Central effects of morphine on GI motility in conscious dogs

doi:10.1016/j.brainres.2007.06.048

Brain Research

Volume 1166, 29 August 2007, Pages 29-34

https://doi.org/10.1016/j.brainres.2007.06.048 Get rights and content

Abstract

It has been suggested that morphine has dual effects; emetic effects and anti-emetic effects. The chemoreceptor trigger zone, which is outside the BBB, mediates the emetic effect. In contrast, the vomiting center mediates the anti-emetic effect of opioids. Thus, naloxone methiodide, which does not cross the BBB, antagonizes emetic effects of opioids. We studied whether naloxone methiodide alters abnormal motility pattern induced by morphine in gastrointestinal (GI) tract. Strain gauge force transducers were sutured on the serosal surface of upper GI tract to record the circular muscle contractions in eight dogs. The ventricular access system was implanted to inject morphine intracerebroventricularly (icv). Effects of icv-injection of morphine (0.3–3.0 μg/kg, bolus) on GI motility were studied during intravenous infusion of naloxone hydrochloride or naloxone methiodide. Icv-injection of morphine (3.0 μg/kg) induced retching and vomiting in all dogs tested. Phasic contractions of the jejunum were observed after icv-injection of morphine. These contractions in the jejunum migrated orally to the antrum (retrograde peristaltic contractions; RPCs). Both naloxone hydrochloride and naloxone methiodide treatment virtually abolished the emetic effects of morphine. Naloxone hydrochloride completely abolished morphine-induced RPCs in all dogs, whereas naloxone methiodide converted morphine-induced RPCs to anterograde peristaltic contractions (APCs) in 6 of 8 dogs. Our current study suggests that central opioids may induce APCs and prevent emesis in conscious dogs. Naloxone methiodide may be useful to prevent the undesired side effects of morphine.

Introduction

Morphine is commonly used for treatment of moderate to severe pain. However, its administration is frequently associated with several troublesome side effects. Emesis is one of the undesirable side effects. Morphine induces emesis by stimulating the chemoreceptor trigger zone (CTZ) in the area postrema of the medulla (Wang and Glaviano, 1954). Area postrema is the circumventricular organ, which is outside the blood–brain barrier (BBB).

Morphine can cross the blood–brain barrier (BBB) (Noel and Byrne, 1985) and acts on both of peripheral and central opioid receptors. Since methylnaltrexone, a quaternary opioid antagonist, has limited ability to cross the BBB, it can block the emetic effect of morphine without affecting the analgesic effect of central opioids (Foss et al., 1993).

The vomiting center is located beneath the solitary tract of the caudal brain stem (Andrews, 1992, Foss et al., 1998). The stimulation of the opioid receptors in the vomiting center inhibits the emesis (Borison and Wang, 1953, Costello and Borison, 1977). Thus, morphine can have an emetic effect by stimulating the CTZ and an anti-emetic effect by stimulating the vomiting center. A peripheral opioid antagonist combined with morphine reduces apomorphine-induced emesis and blocks cisplatin-induced emesis (Foss et al., 1998).

Opioid is well known to delay gastric emptying in humans. Morphine-induced delay in gastric emptying is attenuated by methylnaltrexone. This suggests that the inhibitory effect of opioid is mediated outside the central nervous system (CNS) (Murphy et al., 1997).

It has been shown that apomorphine (Lang et al., 1986b), copper sulfate (Furukawa and Hatano, 1998), alpha-2 adrenoceptor agonists (Lang and Sarna, 1992), erythromycin (Holle et al., 1992, Pilot and Qin, 1988), cholecystokinin octapeptide (CCK-8) (Lang et al., 1988) and motion sickness (Kolev and Altaparmakov, 1996, Lang et al., 1999) cause emesis in animals and humans.

Abnormal gastrointestinal (GI) motility is frequently associated with the emetic events. Prior to vomiting, a giant contraction propagates orally from the mid-small intestine to the stomach and this is followed by a series of phasic contractions (Lang et al., 1986a, Sha et al., 1996). These oral contractions were defined as retrograde peristaltic contractions (RPCs).

Morphine (0.5 mg/kg, sc) produces gastric relaxations with vomiting in conscious dogs (Lefebvre et al., 1981). It still remains unclear whether morphine-induced emesis is associated with RPCs of GI tract. We have previously showed that intravenous (iv) infusion of morphine (0.3 mg/kg, bolus) caused RPCs in upper GI tract in conscious dogs. RPCs were followed by a frequent episode of retching and vomiting (Tsuchida et al., 2004).

In contrast, small doses of continuous iv-infusion of morphine (20–200 μg/kg/h) initiates aborally migrating giant contractions in the small intestine in conscious dogs (Sarna, 1987).

