Morphine-induced Constipation Research Articles

PEG-4000 Ameliorates morphine-induced constipation in mice through inhibition of AQP-3 mRNA Expression

Morphine is μ-opioid receptor (MOR) agonist that is used clinically for patients suffering from moderate to severe pain. Morphine can cause constipation due to activation of μ-opioid receptors in the central nervous system and the nervous system in the gastrointestinal tract. It is caused by increasing the expression of AQP-3 in the instestine through increased of serotonin by enterochromaffin cells. PEG 4000 is one of the osmotic laxatives used to treat Opioid Induced Constipation (OIC). PEG 4000 affects the upregulation of serotonin re-uptake which can lead to expression enhancement of AQP-3. The purpose of this study was to analyze the effect of PEG 4000 on expression changes of aquaporin-3 in mice colon induced acute constipation with morphine.Constipation conditions and the effectiveness of laxative therapy are indicated by constipation parameters in the form of fecal water content and stool weight. This study used 36 male mice of the Balb/c line genus which were divided into 3 groups, normal saline, morphine, and morphine + PEG 4000. Each group was further divided into 2 subgroups based on the time of observation, namely the first hour and fifth hour after morphine induced. The expression of AQP-3 was observed using Polymerase Chain Reaction (PCR) method. The result of this study showed that the administration of PEG 4000 to mice induced constipation with morfine could decrease the expression of AQP-3 from (146,413±1,736) to (118,411±3,476) with p value <0,05, increase the percentage of fecal water content from (0,000±0,000%) to (28,903±12,930%) with p value <0,05 and increase the stool weight from (0,000±0,000g) to (0,928±0,178g) with p value <0,01 From these results, it can be concluded that the administration of PEG 4000 in morphine induced constipation to mice was effective in reducing AQP-3 expression as well as increasing the percentage of fecal water content and stool weight.

Bisacodyl overcomes morphine-induced constipation by decreasing colonic Aquaporin-3 and Aquaporin-4 expression

Introduction: Morphine is an opioid prescribed to treat aches and pains. However, morphine often causes opioid-induced constipation (OIC). Aquaporin (AQP) transporters, especially AQP3 and AQP4, play an essential role in mediating constipation. Bisacodyl is a common laxative used to treat constipation. To date, the effects of bisacodyl on AQP3 and AQP4 expression and the role this interaction plays in constipation are unclear. This study aimed to determine the effects of bisacodyl on AQP3 and AQP4 expression in mice after induction of constipation with morphine.
 Materials and methods: The laxative effects of bisacodyl on both acute and chronic morphine-induced constipation were determined. Fecal water content, colonic bead expulsion, and colonic mRNA levels for AQP3 and AQP4 mRNA were measured.
 Results and discussion: The administration of morphine to mice resulted in decreased fecal water content, longer bead expulsion times, and increased AQP3 and AQP4 mRNA levels in the colon. Meanwhile, bisacodyl administration prevented the morphine-induced changes in fecal water content, bead expulsion time, and AQP3 and AQP4 mRNA levels in the colons of mice.
 Conclusion: This study suggests that bisacodyl may prevent morphine-induced constipation by preventing morphine-induced increases in AQP3 and AQP4 expression in the colon.
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Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment.

Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6β-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.

μ-Opioid Receptor-Mediated Enteric Glial Activation Is Involved in Morphine-Induced Constipation.

