Effects of centrally administered naloxone on gastrointestinal myoelectrical activity in morphine-dependent rats

The gastrointestinal myoelectrical alterations associated with morphine tolerance and subsequent withdrawal with naloxone were studied before and after treatment with adrenergic blockers, atropine, indomethacin and methysergide administered either i.c.v. or s.c. The rats were prepared chronically with electrodes implanted on the stomach, duodeno-jejunum and colon and two small polyethylene catheters were inserted into the lateral ventricles of the brain. They were rendered physically dependent on morphine by the s.c. administration of a slow-release emulsion containing morphine (75 mg over 48 hr). Morphine treatment was associated with an immediate (15-30 min) inhibition of gastric and colonic spiking activity and intestinal migrating myoelectric complex lasting 6 to 8 hr, followed by a partial recovery of gastric spiking activity while a permanent disorganized motility pattern persisted on the intestine. After 48 hr of morphine treatment the i.c.v. and s.c. administrations of naloxone at doses of 0.03 and 3 mg X kg-1, respectively, promoted typical electrical activity lasting 2 to 3 hr, characterized by the presence of five to seven grouped spike bursts and termed "minute rhythm." Previous central but not peripheral administration of either tolazoline or phentolamine at a dose of 0.3 mg X kg-1 inhibited the i.c.v. naloxone precipitated withdrawal. Neither atropine i.c.v. (30 micrograms X kg-1) nor methysergide i.c.v. (20 micrograms X kg-1) and s.c. (0.2 mg X kg-1) nor indomethacin s.c. (4 mg X kg-1) were found to have any effect on i.c.v. naloxone induced minute rhythm pattern.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral delta opioid receptors mediate analgesia but not the intestinal motility effects of intracerebroventricularly administered opioids

Conformationally constrained cyclic enkephalin analogs which possess a high selectivity for the delta opioid receptor were used to determine the relative contribution of mu and delta receptors to brain-mediated changes in small intestinal propulsion and increases in hot-plate response time. Receptor preferences were determined by comparing the relative potencies of several opioid agonists in suppressing the electrically evoked contractions of the guinea-pig ileum and mouse vas deferens preparations. The ratio of IC50 values obtained in the guinea-pig ileum and the mouse vas deferens was used as an index of delta receptor selectivity. Effects on intestinal transit were determined in rats in which a silastic cannula had been implanted in the proximal duodenum and a polyethylene cannula in the right lateral cerebral ventricle (i.c.v.). Movement of a radioactive marker along the length of the small intestine after instillation into the duodenum was used to evaluate drug-induced changes in intestinal transit. The analgesic effects of i.c.v. administered opioids were determined in a second group of rats in which i.c.v. cannulas alone had been implanted. After i.c.v. administration of the agonist, the rats were placed on a 55 degrees C hot plate and the latency to rear paw-lick was timed. Compounds which showed a preference for the mu receptor [( D-Ala2, N-methyl-Phe4, Gly5 -ol]enkephalin and morphine/normorphine) were the most potent agonists at producing thermal analgesia and inhibition of small intestinal transit, whereas nonselective compounds (beta-endorphin and [D-Ala2, Met5]enkephalinamide) were slightly less potent in these assays.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociation of opioid antinociception and central gastrointestinal propulsion in the mouse: studies with naloxonazine

