg/kg, s.c.) had no significant effect on change in body weight.

Fig. 1. Effect of BMS182874 (50 μg, i.c.v.) pretreatment on morphine (6.0 mg/ kg, s.c.) induced analgesic response. Values are expressed as mean ± S.E.M. N = 7 in each group. ⁎P < 0.05 compared to vehicle control group (Vehicle + Vehicle). #P < 0.05 compared to morphine control group (Vehicle + Morphine).

(control) latency was determined before any drug administration. Only mice with a control reaction time from 1 to 2 s were used. A 10 s maximum cut-off time was imposed to prevent tissue damage to the tail of mice. The basal latency was subtracted from that induced by morphine and the analgesic response in each mouse was converted to AUC0→360 min (Bhalla et al., 2003; Suzuki et al., 2001) and expressed as mean ± S.E.M. 2.3.2. Gastrointestinal transit testing Mice were fasted for 14 h with water available ad libitum before the experiment. Administration of saline, BMS182874 or IRL1620 was followed 30 min later by administration of saline or morphine sulfate. A 5% (w/v) charcoal suspension in water containing 10% (w/v) of gum Arabic was administered orally (0.1 ml/10 g body weight) 30 min after the administration of morphine or saline. 30 min after ingestion of charcoal meal, the mice were euthanized by CO2 asphyxiation and the gastrointestinal tract was removed from the pylorus to the ileocecum. Percent gastrointestinal transit in the small intestine was calculated by measuring the distance traveled by the charcoal divided by the length of the intestine from the pylorus to the ileocecum and was expressed as the mean ± S.E.M. of each group. 2.3.3. Experimental design Mice were divided into the following 10 groups: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

3.1. Effect of BMS182874 and IRL1620 on morphine-induced analgesia Baseline tail-flick analgesic latency before morphine administration was similar in all the groups (Figs. 1 and 2). In the vehicle-pretreated mice, morphine produced significant analgesia (P < 0.05) compared to baseline over a duration of 6 h. The area under the curve AUC0 → 360 min for tail flick analgesic latency (Fig. 3) in the vehicle + morphine treated group was 141.1 ± 10.0, which was significantly greater (P < 0.05) compared to vehicle group. The effect of BMS182874 and IRL1620 pretreatment on morphine (6 mg/kg, s.c.) induced changes in tail-flick analgesic latency in mice are shown in Figs. 1 and 2, respectively. In the first experiment conducted to study the effect of endothelin ETA receptor antagonist, peak tail-flick latency (7.70 ± 1.04 s) was reached at 1 h after morphine administration. This increase in analgesic response lasted for 2 h after morphine administration. Peak tail-flick latency in BMS182874 + morphine treated mice was 9.01 ± 0.66 s and lasted for 6 h after morphine administration. This was significantly higher than the response in the vehicle + morphine treated mice. BMS182874 (50 μg, i.c.v.) administration alone did not alter tail-flick latency values over the 6-h observation period. However, pretreatment with BMS182874 significantly enhanced (P < 0.05) the analgesic response produced by morphine (6 mg/kg, s.c.) (Fig. 1). IRL1620 (30 μg, i.c.v.) administration alone did not produce any change in tail-flick latency values over 6 h. Morphine (6 mg/kg, s.c.) induced analgesic response was not affected by IRL1620 pretreatment (Fig. 2). Peripheral administration of BMS182874 (10 mg/kg, i.p.) and IRL1620

Vehicle + Vehicle (100 μl/kg, s.c.), Vehicle + Morphine (6 mg/kg, sc), BMS182874 (50 μg, i.c.v.) + Vehicle (100 μl/kg, s.c.), BMS182874 (50 μg, i.c.v.) + Morphine (6 mg/kg, sc), IRL1620 (30 μg, i.c.v.) + Vehicle (100 μl/kg, s.c.), IRL1620 (30 μg, i.c.v.) + Morphine (6 mg/kg, sc). BMS182874 (10 mg/kg, i.p.) + Vehicle (100 μl/kg, s.c.), BMS182874 (10 mg/kg, i.p.) + Morphine (6 mg/kg, sc), IRL1620 (10 mg/kg, i.v.) + Vehicle (100 μl/kg, s.c.), IRL1620 (10 mg/kg, i.v.) + Morphine (6 mg/kg, sc).

