Reducing the side effects of pain treatment is one of the most important strategies for improving the quality of life of cancer patients. However, little is known about the mechanisms that underlie these side effects, especially constipation induced by opioid receptor agonists; i.e., do they involve naloxonazine-sensitive versus -insensitive sites or central-versus-peripheral μ-opioid receptors? The present study was designed to investigate the mechanisms of μ-opioid receptor agonist-induced constipation (i.e., the inhibition of gastrointestinal transit and colonic expulsion) that are antagonized by the peripherally restricted opioid receptor antagonist naloxone methiodide and naloxonazine in mice. Naloxonazine attenuated the fentanyl-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine or oxycodone. Naloxone methiodide suppressed the oxycodone-induced inhibition of gastrointestinal transit more potently than the inhibition induced by morphine, indicating that μ-opioid receptor agonists induce the inhibition of gastrointestinal transit through different mechanisms. Furthermore, we found that the route of administration (intracerebroventricular, intrathecally, and/or intraperitoneally) of naloxone methiodide differentially influenced the suppressive effect on the inhibition of colorectal transit induced by morphine, oxycodone, and fentanyl. These results suggest that morphine, oxycodone, and fentanyl induce constipation through different mechanisms (naloxonazine-sensitive versus naloxonazine-insensitive sites and central versus peripheral opioid receptors), and these findings may help us to understand the characteristics of the constipation induced by each μ-opioid receptor agonist and improve the quality of life by reducing constipation in patients being treated for pain.
Pain is a common medical problem, and the relief of pain is an important goal in pain management. μ-Opioid receptor agonists, especially morphine, have been considered to be the “gold standard” for the treatment of patients who are experiencing moderate to severe cancer pain (WHO, 1996) or noncancer pain such as chronic inflammatory and postoperative pain. Reducing the side effects of μ-opioid receptor agonists, such as emesis, constipation, drowsiness, hallucination, and delirium, is an important strategy for improving the quality of life (QOL) of patients suffering from pain. Constipation is an especially distressing side effect of opioids used to manage pain that occurs in 40–95% of patients treated with opioids (Swegle and Logemann, 2006). Furthermore, severe constipation, caused by the activation of μ-opioid receptors in the central nervous system (through the autonomic system) and gastrointestinal tract (through direct stimulation of the enteric nervous system) that are responsible for gut motility (Shook et al., 1987), reduces the amount of opioid that can be obtained from a given dose, which in turn decreases the antinociceptive effects of opioids.
The QOL of patients suffering from cancer pain is complicated by tolerance, which involves the loss of analgesic potency that in turn leads to an increase in the required dose and hence an increase in possible side effects (Finkel et al., 2007). Opioid rotation (switching) and the use of peripherally restricted opioid-receptor antagonists, such as methylnaltrexone, which has a limited ability to cross the blood-brain barrier, or oral naloxone administered in a prolonged-release manner, have been shown to reverse opioid-induced refractory constipation (Holzer et al., 2009; Leppert, 2010), which indicates that the stimulation of peripheral opioid receptors is important for the expression of μ-opioid receptor agonist-induced constipation. In fact, peripheral μ-opioid receptors contribute to intestinal function (Gmerek et al., 1986; Radbruch and Elsner, 2004; Ross et al., 2008; Kang et al., 2012). Animal studies have shown that both the i.c.v. and i.t. administration of opioid receptor agonists can induce the delay of intestinal movement (Koslo et al., 1986; Raffa et al., 1987; Heyman et al., 1988). On the other hand, pharmacological findings have suggested that there are at least two μ-opioid-receptor sites indicated as follows: naloxonazine-sensitive (μ1-opioid receptors) and naloxonazine-insensitive (μ2-opioid receptors) (Pasternak, 1993; Elliott et al., 1994; Cadet, 2004). Naloxonazine, a so-called μ1-opioid receptor antagonist, is frequently used to discriminate the pharmacological actions of μ-opioid receptor subtypes. However, the mechanisms by which opioid receptor agonists induce constipation are not yet clear; i.e., do they involve naloxonazine-sensitive or -insensitive sites and central (spinal or supraspinal) or peripheral receptors?