Among all the side effects, opioid-induced constipation (OIC) has the highest incidence rate in people who take chronic opioid therapy. Increasing evidence shows that enteric glial cells (EGCs) play a pivotal role in the modulation of gastrointestinal motility. We aim to investigate whether EGCs are involved in OIC and possible mechanisms. Eight-week male C57BL/6 mice were randomized into four groups: the control group, the morphine group, the gliotoxin fluorocitrate (FC) group, and the FC plus morphine group. OIC was induced by injection of morphine subcutaneously. Colonic motility was evaluated by in vivo motility assays and colonic migrating motor complex (CMMC) in vitro. Both the Ca2+ responses and the release of inflammatory cytokine by EGCs were detected in vitro. Proteins were detected by immunofluorescence staining and Western blot. The morphine group showed prolonged gastrointestinal motility compared with the control group. Once EGCs were disrupted by FC, such inhibitory effect was abolished. There was a remarkable enhancement of the GFAP expression on colonic EGCs. Immunofluorescence exhibited that μ-opioid receptor (MOR) collocated with GFAP, indicating the existence of MOR in EGCs. Moreover, morphine activated the EGCs significantly through enhancing GFAP expression and Ca2+ amplitude. Both effects can be reversed by MOR-siRNA. Morphine treatment elevated the enteric glial release of proinflammatory cytokines notably and this effect was abolished when EGCs were silenced by MOR-siRNA. The activation of EGCs via MOR and the increased proinflammatory cytokine from EGCs may be involved in morphine-induced constipation. These results provided a potential therapeutic target for OIC.

Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.

Opioids such as morphine—acting at the mu opioid receptor—are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(−/−)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(−/−) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR–17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR–17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or ‘apparent bias’. Overall, the current data suggests—and we support—caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.

Improved efficacy, tolerance, safety, and abuse liability profile of the combination of CR4056 and morphine over morphine alone in rodent models.

Background and PurposeProlonged use of opioids causes analgesic tolerance and adverse effects including constipation and dependence. Compounds targeting imidazoline I2 receptors are known to potentiate opioid analgesia in rodents. We investigated whether combination with the I2 receptor ligand CR4056 could improve efficacy and safety of morphine and explored the mechanisms of the CR4056–opioid interaction.Experimental ApproachWe used the complete Freund's adjuvant (CFA) model in rats to study the effects of treatments on hyperalgesia, morphine tolerance and microglia activation as measured by immunofluorescence. Opioid‐induced adverse effects were assessed in rodent models of morphine‐induced constipation, sedation (open field, sedation rating scale, and rotarod), physical dependence (naloxone‐induced withdrawal), and abuse (conditioned place preference‐associated reward). Chemiluminescence assays tested CR4056 as allosteric modulator of μ‐opioid receptors.Key ResultsCR4056 (ED50 = 4.88 mg·kg−1) and morphine (ED50 = 2.07 mg·kg−1) synergized in reducing CFA‐induced hyperalgesia (ED50 = 0.52 mg·kg−1; 1:1 combination). Consistently, low doses of CR4056 (1 mg·kg−1) spared one third of the cumulative morphine dose administered during 4 days and prevented/reversed the development of tolerance to morphine anti‐hyperalgesia. These opioid‐sparing effects were associated with decreased activation of microglia, independent of CR4056 interactions on μ‐opioid receptors. Importantly, the low doses of CR4056 and morphine that synergize in analgesia did not induce constipation, sedation, physical dependence, or place preference.Conclusion and ImplicationsWe showed selective synergism between CR4056 and morphine as analgesics. Their combination showed an improved safety and abuse liability profile over morphine alone. CR4056 could be developed as an opioid‐sparing drug in multimodal analgesia.

Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.

Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance, limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut, predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment (in vivo) but not upon direct exposure of glia to morphine (in vitro). LPS, a major bacterial product, also increased ATP-induced currents, as well as expression of P2X4, P2X7, IL6, IL-1β mRNA in enteric glia. LPS increased connexin43 (Cx43) expression and enhanced ATP release from enteric glia cells. LPS-induced P2X currents and proinflammatory cytokine mRNA expression were blocked by the Cx43 blockers Gap26 and carbenoxolone. Likewise, colonic inflammation related to prolonged exposure to morphine was significantly attenuated by carbenoxolone (25 mg/kg). Carbenoxolone also prevented gut wall disruption and significantly reduced morphine-induced constipation. These findings imply that enteric glia activation is a significant modulator of morphine-related inflammation and constipation.-Bhave, S., Gade, A., Kang, M., Hauser, K. F., Dewey, W. L., Akbarali, H. I. Connexin-purinergic signaling in enteric glia mediates the prolonged effect of morphine on constipation.

Enhanced Sensitivity of α3β4 Nicotinic Receptors in Enteric Neurons after Long-Term Morphine: Implication for Opioid-Induced Constipation.