2.4. Statistics All data are presented as mean ± S.E.M. Paired t-test was used to determine the statistical significance. Differences within

Fig. 2. Effect of IRL1620 (30 μg, i.c.v.) pretreatment on morphine (6.0 mg/kg, s.c.) induced analgesic response. Values are expressed as mean ± S.E.M. N = 5 in each group. ⁎P < 0.05 compared to vehicle control group (Vehicle + Vehicle).

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Fig. 3. Effect of BMS182874 (50 μg, i.c.v.) and IRL1620 (30 μg, i.c.v.) pretreatment on morphine (6.0 mg/kg, s.c.) induced analgesic response as depicted by AUC0→360 min. BMS182874 (50 μg, i.c.v.) pretreatment significantly increased the analgesic tail-flick latency by morphine, while IRL1620 (30 μg, i.c.v.) had no effect on latency. Values are expressed as mean ± S.E.M. N = 7 in each group for BMS182874/morphine experiment, and N = 5 in each group for IRL1620/morphine experiment. ⁎P < 0.05 compared to vehicle control group (Vehicle + Vehicle). #P < 0.05 compared to morphine control group (Vehicle + Morphine).

(10 mg/kg, i.v.) did not affect morphine analgesia (data not shown). 3.2. Effect of BMS182874 and IRL1620 on morphine-induced changes in gastrointestinal transit The distance traveled by charcoal was expressed as the percentage of the total length of the small intestine (Figs. 4 and 5). The distance traveled by charcoal in control vehicle treated mice was 85.07 ± 1.82% of the length of the small intestine. In morphine (6 mg/kg, s.c.) treated mice, the distance traveled by charcoal was 48.45 ± 5.65% of the length of the small intestine. Therefore, morphine significantly (P < 0.05) decreased gastro-

Fig. 4. Effect of BMS182874 (50 μg, i.c.v.) and IRL1620 (30 μg, i.c.v.) pretreatment on the percent inhibition of GI transit in the small intestine induced by morphine (6.0 mg/kg, s.c.) administration. Mice were pretreated with BMS182874 (50 μg, i.c.v.) and IRL1620 (30 μg, i.c.v.) 30 min prior to administration of morphine or vehicle. Values are expressed as mean ± S.E.M. N = 10 each group. ⁎P < 0.05 compared to respective vehicle + BMS182874, or vehicle + IRL1620 treated group.

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Fig. 5. Effect of BMS182874 (10 mg/kg, i.p.) and IRL1620 (10 mg/kg, i.v.) pretreatment on the percent inhibition of GI transit in the small intestine induced by morphine (6.0 mg/kg, s.c.) administration. Mice were pretreated with BMS182874 (10 mg/kg, i.p.) and IRL1620 (10 mg/kg, i.v.) 30 min prior to morphine or vehicle administration. Values are expressed as mean ± S.E.M. N = 5 each group. ⁎P < 0.05 compared to respective vehicle + BMS182874, or vehicle + IRL1620 treated group.

intestinal transit distance in the small intestine by 43.53 ± 3.23%. In mice treated with BMS182874 (50 μg, i.c.v.) alone, gastrointestinal transit distance (78.79 ± 4.96%) was statistically similar to control (P > 0.05) (Fig. 4). In BMS182874 pretreated mice, morphine (6 mg/kg, s.c.) decreased gastrointestinal transit distance by 35.57 ± 4.71%. Therefore, BMS182874 pretreatment did not have any effect on morphine-induced reduction in gastrointestinal transit. IRL1620 (30 μg, i.c.v.) administration alone did not affect gastrointestinal transit (82.44 ± 3.16%) when compared to control vehicle treated mice (P > 0.05) (Fig. 4). In mice pretreated with IRL1620, morphine decreased gastrointestinal transit by 37.83 ± 4.88%. This was not statistically different from mice treated with morphine alone. These results suggest that both BMS182874 and IRL1620 administered centrally did not affect morphine induced changes in gastrointestinal transit. In BMS182874 (10 mg/kg, i.p.) pretreated mice, morphine (6 mg/kg, s.c.) decreased gastrointestinal transit distance by 47.34 ± 4.43%. This suggests that BMS182874 pretreatment did not have any effect on morphine-induced reduction in gastrointestinal transit. IRL1620 (10 mg/kg, i.v.) administration alone did not affect gastrointestinal transit (Fig. 5). In mice pretreated with IRL1620 (10 mg/kg, i.v.), the decrease in gastrointestinal transit after morphine administration was 42.61 ± 4.17%. These results were not statistically different from mice treated with morphine alone. Therefore, both BMS182874 and IRL1620 administered peripherally did not affect morphine-induced changes in gastrointestinal transit. 4. Discussion Morphine is a widely used opioid analgesic for management of severe acute and chronic pain. However, with repeated use of morphine, the analgesic effect of morphine is attenuated significantly. Therefore, the dose of morphine needs to be

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increased during chronic administration in order to maintain adequate pain relief. In addition, morphine and other opioid analgesics exhibit serious adverse effects such as hallucinations, dry mouth, dizziness, drowsiness, nausea, and constipation, which decrease the patient's quality of life. Opioid rotation (the switch from one opioid to another with the aim of achieving a better balance between analgesia and adverse effects (Fallon, 1997)) and the use of opioid receptor antagonists to reverse morphine-induced constipation have been common clinical practices. However, opioid antagonists such as naloxone, naltrexone, and nalmefene have been shown to reverse the analgesic effect of opioids and also induce withdrawal symptoms (Foss, 2001). Magnesium oxide or sennosidecontaining drugs have been administered for the treatment of constipation, but these therapies have not been well-tolerated by patients (Durlach et al., 1994; Fujita et al., 2004). More recent approaches including herbal medicines, such as Dai-kenhcu-to (Nakamura et al., 2002) and black tea (Camellia sinensis) (Chaudhuri et al., 2000), have been shown to reverse morphineinduced inhibition of gastrointestinal transit. We have previously reported that centrally administered endothelin ETA receptor antagonists significantly potentiate morphine analgesia (Bhalla et al., 2002, 2003). The clinical implications are important since inhibitory disturbances in the gastrointestinal tract are frequently observed in patients treated with opiates. Therefore, it was of interest to determine whether endothelin ETA antagonists potentiate morphine-induced decrease in gastrointestinal transit in addition to potentiating morphine analgesia. Results of the present study demonstrate that although BMS182874 significantly potentiated the analgesic effect of morphine, it did not produce any effect on the inhibition of gastrointestinal transit in morphine treated mice. These results suggest that endothelin ETA receptor antagonists can be used to potentiate the analgesic properties of morphine without potentiating a decrease in gastrointestinal tract transit. Endothelin ETB receptor agonist, IRL1620, did not have any effect on morphine analgesia. IRL1620 did not affect morphine induced decrease in gastrointestinal transit, indicating that central endothelin ETB receptor stimulation in the CNS and in the periphery did not affect the pharmacological actions of morphine. Therefore, activation of central or peripheral endothelin ETB receptors does not appear to modulate morphine's analgesic or gastrointestinal actions. While endothelin ETA receptor blockade in the CNS enhances analgesic actions of morphine, it does not produce any changes in gastrointestinal transit. Similarly, blockade of peripheral endothelin ETA receptors using BMS182874 does not have an effect on inhibition of gastrointestinal transit produced by morphine. Conventional laxative measures in treating opioid bowel dysfunction have been ineffective, leading to the need for investigation of alternative approaches (Kurz and Sessler, 2003; Pappagallo, 2001). Methylnaltrexone (MNTX), a naltrexone derivative, is a selective peripheral opioid receptor antagonist. MTNX does not cross the blood–brain barrier and reverses opioid-induced reduction in bowel motility without affecting analgesia, possibly through a local luminal action of MNTX on the gut (Foss, 2001). A number of other opioid derivatives are

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