Morphine, oxycodone, and fentanyl are clinically prescribed opioids that have prominent antinociceptive effects. Each μ-opioid receptor agonist has a distinct pharmacological profile by which it exerts its antinociceptive effects (Minami et al., 2009; Nakamura et al., 2011). These different pharmacological effects can be explained by differences in patterns of plasma concentrations (Nakamura et al., 2011), blood-brain barrier transport (Dagenais et al., 2004; Bostrom et al., 2008), receptor subtypes (Cadet, 2004), and intracellular signal transduction. However, limited information is available regarding the different pharmacological mechanisms of opioid receptor agonist-induced constipation. Therefore, the present study was designed to investigate the adverse effects of opioid receptor agonists, especially those that target bowel function, using the peripherally restricted opioid receptor antagonists naloxone methiodide and naloxonazine.
Materials and Methods
In the present study, male imprinting control region (ICR) mice (20–25 g) (Tokyo Laboratory Animals Science Co. Ltd., Tokyo, Japan) were used. Food and water were available ad libitum for mice in their individual home cages. Mice were housed in a room maintained at 22 ± 1°C with a 12-hour light-dark cycle (light on 8:00 AM to 8:00 PM). The present study was conducted in accordance with the Guiding Principles for the Care and Use of Laboratory Animals at Hoshi University, as adopted by the Committee on Animal Research of Hoshi University. Every effort was made to minimize the numbers and any suffering of animals used in the following experiments.
The antinociceptve response was evaluated by recording the latency to paw licking or tapping in the hot-plate test (55 ± 0.5°C; Muromachi Kikai Co., Ltd., Tokyo, Japan) as described previously (Narita et al., 2005). To prevent tissue damage, we established a 30-second cut-off time. Antinociceptive effects were measured at 30 minutes after the administration of morphine (1–10 mg/kg s.c.), and 10 minutes after the administration of oxycodone (1–10 mg/kg s.c.) and fentanyl (10–300 μg/kg s.c.). Each animal served as its own control, and the latency to a response was measured both before and after drug administration. Antinociception was calculated as a percentage of the maximum possible effect (% antinociception) according to the following formula: % antinociception = (test latency − predrug latency)/(cut-off time − predrug latency) × 100. The antinociceptive response represents the mean ± S.E.M. of the % antinociception.
In the study of gastrointestinal transit (Torigoe et al., 2012), mice were fasted for 12 hours before the experiments. At 30 minutes after the administration of morphine (0.3–10 mg/kg s.c.), 10 minutes after the administration of oxycodone (0.3–10 mg/kg s.c.), or 10 minutes after the administration of fentanyl (10–300 μg/kg s.c.), blue ink (0.3 ml/mouse; Pilot Co. Ltd., Tokyo, Japan) was administered orally. Thirty minutes after the administration of blue ink, the animal was killed by cervical dislocation and the small intestine was removed. The percentage inhibition of gastrointestinal transit was calculated as follows: (distance traveled by the ink/length from the pylorus to the cecum) × 100. In antagonism tests, naxolonazine (35 mg/kg i.p., 24-hour pretreatment), naloxone methiodide (10 mg/kg i.p.; 4 mM i.c.v. or i.t., 10-minute pretreatment), or saline was administered before the injection of morphine, fentanyl, or oxycodone.
Effect on Colonic Expulsion.
The effects of morphine, oxycodone, and fentanyl on colonic propulsion were evaluated as described previously (Yamada and Onoda, 1992). In brief, 30 minutes after the administration of morphine (1–10 mg/kg s.c.) and 10 minutes after the administration of oxycodone (0.3–10 mg/kg s.c.), fentanyl (10–300 μg/kg s.c.), or saline, a glass bead (approximately 3 mm in diameter; BZ-3 Ikeda Rika, Tokyo, Japan) was inserted into the distal colon to a depth of 2 cm from the anus with a silicone tube (approximately 2 mm in diameter). In the antagonism tests, naloxonazine (35 mg/kg i.p.) or saline was administered 24 hours before treatment with morphine, fentanyl, or oxycodone. Naloxone methiodide (10 mg/kg i.p., or 4 mM i.c.v. and i.t.) was administered 10 minutes before treatment with morphine, fentanyl, or oxycodone. The time required to expel the bead was measured up to 120 minutes.
Intracerebroventricular and Intrathecal Injection.
Intracerebroventricular administration was given as described previously (Haley, 1957). The injection was made with a 2-mm double-needle (Natsume Seisakusho, Co., Ltd., Tokyo, Japan) attached to a 25-μl Hamilton microsyringe. Solution was injected in a volume of 4 μl per mouse. Administration was done intrathecally as described previously (Hylden and Wilcox, 1980), using a 25-μl Hamilton syringe with a 30-gauge needle. Solution was injected in a volume of 4 μl per mouse. Three days before intracerebroventricular administration, a hole was made under ether analgesia, for ethical reasons, to reduce the stress in mice.