The effect of pretreatment with naloxonazine on opioid-mediated antinociception against a thermal stimulus (55 degrees C warm-water tail-flick test) and inhibition of gastrointestinal transit at supraspinal and spinal levels was studied in unanesthetized mice. The mu-selective agonist [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAGO), the delta-selective agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) and the reference mu-acting agonist morphine, all produced antinociception after either i.c.v. or intrathecal(ly) (i.t.) administration. Morphine and DAGO, but not DPDPE, inhibited gastrointestinal transit after i.c.v. administration, whereas all three agonists slowed gut propulsion when given i.t. A single s.c. naloxonazine pretreatment, 35 mg/kg given 24 hr earlier, failed to displace the dose-response line for i.c.v. DPDPE antinociception but produced a marked rightward displacement of the i.c.v. morphine and DAGO dose-response lines for antinociception. In contrast, naloxonazine (35 mg/kg) pretreatment did not alter the antinociceptive effects of i.t. morphine, DAGO or DPDPE. The effects of naloxonazine pretreatment on inhibition of gut propulsion were the converse of those observed for antinociception at supraspinal and spinal sites; naloxonazine had no effect on the antitransit properties of i.c.v. morphine and DAGO but inhibited the antitransit properties of all three agonists when they were given i.t. These results support the view that opioids may produce their supraspinal antitransit effects at a receptor different from that mediating antinociception; morphine and DAGO mediate their antitransit effects at a naloxonazine-insensitive site, whereas their antinociceptive effects are produced at the naloxonazine-sensitive receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antidiarrheal properties of supraspinal mu and delta and peripheral mu, delta and kappa opioid receptors: inhibition of diarrhea without constipation

We evaluated the ability of mu [morphine, Tyr-Pro-N-MePhe-D-Pro-NH2 (PLO17)], delta (Tyr-D-Pen-Gly-Phe-D-Pen) (DPDPE) and kappa [U50,488H, (trans-3,4-dichloro-N-methyl-N-(2-(1-pyr-rolidinyl) cyclo-hexyl)benzeneacetamine)] opioid receptor selective agonists to inhibit diarrhea induced by castor oil (0.6 ml p.o.) in mice after supraspinal (i.c.v.) and peripheral (s.c.) administration. The antidiarrheal potency of each compound was compared to its analgesic and gastrointestinal antitransit potency when given by the same route of administration. When administered i.c.v., morphine, PLO17 and DPDPE inhibited diarrhea in a dose-related fashion. The mu agonists, morphine and PLO17, given i.c.v, inhibited diarrhea at doses much lower than those needed to produce analgesia or to inhibit gastrointestinal transit. DPDPE (i.c.v.) was equipotent in inhibiting diarrhea and in eliciting analgesia, but did not effect the rate of transit. U50,488H (i.c.v.) inhibited diarrhea only at extremely high doses which also caused profound postural-motor incapacitance. U50,488H given i.c.v. had no effect on transit at any dose. When given peripherally, morphine, PLO17, DPDPE and U50,488H all inhibited diarrhea in a dose-related fashion. All four compounds inhibited diarrhea at doses much below those needed to cause analgesia. Morphine s.c. and PLO17 s.c. both inhibited diarrhea at doses lower than those required to inhibit transit. DPDPE s.c. and U50,488H s.c. had no effect on transit at any dose. The antidiarrheal effects of i.c.v. morphine, i.c.v. PLO17 and i.c.v. DPDPE were antagonized by pretreatment with 1 microgram i.c.v. of naltrexone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Centrally administered bombesin affects gastrointestinal transit and colonic bead expulsion through supraspinal mechanisms

Effects of bombesin on gastrointestinal transit and colonic bead expulsion (CBE) were studied in male, ICR mice. Mice received graded doses of bombesin or saline by either the i.c.v., intrathecal (i.t.) or i.p. routes; morphine was studied as the reference compound. Both compounds slowed gastrointestinal transit in a dose-dependent manner by these routes. Intracerebroventricular bombesin was 13.5 and 3406 times more potent than the i.t. and i.p. peptide, respectively. Intracerebroventricular or i.t. bombesin or morphine also produced dose-related inhibition of CBE. Intracerebroventricular bombesin was 1.54 times more potent than i.t. bombesin, whereas i.p. bombesin at doses 11,000 times greater (10 micrograms/kg; 25-g mouse) had no effect on CBE. Gastrointestinal transit and CBE were also studied in spinally transected (second thoracic vertebra) mice in which brain-spinal cord communication (neural and cerebrospinal fluid) had been interrupted. Cord transection eliminated the inhibition of gastrointestinal transit by i.t., but not i.c.v., bombesin. In contrast, morphine was effective by either route in normal or spinally transected mice. The CBE effects of i.t., but not i.c.v., bombesin were eliminated by spinal transection, whereas morphine was still effective by either the i.c.v. or i.t. route. These results suggest that 1) centrally administered bombesin acts at a central site to produce inhibition of gastrointestinal transit and CBE, 2) morphine inhibits gastrointestinal transit and CBE at both spinal or supraspinal sites, independent of an intact brain-cord axis and 3) i.t., but not i.c.v., bombesin requires communication between these two central sites. Intrathecal bombesin requires activation of supraspinal sites to produce its gut effects.     