Intracerebroventricular (icv)-infusion of morphine (0.1–1.0 μg/kg) induces emesis and RPCs of the duodenum in conscious dogs (De Ponti et al., 1990). However, it remains unknown whether GI motor activity induced by morphine is mediated via peripheral or central opioid receptors.

In our current study, we studied whether central administration of morphine causes RPCs in conscious dogs. We also studied whether naloxone methiodide alters the abnormal motility pattern induced by morphine in GI tract and prevents emesis.

Section snippets

Effect of morphine on retching and vomiting

After icv-injection of morphine (0.3–3.0 μg/kg), emetic episodes (retching and vomiting) were observed in all dogs tested (Fig. 1). Frequent episodes of retching and vomiting were followed by antral contractions (Fig. 2a).

In contrast, intravenous (iv)-injection of morphine (3.0 μg/kg) caused no emetic episodes (Fig. 1).

Both naloxone hydrochloride and naloxone methiodide (0.5 mg/kg plus 0.5 mg/kg/h; iv) treatment virtually abolished the emetic episodes induced by morphine (Figs. 2b and c).

Effect of naloxone hydrochloride and naloxone methiodide on morphine-induced RPCs

Phasic

Discussion

We have previously showed the peripheral administration of morphine (0.3 mg/kg) retching and vomiting. The emetic events induced by morphine were frequently associated with RPCs in conscious dogs (Tsuchida et al., 2004). To further investigate the central effects of morphine, we studied the effects of the central administration of morphine (0.3–3.0 μg/kg) on GI motility.

It has been suggested that morphine has dual effects; emetic and anti-emetic effects (Blancquaert et al., 1986, Costello and

Animal preparation

The experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of Durham VA Medical Center. Eight beagle dogs (9–15 kg body weight) of both sexes were used. The dogs had continuous access to water and were fed pelleted dog food daily. After domestication for 1–2 weeks, a midventral laparotomy was performed to expose the abdominal cavity under general anesthesia.

References (33)

P.L. Andrews
Physiology of nausea and vomiting
Br. J. Anaesth.
(1992)
J.P. Blancquaert et al.
Emetic and antiemetic effects of opioids in the dog
Eur. J. Pharmacol.
(1986)
J. Dundee et al.
Acupuncture to prevent cisplatin-associated vomiting
Lancet
(1987)
N. Furukawa et al.
An acute experiment on retrograde intestinal peristalsis with emesis using decerebrated dogs
J. Auton. Nerv. Syst.
(1998)
J.G. Geoghegan et al.
Intracerebroventricular neuropeptide Y increases gastric acid secretion by decreasing tonic adrenergic inhibition of acid in dogs
Brain Res.
(1994)
J.S. Han
Acupuncture and endorphins
Neurosci. Lett.
(2004)
I.M. Lang et al.
Gastrointestinal motor correlates of vomiting in the dog: quantification and characterization as an independent phenomenon
Gastroenterology
(1986)
R.A. Lefebvre et al.
Gastric relaxation and vomiting by apomorphine, morphine and fentanyl in the conscious dog
Eur. J. Pharmacol.
(1981)
M.A. Noel et al.
The effect of morphine upon CSF opioids in dogs
Neuropeptides
(1985)
K. Streitberger et al.
Acupuncture for nausea and vomiting: an update of clinical and experimental studies
Auton. Neurosci.
(2006)

G.A. Ulett et al.

Electroacupuncture: mechanisms and clinical application

Biol. Psychiatry

(1998)

H.L. Borison et al.

Physiology and pharmacology of vomiting

Pharmacol. Rev.

(1953)

D.J. Costello et al.

Naloxone antagonizes narcotic self blockade of emesis in the cat

J. Pharmacol. Exp. Ther.

(1977)

F. De Ponti et al.

Variations in gastric tone associated with duodenal motor events after activation of central emetic mechanisms in the dog

J. Gastrointest. Motil.

(1990)

J.F. Foss et al.

Dose-related antagonism of the emetic effect of morphine by methylnaltrexone in dogs

J. Clin. Pharmacol.

(1993)

J.F. Foss et al.

Prevention of apomorphine- or cisplatin-induced emesis in the dog by a combination of methylnaltrexone and morphine

Cancer Chemother. Pharmacol.

(1998)

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Research ReportCentral effects of morphine on GI motility in conscious dogs

Abstract

Introduction

Section snippets

Effect of morphine on retching and vomiting

Effect of naloxone hydrochloride and naloxone methiodide on morphine-induced RPCs

Discussion

Animal preparation

Br. J. Anaesth.

Eur. J. Pharmacol.

Lancet

J. Auton. Nerv. Syst.

Brain Res.

Neurosci. Lett.

Gastroenterology