Electrical Stimulation of the Mouse Small and Large Intestine.
Approximately 2 cm of the small intestine (ileum) and large intestine (rectum to distal colon) were dissected and placed in Krebs-Henseleit solution (in mM: NaCl, 112.08; KCl, 5.90; CaCl2, 1.97; MgCl2, 1.18; NaH2PO4, 1.22; NaHCO3, 25.00, and glucose, 11.49). The small or large intestine was placed under 0.5 g of tension in a 20-ml organ bath containing the nutrient solution. The bath was maintained at 37°C and continuously bubbled with a mixture of 95% O2 and 5% CO2. Tissues were stimulated by a platinum needle–ring electrode. After equilibration, the intestine was transmurally stimulated with monophasic pulses (50 V, 5 Hz, 1 millisecond duration) every 1 minute by a stimulator (SEN-7203; Nihon Kohden, Tokyo, Japan). Contractions were isotonically recorded by using a displacement transducer (NEC Type 45347; San-ei Instruments Ltd., Tokyo, Japan). The effects of drug treatment on the twitch contractions evoked by transmural stimulation elicited through the ring electrodes were examined. The height of the twitch response to transmural stimulation was measured before and after drug challenge. The responses are expressed as a percentage, where the twitch response to transmural stimulation before drug challenge was considered to be 100%. β-Funaltrexamine (β-FNA; 40 mg/kg i.p.), naloxonazine (35 mg/kg i.p.), or saline was administered 24 hours prior to isolation of the segment. As previously reported, the irreversible μ-opioid receptor antagonist β-FNA and the irreversible μ1-opioid antagonist naloxonazine reversed the effect of the peripheral opioid agonist loperamide in mice (Baker and Meert, 2002). These antagonistic effects of β-FNA and naloxonazine were substantially maintained under extensive washout in motility experiments using mouse isolated colon (Yu et al., 2007). Thus, we used these protocols to investigate the involvement of μ-opioid subtypes in the inhibitory effects of morphine, oxycodone, and fentanyl on electrically stimulated contraction.
The drugs used in the present study were morphine hydrochloride, oxycodone hydrochloride (Shionogi Pharmaceutical Co., Inc., Osaka, Japan), and fentanyl citrate (Hisamitsu Pharmaceutical Co. Inc., Tokyo, Japan). Naloxonazine and naloxone methiodide were synthesized at Toray Industries (Kanagawa, Japan). All drugs were dissolved in saline and administered in a volume of 10 ml/kg. The pretreatment times and doses of naloxone, naloxone methiodide, and naloxonazine were based on our previous reports (Suzuki et al., 1995; Matsuzawa et al., 2000).
Data are expressed as the mean ± S.E.M. The statistical significance of differences between groups was assessed by the Mann–Whitney test. The 50% effective dose (ED50) values were determined using an analysis of variance and linear regression techniques. Where appropriate, a one-way analysis of variance (ANOVA) followed by the Bonferroni multiple comparisons test was used for statistical analysis. All statistical analyses were performed using Prism software (Version 5.0a; GraphPad Software, Inc., La Jolla, CA). A P value of < 0.05 was considered to reflect significance.
Pharmacological Differences between μ-Opioid Receptor Agonists.
Dose-response curves for the pharmacological effects, such as antinociception and inhibition of gastrointestinal and colorectal transit, of morphine, oxycodone, and fentanyl and the corresponding ED50 values are shown in Fig. 1. The potencies of morphine for inducing pharmacological effects (ED50) were in the order: gastrointestinal transit > colorectal transit > antinociceptive effects. Those of oxycodone were gastrointestinal transit = colorectal transit > antinociceptive effects. There were no differences between the ED50 values of fentanyl for these three pharmacological effects (Fig. 1).
Site-Specific Actions of μ-Opioid Receptor Agonists for the Inhibition of Gastrointestinal Transit.
To confirm the site-specific action of morphine-, fentanyl-, and oxycodone-induced inhibition of gastrointestinal transit, antagonism tests were initiated. The morphine- (1 and 10 mg/kg), fentanyl- (0.03 and 0.1 mg/kg), and oxycodone- (1 and 3 mg/kg) induced inhibition of gastrointestinal transit was significantly attenuated by naloxone methiodide (Fig. 2A). Interestingly, naloxone methiodide, a peripherally restricted opioid-receptor antagonist, had less of an effect on the morphine-induced inhibition of gastrointestinal transit than on that induced by fentanyl (0.1 mg/kg) and oxycodone (3 mg/kg). Therefore, morphine may have different sites of action than those of fentanyl and oxycodone. Fentanyl and oxycodone directly affect peripheral μ-opioid receptors, whereas morphine directly and indirectly regulates transit through the gastrointestinal tract through μ-opioid receptors.