Opioid-induced constipation is a major side effect that persists with long-term opioid use. Previous studies demonstrated that nicotine-induced contractions are enhanced after long-term morphine exposure in guinea pig ileum. In the present study, we examined whether the increased sensitivity to nicotine could be observed in single enteric neurons after long-term morphine exposure, determined the subunits in mouse enteric neurons, and examined the effect of nicotine in reversing opioid-induced constipation. Nicotine (0.03-1 mM) dose-dependently induced inward currents from a holding potential of -60 mV in isolated single enteric neurons from the mouse ileum. The amplitude of the currents, but not the potency to nicotine, was significantly increased in neurons receiving long-term (16-24 h) but not short-term (10 min) exposure to morphine. Quantitative mRNA analysis showed that nicotinic acetylcholine receptor (nAChR) subunit expression in the mouse ileum was α3 ≥ β2 > β4 > α5 > α4 > β3 > α6. Nicotine-induced currents were obtained in neurons from α7, β2, α5, and α6 knockout mice. The currents were, however, inhibited by mecamylamine (10 μM) and the α3β4 blocker α-conotoxin AuIB (3 μM), suggesting that nicotine-induced currents were mediated by the α3β4 subtype of nAChRs on enteric neurons. Conversely, NS3861, a partial agonist at α3β4 nAChR, enhanced fecal pellet expulsion in a dose-dependent manner in mice that received long-term, but not short-term, morphine treatment. Overall, our findings suggest that the efficacy of nAChR agonists on enteric neurons is enhanced after long-term morphine exposure, and activation of the α3β4 subtype of nAChR reverses chronic, but not acute, morphine-induced constipation.

Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice

Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate–dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

Morphine-Induced Constipation Develops With Increased Aquaporin-3 Expression in the Colon via Increased Serotonin Secretion.

Aquaporin-3 (AQP3) is a water channel that is predominantly expressed in the colon, where it plays a critical role in the regulation of fecal water content. This study investigated the role of AQP3 in the colon in morphine-induced constipation. AQP3 expression levels in the colon were analyzed after oral morphine administration to rats. The degree of constipation was analyzed after the combined administration of HgCl(2) (AQP3 inhibitor) or fluoxetine (5-HT reuptake transporter [SERT] inhibitor) and morphine. The mechanism by which morphine increased AQP3 expression was examined in HT-29 cells. AQP3 expression levels in rat colon were increased during morphine-induced constipation. The combination of HgCl(2) and morphine improved morphine-induced constipation. Treatment with morphine in HT-29 cells did not change AQP3 expression. However, 5-HT treatment significantly increased the AQP3 expression level and the nuclear translocation of peroxisome proliferator-activated receptor gamma (PPARγ) 1 h after treatment. Pretreatment with fluoxetine significantly suppressed these increases. Fluoxetine pretreatment suppressed the development of morphine-induced constipation and the associated increase in AQP3 expression in the colon. The results suggest that morphine increases the AQP3 expression level in the colon, which promotes water absorption from the luminal side to the vascular side and causes constipation. This study also showed that morphine-induced 5-HT secreted from the colon was taken into cells by SERT and activated PPARγ, which subsequently increased AQP3 expression levels.

Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation.

Although opioids induce intestinal muscle contraction and provoke constipation, the intestinal region(s) that contribute to the constipation have remained unclear. We report here a region-specific response of intestinal muscle contraction to morphine and its correlation with in vivo constipation. Regions of mice small and large intestines were dissected histologically and circular muscle contractile responses were measured using isometric transducers. Bead expulsion assays were performed to assess in vivo constipation. The strongest contraction in response to morphine was detected in the rectum. The distal and transverse colon also showed strong contractions, whereas weak responses were detected in the proximal colon, jejunum, and ileum. Regarding the sustainability of muscle contractions during morphine exposure, prolonged waves were detected only in the rectum, while the waves diminished gradually in other regions. To identify the mechanism(s) underlying this difference, we focused on nitric oxide synthase (NOS). In the distal colon, decreased contraction during morphine exposure was recovered by application of a NOS inhibitor (L-NAME), while a NOS substrate (L-arginine) enhanced contractile degradation. In contrast L-NAME and L-arginine modestly affected the sustained contraction in the rectum. To confirm the correlation with constipation, beads were inserted into the transverse colon, distal colon, or rectum after morphine administration and expulsion times were examined. Beads tended to stop at the rectum even when inserted in the deeper colonic regions. The rectum showed the greatest response to morphine in both in vitro and in vivo analyses, therefore it may play a key role for opioid-induced constipation.