Influence des agonistes morphiniques sur la motricité intestinale normale et pathologique

Résumé  La morphine et ses dérivés à propriétés agonistes des récepteurs μ, possèdent des effets sur la motricité gastrointestinale et colique. Aux doses actives sur la douleur, la morphine inhibe l’évacuation gastrique et ralentit le transit intestinal et colique. Ces effets sont principalement d’origine centrale pour l’évacuation gastrique, essentiellement périphériques au niveau de l’intestin grêle et d’origine mixte pour le c?lon. Alors que sur le plan moteur on assiste à une inhibition motrice, par contre les effets anti-transit de la morphine au niveau de l’intestin grêle et du c?lon relèvent d’une action de stimulation permanente à tous les niveaux sous forme de séries de contractions simultanées et stationnaires qui empêchent la progression du contenu. Enfin, en période d’iléus postchirurgical, l’utilisation de morphine peut entra?ner des effets moteurs puisque ceux-ci apparaissent pour des doses de morphine n’ayant pas encore d’effets antalgiques et freiner la reprise du transit.

---

Summary  Morphine and its derivatives with μ agonist affinities, affect gastrointestinal and colonic motility. At active doses on pain, morphine inhibits gastric emptying and slows down intestinal and colonic transit. These effects are of central origin for gastric emptying, peripheral for intestinal motility and both central and peripheral for the colon. While morphine inhibits gastric contractions, in contrast, morphine stimulates intestinal and colonic motility with stationnary contractions responsible of its inhibitory effects on intestinal and colonic propulsion of digesta When administered during post-surgical ileus, morphine may delay the occurrence of gas and the recovery of gastrointestinal transit: these effects been observed for doses similar or equal to those able to relief pain sensation.

Texte présenté lors du Congrès SFD-SOFRED des 15–17 juin 2000.     

Inhibition of gastrointestinal transit by morphine in rats results primarily from direct drug action on gut opioid sites

The local intestinal component of the constipating action of morphine was assessed through several integrated approaches in an in vivo animal model. The doses of systemically administered morphine reducing to 50% of drug-free controls (ID50) the small intestinal transit of a charcoal meal fed by gavage to overnight fasted rats were 0.04 and 3.8 mg/kg i.p. and p.o. and 0.5 mg/kg either s.c. or i.v., respectively. Transit inhibition with any of these morphine doses occurred within 10 min and was still measurable 20, 30, 45 and 240 min after i.p., i.v., s.c. and p.o. administration, respectively. Morphine given by any of these systemic routes did not reduce significantly transit in rats receiving the putative peripheral antagonist quaternary naloxone (1 mg/kg i.p., 5 min before morphine) that, unlike naloxone, failed to reverse transit inhibition (to about 50% of drug-free controls) induced by 0.08 mg/kg i.c.v. of morphine. Radioassay of thin-layer chromatograms of extracts of central nervous system, plasma, small intestine and small intestinal longitudinal muscle of rats given tritium-labeled morphine and also tested for gastrointestinal transit, showed that morphine concentrations in the longitudinal muscle (with attached myenteric plexus) after i.v., i.p. and s.c. injection fell within a relatively narrow range and were consistent with the appropriate transit scores. Morphine levels in the central nervous system of the same rats were lower than in any other tissue assayed, presented considerable differences depending on administration routes and did not correlate at all with the corresponding intestinal effects. Morphine administered directly into the rat cerebral ventricles effectively inhibits gastrointestinal transit through an opioid-sensitive central nervous system-located action site.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphine effects on locus ceruleus neurons are dependent on the state of arousal and availability of external stimuli: studies in anesthetized and unanesthetized rats