To confirm these findings for morphine, we also examined the involvement of supraspinal/spinal μ-opioid receptors in the delay of gastrointestinal transit. Central nervous system administration of naloxone methiodide significantly altered the morphine-induced inhibition of gastrointestinal transit (Fig. 2B; F(4,24) = 9.076, P < 0.0001). In particular, the morphine-induced inhibition of gastrointestinal transit in mice was significantly attenuated by the coadministration of naloxone methiodide (intracentroventricularly and intrathecally). The intracentroventricular or intrathecal administration of naloxone methiodide did not affect the inhibitory effect of the intraperitoneal administration of naloxone methiodide on the delay of gastrointestinal transit induced by morphine, and the intracentroventricular or intrathecal plus intraperitoneal administration of naloxone methiodide completely inhibited the delay of gastrointestinal transit (Fig. 2B). Thus, these findings support the notion that the agonistic actions of morphine, not only the direct actions on the gastrointestinal tract but also the synergistic actions at supraspinal and spinal opioid receptors, are required for the inhibition of gastrointestinal transit.
Site of μ-Opioid Receptor Agonist–Induced Inhibition of Colonic Expulsion.
We next examined the effects of a peripheral μ-opioid receptor antagonist on morphine- (3 and 10 mg/kg), fentanyl- (0.03 and 0.1 mg/kg), and oxycodone- (1 and 3 mg/kg) induced inhibition of colonic expulsion. The inhibition of colonic expulsion by morphine, fentanyl, and oxycodone was not significantly altered by pretreatment with naloxone methiodide (Fig. 3A). These results indicate that the inhibition of colonic expulsion induced by μ-opioid receptor agonists is mediated through central nervous system opioid receptors. Previous reports have shown that intracentroventricular and intrathecal injection of morphine and other μ-opioid receptor agonists could attenuate colonic expulsion (Koslo et al., 1986; Raffa et al., 1987). However, to the best of our knowledge, no direct evidence is available concerning the relative contributions of spinal and supraspinal opioid receptors to the attenuation of colonic expulsion by systemically administered opioid-receptor agonists. It is surprising that neither intracentroventricular nor intrathecal pretreatment with naloxone methiodide affected the morphine-induced inhibition of colonic expulsion (Fig. 3B). Therefore, we considered that multiple sites of action might be involved synergistically in the inhibition of colonic expulsion by morphine. Next, we examined the effects of the dual injection of naloxone methiodide on the inhibition of colonic expulsion by morphine. We found that, although intracentroventricular or intrathecal plus intraperitoneal injection of naloxone methiodide slightly reduced the inhibition of colonic expulsion by morphine, intracentroventricular plus intrathecal injection of naloxone methiodide significantly suppressed this effect of morphine (Fig. 3B). Thus, morphine inhibits colonic expulsion through multiple sites of action [F(4,25) = 8.129, P = 0.0002] and especially mediates at least both supraspinal and spinal opioid receptors. On the other hand, we also found that the local injection of naloxone methiodide suppressed the inhibition of colorectal expulsion by fentanyl (Fig. 3C; F(4,23) = 10.43, P < 0.0001) and oxycodone (Fig. 3D; F(3,35) = 12.03, P < 0.0001). In particulat, intrathecal but not intracentroventricular administration of naloxone methiodide significantly attenuated the oxycodone-induced inhibition of colonic expulsion, whereas intracentroventricular but not intrathecal administration of naloxone methiodide significantly attenuated this effect of fentanyl. Furthermore, intracentroventricular plus intrathecal administration of naloxone methiodide did not enhance the effects of intrathecal (in the case of oxycodone) or intracentroventricular (in the case of fentanyl) administration alone. These results indicate that oxycodone and fentanyl inhibit colonic expulsion mainly at spinal and supraspinal levels, respectively.
Involvement of Naloxonazine-Insensitive and -Sensitive Sites in the Inhibition of Intestinal Transition.
