Spinally mediated opioid antidiarrheal effects.

To assess the role of opioid receptors in the spinal cord in regulation of functions of the intestinal mucosa in a secretory model, we evaluated the ability of i.t. administered mu (PL017), delta (DPDPE) and kappa (U50,488H) selective opioid agonists to inhibit diarrhea produced in mice by an injection of prostaglandin E2 (PGE2) (200 micrograms/mouse, i.p.). I.t. PL017 and DPDPE inhibited diarrhea in a dose-related fashion. U50,488H had only minimal antidiarrheal effects. The i.t. doses of PL017 and DPDPE required to inhibit diarrhea were higher than the doses required to produce antinociception and inhibit gastrointestinal transit. Spinally administered PL017 and DPDPE were considerably less potent in the diarrhea model than after i.c.v. administration but far more effective than after peripheral (s.c.) dosing. The antidiarrheal effects of spinally administered opioids were antagonized by concurrently administered naloxone. These data indicate that opioid chemosensitive sites in the spinal cord can modulate diarrhea produced by PGE2, and that the receptor specific opioids, PL017 and DPDPE, and to a lesser extent U50,488H, all possess antidiarrheal activity when administered i.t.

Assessment of the in vivo and in vitro opioid activity of bridged hexahydroaporphine and isoquinoline molecules.

Four novel racemic bridged hexahydroaporphine (1 and 2) and isoquinoline (3 and 4) analogues have been synthesized in an attempt to generate bicyclic derivatives of the morphinan ring system. The opioid activity of these analogues has been assessed through membrane-binding studies, in vitro studies in isolated guinea pig ileum and mouse vas deferens, and in vivo studies utilizing the mouse hot plate technique. The bridged isoquinoline precursor molecules were inactive as antinociceptives. Both the racemic phenolic hexahydroaporphine 1 and its 10-methoxy congener 2 demonstrated dose-dependent, albeit weak, antinociceptive activity when administered icv, but they induced lethal convulsions when given subcutaneously. The antinociception elicited by 1 appeared to show very weak opioid character while that caused by 2 was totally nonopioid.

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)

Opioid receptor selectivity of beta-endorphin in vitro and in vivo: mu, delta and epsilon receptors.

The relative contributions of mu and delta opioid receptors in the response to Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe- Lys-Asn - Ala-Ileu-Ileu-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (B-endorphin) were assessed as reductions in B-endorphin potency in the presence of mu and delta receptor selective antagonists in the guinea pig ileum, mouse vas deferens, rat vas deferens and in analgesic and gastrointestinal transit time tests in mice. We used the nonselective antagonist naloxone, the mu antagonist D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) and the delta antagonist N,N,diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864) in each test system at concentrations that effectively antagonized the respective mu and delta agonists, Tyr-Pro-N-MePhe-D-Pro-NH2 and Tyr-D-Pen-Gly-Phe-D-Pen. In the guinea pig ileum, the inhibitory effects of 1 microM B-endorphin were blocked by 1 microM CTP and 1 microM naloxone, but not by 1 microM ICI 174,864. In the mouse vas deferens, B-endorphin (0.2 microM) was antagonized by 1 microM CTP, 1 microM ICI 174,864 and by 1 microM naloxone. In contrast, in the rat vas deferens, B-endorphin (0.01-1 microM) produced potent inhibitory actions that were blocked by 1 microM naloxone, but not by 1 microM-CTP or by 1 microM ICI 174,864. The mu agonist, Tyr-Pro-N-MePhe-D-Pro-NH2 (0.1-10 microM), like B-endorphin, also had inhibitory actions in the rat vas deferens, but its effects were blocked by 1 microM CTP.(ABSTRACT TRUNCATED AT 250 WORDS)

Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: identification of mu receptor-related functions.

We have shown previously that D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) produces selective antagonism of mu, but not delta or kappa, opioid receptor-selective ligands in the guinea pig ileum and mouse vas deferens bioassays, and in radioligand binding assays using homogenized rat brains. In the present study we characterized the agonist and opioid antagonist profile of CTP in analgesic (hot-plate test, abdominal stretch test) and in gastrointestinal assays (transit time test) in mice. CTP was a potent antagonist of the supraspinal and spinal analgesic effects of the mu selective agonist [MePhe3, D-Pro4]morphiceptin (PL017) in both assays. The gastrointestinal antitransit actions of PL017 were also antagonized by CTP at both supraspinal and spinal sites. CTP did not alter the effects of the kappa agonist trans-3,4-dichloro-N-methyl-N-(2-(1-pyrolidinyl)cyclohexyl)benz eneacetamine in any test. Surprisingly, CTP also antagonized the analgesia produced by i.c.v. and intrathecal administration of [D-Pen2, D-Pen5]enkephalin (DPDPE), a highly delta selective agonist, in both analgesic tests. Differential antagonism of DPDPE, but not PL017, by the delta selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH in the hot-plate test indicates that PL017 and DPDPE may act at separate receptors to produce analgesia (mu and delta, respectively). In contrast, CTP did not reverse the gastrointestinal antitransit effects of intrathecal DPDPE. Schild analysis of the interactions of CTP with supraspinal mu and delta agonists in the hot-plate test indicated that although CTP antagonized PL017 in a competitive fashion (Schild slope = -1.0), the interaction of CTP with DPDPE was not competitive (Schild slope = -0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

A cyclic somatostatin analog that precipitates withdrawal in morphine-dependent mice.

We evaluated the ability of the mu selective, peptidic, opioid antagonist CTP to precipitate withdrawal in morphine-dependent mice after intracerebroventricular (i.c.v.) and subcutaneous (s.c.) administration. The withdrawal syndrome evoked by i.c.v. CTP was different in some respects from that observed after i.c.v. naloxone. Naloxone, given i.c.v., produced shakes and tremors, defecation, diarrhea, wet dog shakes, jumping and weight loss. In contrast, the prominent signs following i.c.v. CTP were grooming, tremors and shakes, defecation, wet dog shakes and weight loss. CTP treated mice exhibited a greatly reduced incidence of jumping behaviors and diarrhea. While s.c. naloxone evoked similar effects to i.c.v. naloxone, CTP given s.c. stimulated defecation and modest weight loss only. The differences in the profile of withdrawal signs between naloxone and CTP may be related to their differences in receptor selectivity or possibly to their respective alkaloidal and peptidic natures. The relative lack of behavioral effects seen after s.c. CTP probably reflects the inability of CTP to pass through the blood brain barrier, and indicates that although the majority of withdrawal signs are mediated by centrally located opioid receptors, the gastrointestinal tract can be withdrawn independently of the central nervous system.