Palliation of Bone Cancer Pain by Antagonists of Platelet-Activating Factor Receptors

Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF) receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC) model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2) protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

『消化管ペプチドで大建中湯の効果を評価する』 消化管ペプチドを介したモルヒネ誘発性便秘に対する大建中湯の効果

大建中湯は消化管術後イレウスや過敏性腸症候群に対して臨床的有用性の高い漢方方剤として知られている．動物を用いた基礎的検討により，本剤はモルヒネ誘発性の消化管障害に対して改善効果を示すことが報告されている．また大建中湯の主要な薬理作用は消化管運動亢進作用と腸管粘膜血流増加作用であり，その作用機序として消化管ペプチドの関与が報告されている．しかしながら現在まで担がん患者のモルヒネ誘発性便秘に対する大建中湯の臨床効果と消化管ペプチドとの関連については不明なままである．本研究では，モルヒネ誘発性便秘を有する担がん患者を対象として大建中湯の効果および消化管機能を反映する5種の消化管ペプチドの血漿中濃度に与える効果について検討した．対象はがん性疼痛に対してモルヒネ治療後に便秘を生じた7名の担がん患者で，大建中湯投与前後における各消化管ペプチドの血漿中濃度を高感度酵素免疫測定法により測定した．また，消化器症状への効果については大建中湯投与前後のGastrointestinal Symptom Rating Scale（GSRS）質問表により検討した．モルヒネ誘発性便秘に対する大建中湯の効果について検討した結果では，大建中湯の投与によりGSRSの便秘サブスコアは7例中4例で有意に低下した．次にGSRS便秘サブスコアが改善した有効群と，変化がなかった無効群で血漿中消化管ペプチド濃度を比較した．その結果，両群ともに健常人と比較して血漿中モチリン濃度は有意に低値であったが，大建中湯投与後，有効群では健常人と同程度の濃度まで上昇し，無効群と比較して有意な上昇が認められた．一方，血漿中calcitonin gene-related peptide（CGRP）濃度も有効群で上昇傾向が認められた．以上の結果から，大建中湯のモルヒネ誘発性便秘への作用は，発現時間および臨床症状ともに血漿中モチリンの変動によってよく説明されるものであり，大建中湯の臨床効果との関連が示唆された．

Activation of TREK-1 by morphine results in analgesia without adverse side effects

Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same μ opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from μ opioid receptor. We demonstrate that the TREK-1 K(+) channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K(+) channel, acting downstream from the μ opioid receptor, might have strong analgesic effects without opioid-like adverse effects.

Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain.

Inhibition of Gβγ-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward

Inhibition of Gβγ-subunit signaling to phospholipase C β3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gβγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the μ-opioid receptor. The Gβγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gβγ-mediated signaling may selectively increase μ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects.

Clinical observation of prophylactic lactulose for prevention of oral morphine-induced constipation

To evaluate the effects of different doses of lactulose on preventing oral morphine-induced constipation. From January 2011 to May 2012, a total of 112 patients received oral lactulose solution to prevent morphine-induced constipation at our hospital and their clinical data were retrospectively analyzed. The doses of morphine were adjusted according to the pain scores and lactulose was taken simultaneously. There were 52 males and 60 females. They were randomized into Group 30 ml/d (n = 40), Group 60 ml/d (n = 43) and Group 90 ml/d (n = 29). The incidences of constipation and adverse reactions were obtained at 1 week after the start of medicine. The measurement data were analyzed with analysis of variance. And the enumeration data were analyzed with χ(2), Kruskal-Wallis and Mann-Whitney U tests. The incidence of constipation was 67.5% (27/40) in Group 30 ml/d, 46.5% (20/43) in Group 60 ml/d, and 37.9% (11/29) in Group 90 ml/d. And there were statistical differences (P = 0.036). The incidence of constipation in Group 30 ml was significantly higher than Group 90 ml/d (P = 0.015). No statistical difference existed in the incidence of constipation between Groups 30 ml/d and 60 ml/d (P = 0.054) or Groups 60 ml/d and 90 ml/d (P = 0.471). The incidence of vomiting was 34.5% (10/29) in Group 90 ml/d and it was significantly higher than 10.0% (4/40) in Group 30 ml/d (P = 0.013) and 9.3% (4/43) in Group 60 ml/d (P = 0.009). No statistical difference existed in the incidence of vomiting between Groups 30 ml/d and 60 ml/d (P = 0.915). The incidence of diarrhea was 17.2% (5/29) in Group 90 ml/d and it was significantly higher than 0 (0/40) in Group 30 ml/d (P = 0.007). No statistical difference existed in the incidence of diarrhea between Groups 30 ml/d and 60 ml/d (4.7% (2/43), P = 0.170) or Groups 60 ml/d and 90 ml/d (P = 0.072). The correct dosage of lactulose for the prevention of oral morphine-induced constipation is 60 ml/d.

Beta‐arrestin2 Contributes to the Development of Opioid‐ Induced Constipation

Constipation is a common and problematic side effect associated with opioid therapy. Opioid analgesics such as morphine exert their physiological effects primarily through activation of the mu opioid receptor (MOR), a G protein‐coupled receptor (GPCR). Although opioids are known to decrease gastrointestinal motility by decreasing secretion and muscle contractions, the cellular signaling mechanisms downstream of MOR activation that mediate these physiologies are not completely understood. We have previously shown that morphine‐induced constipation is significantly reduced in βarrestin2 knockout (βarr2‐KO) mice. Moreover, this reduction appears to be due to altered opioid receptor responses in the enteric nervous system, specifically at the level of the colon. Here, we have assessed the contribution of βarrestin2 in mediating morphine‐inhibition of secretion within the colon by assessing changes in nicotinic stimulation of secretion in colonic tissue preparations using Ussing chambers. We find that the βarr2‐KO mice display significantly less morphine‐induced inhibition of secretion compared to WT controls, suggesting that βarrestin2 may facilitate the effects of constipatory effects of morphine in the colon. These results provide further evidence that βarrestin2 is a critical regulator of morphine‐induced constipation. Supported by NIDA DA021952 (KMR), DA14600 and DA18860 (LMB).

Daikenchuto raises plasma levels of motilin in cancer patients with morphine-induced constipation

Daikenchuto raises plasma levels of motilin in cancer patients with morphine-induced constipation

Morphine‐induced tolerance and dependence develops in the mouse isolated ileum but not colon

Morphine tolerance and dependence have been demonstrated historically in ileum but not in the colon, the major organ associated with constipation. Here we evaluated the development of tolerance and dependence to morphine in the isolated tissue segments from the mouse ileum and colon. Isometric force was measured from longitudinal and circular muscle preparations of ileum and colon from placebo‐ (PP) and morphine‐pelleted (MP) mice. Morphine inhibition of field stimulated contractions of the longitudinal muscle was dose dependent with comparable pD2 values from the ileum (7.1) and colon (7.8) (n=6) of PP mice. However, the dose‐response was shifted to the right for the ileum (pD2= 5.1) but not the colon (pD2= 6.9) of MP mice. Morphine produced contractions of circular muscle preparations in ileum and colon. Repeated administration of morphine in the organ bath produced tolerance in the ileum by the 4th application but not the colon from PP mice. Whereas in tissues from MP mice, where tolerance has already developed, further tolerance to the contractile response to morphine did not develop in the ileum. Naloxone precipitated a withdrawal contracture in the longitudinal muscle after long‐term morphine incubation in the ileum but not the colon. These findings demonstrate that tolerance does not develop in the colon and may explain the lack of tolerance to morphine‐induced constipation. Supported by DK46367, DA01647