The morphine- (3 and 10 mg/kg), fentanyl- (0.03 mg/kg), and oxycodone- (3 mg/kg) induced inhibition of gastrointestinal transit was significantly attenuated by naloxone methiodide (Fig. 2A). On the other hand, the fentanyl- (0.1 mg/kg) and low dose (1 mg/kg) of oxycodone-induced inhibition of gastrointestinal transit was significantly attenuated by naloxonazine (Fig. 4A), which indicates that both peripheral naloxonazine-sensitive and -insensitive sites take part in the attenuation of gastrointestinal transit by fentanyl and oxycodone. Thus, these μ-opioid receptor agonists attenuate gastrointestinal transit by different mechanisms.
The inhibition of colonic expulsion by a medium (3 mg/kg) dose of morphine was not affected by pretreatment with naloxonazine (Fig. 4B). However, oxycodone (3 mg/kg) and a higher dose of morphine (10 mg/kg) induced a severe delay in colonic expulsion that was partially, but significantly, attenuated by naloxonazine (Fig. 4B). These results indicate that both naloxonazine-sensitive and -insensitive sites are involved in the morphine- and oxycodone-induced inhibition of colonic expulsion. On the other hand, the fentanyl-induced inhibition of colonic expulsion, even at a dose of 0.1 mg/kg, was almost completely attenuated by naloxonazine (Fig. 4B), suggesting that the effects of fentanyl on colonic expulsion are mediated mainly through naloxonazine-sensitive sites and that the mechanism of the effect of fentanyl on colonic expulsion is slightly different from those of morphine and oxycodone, which involve both naloxonazine-sensitive and -insensitive sites.
Involvement of Naloxonazine-Insensitive Sites in the Inhibition of Intestinal Contraction In Vitro.
The present study demonstrated that peripheral naloxonazine-insensitive sites regulate the inhibition of gastrointestinal transit and that the direct action of morphine at μ-opioid receptors plays a role in the inhibition of large intestinal movement induced by μ-opioid receptor agonists. Therefore, to clarify the involvement of naloxonazine-sensitive sites in the effects of morphine, oxycodone, and fentanyl on the small and large intestine, we examined the effects of naloxonazine on the inhibitory effects of morphine, oxycodone, and fentanyl on field-stimulated contraction using isolated ileum and rectum to the distal colon (Fig. 5). Morphine, oxycodone, and fentanyl inhibited the twitch contraction in a concentration-dependent manner. Pretreatment with naloxonazine did not affect the inhibitory effects of morphine, oxycodone, and fentanyl on the small and large intestines. In addition, the irreversible μ-opioid receptor antagonist β-FNA significantly attenuated the inhibitory effect of morphine on the large intestine (data not shown). Therefore, naloxonazine-insensitive sites could directly regulate the movement of both the small and large intestines in mice.
µ-Opioid receptor agonists such as morphine, oxycodone, and fentanyl have been reported to have distinct pharmacological profiles by which they exert both their antinociceptive effects in several pain models as well as their adverse effects, such as constipation, behavioral inhibition, and respiratory inhibition in rodents (Minami et al., 2009; Nakamura et al., 2011). In the present study, these μ-opioid receptor agonists exerted different pharmacological profiles to inhibit gastrointestinal transit and colorectal expulsion in comparison with their antinociceptive effects. Previous studies have demonstrated that intracentroventricular and intrathecal administration of morphine inhibits gastrointestinal and colonic function (Koslo et al., 1986; Heyman et al., 1988; Pol et al., 1999), whereas peripheral μ-opioid receptors also contribute to morphine-induced intestinal movement in rodents (Gmerek et al., 1986; Pol et al., 1999; Ross et al., 2008). On the other hand, naloxonazine could not reverse the morphine-induced inhibition of gastrointestinal transit, even though it reversed the morphine-induced (intrathecally) inhibition of gastrointestinal transit (Heyman et al., 1988), and partially reversed the morphine-induced inhibition of colonic transit (Koslo et al., 1986). Thus, the mechanism by which opioid receptor agonists induce constipation through naloxonazine-sensitive or -insensitive sites and supraspinal, spinal, or peripheral receptors remains unclear. Furthermore, little information is available regarding the differential pharmacological profiles of morphine, oxycodone, and fentanyl with regard to intestinal transit (Gmerek et al., 1986).