Because the physiological characteristics of noradrenergic locus ceruleus (LC) neurons differ in anesthetized and unanesthetized rats, the effects of morphine on LC activity recorded in both conditions were compared. Intracerebroventricular administration of morphine inhibited spontaneous LC discharge of both anesthetized and unanesthetized rats but morphine was at least 10 times more potent in anesthetized rats. In anesthetized rats LC discharge evoked by sciatic nerve stimulation was insensitive to doses of morphine (0.03 or 0.1 microgram) that inhibited LC spontaneous activity. Only the highest dose of morphine (0.3 microgram) which inhibited completely tonic activity decreased significantly evoked discharge. In parallel experiments in unanesthetized rats, the presentation of auditory stimuli evoked a pattern of LC discharge similar to that evoked by sciatic nerve stimulation in anesthetized rats. Morphine (1.0 and 3.0 micrograms) decreased both spontaneous and evoked activity in these rats; however, spontaneous LC discharge was more sensitive to morphine, as was observed with anesthetized rats. Quantitative analyses of these effects indicated that morphine tends to alter the pattern of LC discharge to sensory stimuli such that the signal-to-noise ratio (ratio of evoked/tonic activity during stimulus presentation) is increased. Morphine effects were reversed by naltrexone (1.0 mg/kg s.c.) in anesthetized rats and 1.0 microgram i.c.v. in unanesthetized rats. The present results indicate that the degree of arousal and the availability of environmental stimuli are important determinants of opiate effects on LC activity.     

Opioid modulation of basal intestinal fluid transport in the mouse: actions at central, but not intestinal, sites

Central and peripheral sites of opioid action on net basal fluid transport were studied in loops of jejunum in urethane-anesthetized mice. Intracerebroventricular administration of morphine, [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO), D-Pen2, D-Pen5] enkephalin (DPDPE) or U50,488H produced dose-related increases in net basal intestinal absorption. Intracerebroventricular DAMGO was approximately 2.6, 1278 and 2674 times more potent than morphine, DPDPE and U50,488H, respectively. The increase in net basal fluid absorption mediated by i.c.v. administration of all these compounds, except DPDPE, was antagonized in a dose-related manner by coadministration of i.c.v. naloxone, an opioid antagonist which did not produce any effects when given alone. Neither the increase in net basal fluid absorption produced by DPDPE nor the fluid transport effects produced by the other agonists tested was antagonized by the delta antagonist, N,N-diallyl-Tyr-alpha-aminoisobutyric acid [( Aib]-Aib-Phe-Leu-OH) and no effects were observed with this delta antagonist alone. Intracerebroventricular administration of beta-funaltrexamine (18.8 nmol, 4 hr before testing) blocked the i.c.v. effects of DAMGO, but not those of U50,488H. In contrast to the effects seen following i.c.v. administration of these agonists, no changes in net basal fluid transport were obtained by the i.p. route for DAMGO, DPDPE, [D-Ala2,D-Leu5]enkephalin, [D-Ala2, Met5]enkephalinamide or U50,488H; of the compounds tested, only morphine produced an increase in net basal fluid absorption after i.p. administration. The effects of i.c.v. or i.p. morphine were blocked by i.c.v. SR 58002C, a quaternary opioid antagonist which had no effects alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphine in cancer pain management: a practical guide

Morphine is the most practical and versatile analgesic for the relief of severe pain associated with advanced cancer. Information is available in the literature about its use in routine clinical practice. Morphine induces analgesia by reducing neurotransmitter release presynaptically and hyperpolarizing dorsal horn neurons at the postsynaptic level, thus preventing rostral transmission of nociception. Morphine has a unique metabolism via glucuronidation (UGT2B7), which results in an active metabolite (morphine-6-glucuronide). The pharmacokinetics of morphine relate to its hydrophilic characteristic, volume of distribution, route of administration and clearance. Renal failure alters its pharmacokinetics more than cirrhosis. The age of the patient and multiple medications will alter morphine pharmacokinetics. Morphine can be given by several different routes: oral, rectal, subcutaneous (s.c.), intravenous (i.v.), epidural and intrathecal. Recent experience confirms benefits of topical morphine for cutaneous pain associated with benign or malignant ulcers. Guidelines for morphine administration are reviewed, and in particular those of the Harry R. Horvitz Center for Palliative Medicine are outlined.     

Differential modulation by [D-Pen2, D-Pen5]enkephalin and dynorphin A-(1-17) of the inhibitory bladder motility effects of selected mu agonists in vivo

The possibility that the delta agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE) and the putative endogenous kappa agonist, dynorphin A-(1-17) could differentially modulate the effects of a group of chemically diverse mu agonists was evaluated using inhibition of volume-induced contractions of the rat urinary bladder as a model of central nervous system opioid receptor function in vivo. Intracerebroventricular administration of equieffective doses of the mu agonists [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), [N-MePhe3, D-Pro4]enkephalin (PL017), morphine, normorphine, sufentanil, etorphine, phenazocine, meperidine and methadone inhibited spontaneous bladder contractions for approximately 20 to 30 min. Low doses of DPDPE or dynorphin A-(1-17) failed to affect spontaneous bladder contractions; higher doses of DPDPE (greater than 15.5 nmol) and dynorphin A-(1-17) (i.e., greater than 3.7 nmol), inhibited bladder contractions. When coadministered i.c.v., DPDPE displaced the morphine dose-response line to the left and also potentiated the effects of normorphine and etorphine. In contrast, DPDPE failed to alter the actions of equieffective doses of DAGO, PL017, meperidine, methadone, phenazocine or sufentanil. The potentiation of the effects of morphine by DPDPE were prevented by i.c.v. coadministration of the delta antagonist, ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH); at the dose tested, the delta antagonist had no agonist effects alone and did not antagonize the effects of morphine directly. Furthermore, the agonist effects of morphine were potentiated by several different doses of DPDPE. Administration of i.c.v. dynorphin A-(1-17) produced a rightward displacement of the morphine dose-response line and also antagonized the effects of normorphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents

Marijuana has been reported to be an effective antinauseant and antiemetic in patients receiving cancer chemotherapy. Whether this is due to psychological changes, central antiemetic properties and/or direct effects on gastrointestinal (GI) function is not known. The purpose of these investigations was to determine whether the major constituents of marijuana and the synthetic cannabinoid nabilone have any effects on GI function which can be detected in rodent models of GI transit and motility. Intravenous delta 9-tetrahydrocannabinol (delta 9-THC) slowed the rate of gastric emptying and small intestinal transit in mice and in rats. Delta 9,11-THC, cannabinol and nabilone given i.v. also inhibited small intestinal transit in mice, but were less effective in reducing gastric emptying. Cannabidiol given i.v. had no effect on gastric emptying or intestinal transit. Those cannabinoids which inhibited GI transit did so at doses equal to, or lower, than those reported to produce central nervous system activity. In rats, delta 9-THC produced greater inhibition of gastric emptying and small intestinal transit than large bowel transit, indicating a selectivity for the more proximal sections of the gut. In addition, i.v. delta 9-THC decreased the frequency of both gastric and intestinal contractions without altering intraluminal pressure. Such changes probably reflect a decrease in propulsive activity, without change in basal tone. These data indicate that delta 9-THC, delta 9,11-THC, cannabinol and nabilone (but not cannabidiol) exert an inhibitory effect on GI transit and motility in rats.     

Involvement of supraspinal epsilon and mu opioid receptors in inhibition of the tail-flick response induced by etorphine in the mouse.

Etorphine, a potent opioid agonist, has been reported to bind to both mu and epsilon opioid receptors. The present studies were designed to determine what types of opioid receptors and neurotransmitters for descending pain control systems were involved in antinociception induced by etorphine in mice. Morphine, a typical mu opioid receptor agonist, and beta-endorphin, an epsilon opioid receptor agonist, were used for comparison. Antinociceptive response induced by etorphine (20 ng) given i.c.v was blocked by i.c.v administration of D-Phe-Cys-Tyr-D-Tyr-Orn-Thr-Pen-Thr-NH2 (CTOP, 25 ng) and beta-endorphin-(1-27) [beta-EP-(1-27)] (6 micrograms), but not ICI 174,864 (ICI, 5 micrograms) or norbinaltorphimine (N-BNI, 5 micrograms). The antinociception induced by i.c.v. etorphine was also antagonized by the i.c.v. pretreatment of beta-funaltrexamine (beta-FNA, 50 ng, 24 hr). Intracerebroventricular administration of beta-EP-(1-27) (3 micrograms) caused a further attenuation of the i.c.v. etorphine-induced antinociception in mice pretreated with beta-FNA. The antinociceptive response induced by morphine (2 micrograms) given i.c.v. was blocked by i.c.v. administration of CTOP (25 ng) or beta-FNA (50 ng), but not beta-EP-(1-27) (6 micrograms), ICI (5 micrograms) or N-BNI (5 micrograms). These results indicate that the antinociception induced by etorphine given i.c.v. is mediated by the stimulation of both mu and epsilon opioid receptors whereas the antinociception induced by morphine given i.c.v. is mediated by the stimulation of mu, but not epsilon opioid receptors at supraspinal sites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of leucine and methionine enkephalin on morphine-induced analgesia, acute tolerance and dependence

Intracerebroventricular (40-80 microgram) or i.p. (5-20 mg/kg) injection of leucine enkephalin 15 min before or after s.c. morphine administration resulted in a marked, dose-dependent enhancement of morphine analgesia as measured by the mouse tail-flick assay. Further, i.p. injection of leucine enkephalin (5 mg/kg) enhanced the analgesia produced by methadone and levorphanol in the tail-flick assay but not that by nalorphine in the abdominal constriction assay. Met- but not leu-enkephalin was an active analgesic in the abdominal constriction assay with the doses used. (D-Ala2, D-leu5)-enkephalin (1 mg/kg) treatment also markedly enhanced morphine analgesia. Similarly, administration of leucine enkephalin enhanced the development of acute tolerance and dependence produced by a single dose of morphine. Methionine enkephalin had no effect on any of the pharmacological responses produced by morphine, methadone or levorphanol. Morphine brain levels of mice after treatment with leucine or methionine enkephalin were found to be no different than those of saline-treated control animals. These results suggest that leucine enkephalin may be an important and potent physiological modulator of narcotic efficacy.     

Autonomic mechanisms for morphine and amphetamine mydriasis in the rat

Morphine sulfate and amphetamine sulfate dilate the pupil of the conscious, unrestrained rat. To examine the mechanisms underlying amphetamine and morphine mydriasis, the pupil diameter of freely moving rats was measured from photographs taken before and after these drugs were administered s.c., i.c.v. or by instillation into the eye. Some rats received monoamine antagonists, sympathetic denervation, or adrenalectomy before drug administration. The results indicate that both amphetamine and morphine mydriasis are primarily due to centrally mediated inhibition of parasympathetic outflow, although for both drugs there may be a sympathetic component. Pharmacological evidence indicates that the mydriatic effect of a low dose of amphetamine is mediated by actions on both alpha-1 and alpha-2 adrenergic receptors, whereas only alpha-2 adrenergic receptors are involved in morphine mydriasis.     

Dual effects of cholecystokinin-octapeptide on duodenal motility of urethane-anesthetized rats

Intravenous administration of cholecystokinin octapeptide (CCK-8) to urethane-anesthetized rats produced both inhibitory and excitatory effects on intestinal motility. The inhibitory effect, evident as a transient relaxation or inhibition of distension-induced reflex contractions, was abolished by adrenoreceptor blockade, guanethidine pretreatment or removal of the celiac ganglion complex, but was hexamethonium-and atropine-insensitive. The excitatory action of CCK-8 was atropine- and hexamethonium-sensitive, while being unaffected by guanethidine pretreatment. Ligation experiments indicated that the excitatory effect of CCK-8 originates from a stimulant action on structures in the upper duodenum/pyloric sphincter from which a propagated contraction travels to the distal duodenum. We conclude that i.v. CCK-8 inhibits small intestinal motility by directly activating sympathetic neurons in the celiac ganglion and initiates a propagated form of intestinal motility by stimulating neural elements in the upper part of the small intestine.     

Differential contribution of descending serotonergic and noradrenergic systems to central Tyr-D-Ala2-Gly-NMePhe4-Gly-ol5 (DAMGO) and morphine-induced antinociception in mice

Differences in antinociceptive (inhibition of tail-flick response) action of morphine and Tyr-D-Ala2-Gly-NMePhe4-ol5 (DAMGO) were demonstrated by intracerebroventricular (i.c.v.) administration of these agonists along with intrathecal (i.t.) administration of a variety of antagonists: yohimbine, methysergide, naloxone and nor-binaltorphimine. Intracerebroventricular morphine analgesia was antagonized by either i.t. yohimbine or methysergide, whereas i.c.v. DAMGO analgesia was only antagonized by i.t. methysergide. Thus, for i.c.v. morphine-induced analgesia, descending spinal noradrenergic and serotonergic systems were involved, whereas for DAMGO analgesia, only the serotonergic system was involved. The dose-response curve for i.c.v. morphine reached a plateau at high doses, whereas i.c.v. DAMGO analgesia peaked at 10 ng and then decreased thereafter, producing a bell-shaped dose-response curve. This decrement in analgesic response could be reversed by low doses of i.t. methysergide and i.t. pindolol. It was concluded that activation of serotonin-1 (5-HT1) receptors plays a role in the decrease in analgesia from high doses of DAMGO. Combinations of i.t. morphine with i.t. 5-HT or i.t. clonidine produced additive or greater analgesic responses. Combinations of i.t. DAMGO with i.t. 5-HT or i.t. clonidine produced less than additive interactions. Part of the latter responses appeared to be due to activation of 5-HT1 receptors; blockade of these receptors by pindolol enhanced i.t. DAMGO-induced analgesia. Morphine and DAMGO differ further because i.c.v. morphine activated a descending antianalgesic pathway mediated by spinal dynorphin A(1-17), whereas i.c.v. DAMGO at a high dose did not. Thus, morphine and DAMGO differ in their modes of antinociceptive action as measured by the tail-flick response.     

Roles of central and peripheral mu, delta and kappa opioid receptors in the mediation of gastric acid secretory effects in the rat

The opioid receptors involved in the mediation of gastric acid secretory effects were studied in the pylorus-ligated rat. The effects of i.c.v. and i.v. administration of morphine and mu ([D-Ala2, NMePhe4, Gly5-ol]enkephalin and Tyr-Pro-NMePheD-Pro-NH2)-, delta ([D-Pen2,D-Pen5]enkephalin)- and kappa-selective [trans-3,4-dichloro-N-methyl-N-[2-91-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate (U-50,488H), dynorphin-(1-9), dynorphin-(1-17), nalorphine, alpha-neoendorphin and ethyl-ketocyclazocine) opioid receptor agonists on gastric volume and acid output were examined. Morphine, [D-Ala2, NMePhe4, Gly5-ol]enkephalin and Tyr-Pro-NMePhe-D-Pro-NH2 decreased gastric acid secretion more potently after i.c.v. than after i.v. administration. The inhibitory effect of i.v. administered morphine on gastric acid secretion was not blocked by the quaternary opioid antagonist naltrexone methylbromide when given s.c. However, when naltrexone methylbromide was administered i.c.v., it blocked completely the effects of i.c.v. morphine and partially antagonized the effects of i.v. morphine, indicating a central site of action for morphine. The delta-selective agonist [D-Pen2,D-Pen5]enkephalin did not alter gastric acid secretion after i.c.v. or i.v. administration. The kappa-selective opioid agonist U-50,488H produced a dose-dependent increase in gastric acid secretion after i.v. but not i.c.v. administration. The other kappa-selective agonists tested did not produce a significant increase in gastric acid secretion after i.c.v. or i.v. administration. The increase in gastric acid secretion produced by U-40,488H was blocked by pretreatment with the opioid receptor antagonist naloxone, the nonselective muscarinic receptor antagonist atropine and the M1 selective muscarinic receptor antagonist pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Nepadutant pharmacokinetics and dose-effect relationships as tachykinin NK2 receptor antagonist are altered by intestinal inflammation in rodent models

Tachykinin NK2 receptor antagonists could reduce motility and symptoms during gastrointestinal diseases characterized by local inflammation such as diarrhea or colitis; however, how these conditions change pharmacodynamic and pharmacokinetic characteristics of NK2 receptor antagonists is unknown. We investigated the effect of the peptide NK2 receptor antagonist nepadutant on spontaneous intestinal motility or [betaAla8]NKA(4-10)-induced colonic and bladder contractions in rodent models of intestinal inflammation (enteritis induced by castor oil and rectocolitis induced by local instillation of acetic acid in rats, enteritis induced by bacterial toxins in mice). In the castor oil model, the oral/intraduodenal bioavailability of nepadutant was also determined. The intrarectal (i.r.) administration of nepadutant (100 nmol/kg) did not reduce [betaAla8]NKA(4-10) (10 nmol/kg i.v.)-induced colonic and bladder contractions in normal animals, but the same dose of nepadutant produced an inhibitory effect in the two organs following rectocolitis; in contrast, nepadutant is equieffective by the intravenous route in normal and colitic animals. In this model, nepadutant (100 nmol/kg i.r. or i.v.) decreased spontaneous colonic hypermotility, without affecting motility in controls. The intraduodenal administration of nepadutant (30 nmol/kg), which was ineffective on [betaAla8]NKA(4-10) (10 nmol/kg i.v.)-induced colonic and bladder contractions in control animals, abolished bladder contractions in castor oil-pretreated animals. In this latter group, the oral and intraduodenal bioavailability of nepadutant showed a 7- to 9-fold increase with respect to controls. Oral administration of nepadutant, in nanomolar or subnanomolar dosage, reduced diarrhea induced by bacterial toxins in mice. It is concluded that intestinal inflammation increases nepadutant absorption in the intestine, enhancing its activity. These results suggest that a drug with a limited oral bioavailability could be used for treating gastrointestinal diseases associated with a local inflammation.     

Determination of the role of conventional, novel and atypical PKC isoforms in the expression of morphine tolerance in mice

This study comprehensively determines the role of all the major PKC isoforms in the expression morphine tolerance. Pseudosubstrate and receptors for activated C-kinase (RACK) peptides inhibit only a single PKC isoform, while previously tested chemical PKC inhibitors simultaneously inhibit multiple isoforms making it impossible to determine which PKC isoform mediates morphine tolerance. Tolerance can result in a diminished effect during continued exposure to the same amount of substance. In rodents, morphine pellets provide sustained exposures to morphine leading to the development of tolerance by 72 h. We hypothesized that administration of the PKC isoform inhibitors i.c.v. would reverse tolerance and reinstate antinociception in the tail immersion and hot plate tests from the morphine released solely from the pellet. Inhibitors to PKC alpha, gamma and epsilon (100-625 pmol) dose-dependently reinstated antinociception in both tests. The PKC beta(I), beta(II), delta, theta, epsilon, eta and xi inhibitors were inactive (up to 2500 pmol). In other mice, the degree of morphine tolerance was determined by calculating ED50 and potency-ratio values following s.c. morphine administration. Morphine s.c. was 5.6-fold less potent in morphine-pelleted vs. placebo-pelleted mice. Co-administration of s.c. morphine with the inhibitors i.c.v. to either PKC alpha (625 pmol), gamma (100 pmol) or epsilon (400 pmol) completely reversed the tolerance so that s.c. morphine was equally potent in both placebo- and morphine-pelleted mice. The PKC beta(I), beta(II), delta, theta, epsilon, eta and xi inhibitors were inactive. Thus, PKC alpha, gamma and epsilon appear to contribute to the expression of morphine tolerance in mice.