Similar to the results in previous studies (Koslo et al., 1986; Heyman et al., 1988; Pol et al., 1999; Ross et al., 2008), we showed that morphine can inhibit gastrointestinal transit mainly through peripheral, and in part through supraspinal as well as spinal, naloxonazine-insensitive sites of μ-opioid receptors, whereas morphine inhibits colonic transit through peripheral naloxonazine-sensitive and -insensitive sites of μ-opioid receptors. In the present study, we showed that oxycodone and fentanyl inhibit gastrointestinal transit mainly through peripheral μ-opioid receptors. Furthermore, we found that fentanyl predominantly inhibits gastrointestinal and colonic transit thorough naloxonazine-sensitive sites compared with morphine and oxycodone. Interestingly, we demonstrated that spinal as well as supraspinal μ-opioid receptors participate in the morphine-induced inhibition of colonic transit, whereas supraspinal (in the case of fentanyl) and spinal (in the case of oxycodone) μ-opioid receptors play important roles in the inhibition of colonic transit induced by fentanyl and oxycodone. Thus, our findings indicate that these μ-opioid receptor agonists produce gastrointestinal and colonic dysfunction through different mechanisms (Fig. 6).
Overall our results showed that fentanyl inhibits intestinal movement only slightly compared with morphine and oxycodone, particularly considering their antinociceptive effects. These findings parallel clinical findings that morphine- and oxycodone-induced constipation is problematic in patients when these compounds are used to control pain (Weschules et al., 2006), whereas fentanyl may have a lower risk of producing constipation than oxycodone (Ackerman et al., 2004) or morphine (Radbruch and Elsner, 2004). Our present findings demonstrate that the inhibitory effects of fentanyl on intestinal transit are mainly mediated through naloxonazine-sensitive sites. Therefore, the activation of naloxonazine-insensitive sites might be responsible for the severe constipation under treatment with morphine or oxycodone in humans.
The long-term use of opioids for the treatment of severe pain induces side effects such as bowel dysfunction, e.g.constipation, which is difficult to relieve with the use of laxatives (Greenwood-Van Meerveld and Standifer, 2008). A recent clinical study showed that when laxative therapy was insufficient in patients with opioid-induced constipation, the peripherally restricted opioid-receptor antagonist methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating opioid withdrawal syndrome (Thomas et al., 2008). We showed that the activation of central μ-opioid receptors, rather than any action in the periphery, plays an important role in the inhibition of colorectal functions by μ-opioid receptor agonists. However, we also found that the peripheral μ-opioid receptor antagonist naloxone methiodide significantly attenuated the gastrointestinal dysfunction induced by fentanyl and oxycodone (and partially attenuated the dysfunction induced by morphine), indicating that peripheral opioid receptor antagonists could be a useful adjunct for the treatment of severe gastrointestinal constipation induced by opioid analgesia, especially in the case of fentanyl and oxycodone.
Pol et al. (1999) showed that the intracentroventricular administration of morphine had a greater ability to inhibit intestinal function than that of fentanyl. Their data suggested that activation of central μ-opioid receptors is important for the inhibition of gastrointestinal transit by μ-opioid-receptor agonists, and that lipophilicity, which is associated with penetration of the blood-brain barrier, reflected the difference in the abilities of morphine and fentanyl to induce constipation. Nevertheless, our findings indicate that each opioid receptor agonist inhibits intestinal movement though different mechanisms (Fig. 6). Therefore, our findings strongly suggest that movement of the intestinal tract could be governed by μ-opioid receptor agonists through several mechanisms, and these inhibitory effects of μ-opioid receptor agonists on the gastrointestinal tract depend on the particular characteristics of each opioid.
In conclusion, morphine, oxycodone, and fentanyl were shown to induce constipation though different mechanisms that involved naloxonazine-sensitive versus -insensitive sites and supraspinal/spinal-versus-peripheral opioid receptors. Our findings suggest that peripherally acting μ-receptor antagonists, such as methylnaltrexone and alvimopan, would be beneficial for gastrointestinally originated constipation induced by opioid receptor agonists without compromising pain relief (Becker and Blum, 2009). Other laxatives that target colorectal-originated constipation could be useful as a cotreatment along with peripherally acting μ-receptor antagonists to suppress opioid receptor agonist–induced constipation. We believe that our findings provide some insight into the receptor agonists studied as well as information that could contribute to the application of peripherally restricted opioid receptor antagonists in addition to future drug design for improving the QOL of patients under pain control.
Participated in research design: Mori, Shibasaki Y., Shibasaki M., Horie, Suzuki.
Conducted experiments: Matsumoto, Hasegawa, Wang, Masukawa.
Performed data analysis: Mori, Yoshizawa.
Wrote or contributed to the writing of the manuscript: Mori, Shibasaki Y., Yoshizawa, Suzuki.
- Received April 3, 2013.
- Accepted July 24, 2013.
- gastrointestinal transit
- naloxone methiodide
- quality of life
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics