u-50488 and deltakephalin

Agonist-promoted internalization (endocytosis) of G-protein-coupled receptors (GPCRs), including all three opioid receptor types (mu, delta and kappa), has been shown to occur via the clathrin endosomal pathway in response to receptor phosphorylation and the actions of the proteins, beta-arrestin and dynamin. Many members of the GPCR family stimulate mitogen-activated protein kinases (MAPK or ERK) activity and, in several cases, it appears that MAPK activation is dependent on receptor internalization. We have reinvestigated the question of whether internalization is obligatory for MAPK activation by opioid receptors, using cell lines expressing the cloned mu or delta receptor. Morphine, which is known to activate both mu and delta receptors, does not induce their rapid internalization into clathrin-coated endosomes. However, morphine produced a robust stimulation of MAPK in both cell lines, as demonstrated by the appearance of phosphorylated MAPK. Moreover, pre-exposure of cells to the internalization inhibitors, concanavalin A or hypertonic sucrose, totally blocked DAMGO mu-selective agonist) and DTLET (delta-selective agonist)-mediated receptor internalization, yet neither treatment affected MAPK phosphorylation induced by these peptides. Our results provide evidence that receptor internalization is not an obligatory requirement for MAPK activation by mu and delta opioid receptors. Hypotheses are presented to explain the seemingly contradictory results obtained from different laboratories.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Binding, Competitive; CHO Cells; Concanavalin A; Cricetinae; Dose-Response Relationship, Drug; Endocytosis; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enzyme Activation; Hypertonic Solutions; Mitogen-Activated Protein Kinases; Morphine; Oligopeptides; Phosphorylation; Radioligand Assay; Receptors, Opioid, delta; Receptors, Opioid, mu; Sucrose; Time Factors

Previous studies showed that spinal opioidergic neurotransmission is markedly altered in the polyarthritic rat, a model of chronic inflammatory pain. Present investigations aimed at assessing possible changes in opioid-mediated control of the spinal outflow of met-enkephalin (ME) and dynorphin (DYN) in these animals. Intrathecal (i.t.) perfusion under halothane anesthesia showed that polyarthritis was associated with both a 40% decrease in the spinal outflow of ME-like material (MELM) and a 90% increase in that of DYNLM. Local treatment with the mu-opioid agonist DAGO (10 microM i.t.) inhibited equally (-30%) the MELM outflow in polyarthritic and control rats, whereas the delta agonist DTLET (10 microM i.t.) also reduced the peptide outflow in controls (-27%) but enhanced it in polyarthritic animals (+56%). On the other hand, both DAGO (10 microM i.t.) and DTLET (10 microM i.t.) decreased (-40 and -49%) DYNLM outflow in polyarthritic rats, but were inactive in controls. Finally, neither MELM outflow nor that of DYNLM were affected by the kappa-agonist U50488H (10 microM i.t.) in both groups of rats. In all cases, the changes due to active agonists could be prevented by specific antagonists which were inactive on their own except the kappa antagonist nor-binaltorphimine (10 microM i.t.) that decreased (-38%) DYNLM outflow in polyarthritic rats. These data indicate that functional changes in spinal opioid receptors may promote enkephalinergic neurotransmission and reduce dynorphinergic neurotransmission in polyarthritic rats, thereby contributing to the analgesic efficacy of opioids in inflammatory pain.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Anesthesia; Animals; Arthritis; Dynorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Iodine Radioisotopes; Ligands; Male; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord

In the present study, we found that complement C3a exerted central effects after intracerebroventricular administration in mice. At doses of 3 and 10 pmol/mouse, the peptide showed an antagonistic effect on analgesia induced by morphine and U-50488H, known to be mu- and kappa-opioid receptor agonists, respectively. Moreover, complement C3a improved scopolamine- and ischemia-induced amnesia at a dose of 10 pmol/mouse. Anti-analgesia was not observed by C3a des-Arg at 10 pmol/mouse. The present findings suggest that complement C3a may act as a peptide with anti-opioid activity in the central nervous system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Avoidance Learning; Cerebral Ventricles; Complement C3a; Dose-Response Relationship, Drug; Electroshock; Humans; Injections, Intraventricular; Ischemia; Male; Mice; Mice, Inbred Strains; Morphine; Oligopeptides; Pain; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

In this work, we have characterized the opioid receptor expressed by the human neuroblastoma cell line SK-N-BE and compared its hydrodynamic behaviour with those of well known opioid receptors: mu-opioid receptor of rabbit cerebellum and delta-opioid receptor of the hybrid cell line NG 108-15. Human neuroblastoma cell line SK-N-BE expresses a substantial amount of opioid receptors (200-300 fmoles/mg of protein). Pharmacological characterization suggests an heterogenous population of receptors and the presence of two delta subtypes which are, at least partially, negatively coupled with adenylate cyclase via a Gi protein. These receptors exist under two different molecular forms and, in this respect, strikingly contrast with the archetypic delta receptors of NG 108-15 hybrid cell line which show only a high molecular weight form and appear more tightly coupled with the G protein. Hydrodynamic behaviour of SK-N-BE opioid receptors is reminiscent of the profile observed with the rabbit cerebellum mu-opioid receptor. This observation is consistent with the presence of two delta-opioid receptors subtypes, one of which exhibiting properties close to those of mu opioid receptors. Taken overall, our results suggest that different types and subtypes of opioid receptors, even if they are coupled to the same inhibitory G protein, are more or less tightly coupled with their transduction proteins and that closely related opioid receptors can form allosterically interacting complexes.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adenylyl Cyclases; Amino Acid Sequence; Animals; Binding, Competitive; Cerebellum; Colforsin; Diprenorphine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Etorphine; GTP-Binding Proteins; Guinea Pigs; Humans; Hybrid Cells; Molecular Sequence Data; Morphine; Naloxone; Neoplasm Proteins; Nerve Tissue Proteins; Neuroblastoma; Oligopeptides; Pyrrolidines; Rabbits; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Tumor Cells, Cultured

The modulation by morphine of the spinal release of met-enkephalin-like material (MELM) was investigated in anaesthetized rats whose intrathecal space was perfused with an artificial CSF (ACSF). Morphine (10 microM in the ACSF), as well as a mu- (DAGO, 10 microM) or delta opioid receptor agonist (DTLET, 10 microM), significantly decreased the outflow of MELM. The effects of morphine and DTLET were prevented by the delta antagonist, naltrindole (10 microM), but not by naloxone (10 microM). Conversely, naloxone, but not naltrindole, prevented the inhibitory effect of DAGO. Although neither the kappa 1 agonist, U 50488H (10 microM), nor the kappa 1 antagonist, norbinaltorphimine (10 microM), exerted on their own any significant effect, norbinaltorphimine enhanced the inhibitory action of morphine. In contrast to the inhibition induced by morphine (with or without naloxone) which was preventable by 10 microM naltrindole, the inhibition of MELM release by morphine plus norbinaltorphimine was only partly reduced by naltrindole. Thus, concomitant stimulation of mu, delta and kappa 1 receptors might account for the apparent delta opioid receptor-dependent inhibition of MELM release by morphine. Indeed, its potential inhibitory effect through the stimulation of mu receptors (normally prevented by the concomitant stimulation of kappa 1 receptors) becomes efficient only when kappa 1 receptors are blocked.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Enkephalins; Injections, Spinal; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Spinal Cord

The possible modulations by morphine and various opioids of the spinal release of cholecystokinin-like material (CCKLM) evoked by 30 mM K+ was studied in vitro, using slices of the dorsal part of the rat lumbar enlargement superfused with an artificial cerebrospinal fluid. Addition of the mu agonist, DAGO (0.1-10 microM), to the perfusing fluid produced a concentration-dependent decrease in the peptide release, which could be prevented by the preferential mu antagonist, naloxone. Complex modulations were induced by the delta agonist, DTLET, as this drug inhibited CCKLM release when added at 10 nM-3 microM to the perfusing fluid, but enhanced it at 10 microM. Both effects were preventable by the delta antagonists naltrindole and ICI 154129, suggesting that delta receptors, possibly of different subtypes, mediated the inhibition and stimulation by DTLET. Morphine also exerted a biphasic effect, as the alkaloid decreased CCKLM release at 0.01-0.1 microM and enhanced it at 10 microM. Morphine-induced inhibition was preventable by naloxone, whereas its stimulatory effect could be blocked by naltrindole and ICI 154129. Although inactive on its own on CCKLM release, the selective kappa 1 agonist U 50488H (1 microM) prevented the inhibitory effects of both DAGO (10 microM) and morphine (0.1 microM), suggesting the existence of interactions between kappa 1 and mu receptors within the dorsal zone of the rat spinal cord. These data indicate that low concentrations of morphine exert an inhibitory influence on spinal CCKergic neurons that depends on the stimulation of mu opioid receptors. The excitatory influence of 10 microM morphine likely results from the simultaneous stimulation of mu, delta and kappa receptors, as the inhibitory effect of mu receptor stimulation can be masked by that of kappa 1 receptors, allowing only the expression of a delta-dependent excitatory effect similar to that induced by 10 microM DTLET.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cholecystokinin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Morphine; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Spinal Cord

The possible control by opioids of the spinal release of calcitonin gene-related peptide-like material (CGRPLM) was investigated in halothane-anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid. Morphine (20 mg/kg i.v.; or at 10-100 microM added to the perfusing fluid), the mu selective agonist DAGO (10 microM) and the kappa selective agonist U 50488 H (10 microM) did not affect the spontaneous outflow of the CGRPLM. In contrast, the selective delta agonist DTLET (10 microM) significantly increased CGRPLM release. The latter effect could be prevented by the selective delta antagonist naltrindole (10 microM) as expected from the involvement of this class of opioid receptors. However, the addition of naltrindole alone to the perfusing fluid did not modify CGRPLM outflow, indicating that endogenous opioids do not exert a tonic control of CGRP-containing fibers through the stimulation of delta receptors. In contrast, intrathecal perfusion with naloxone (10 microM) or nor-binaltorphimine (10 microM), a selective antagonist of kappa receptors, produced a marked increase in spinal CGRPLM release, suggesting that endogenous opioids acting at mu and kappa receptors, respectively, exert a tonic inhibitory control of CGRP-containing fibers. Indeed, a significant decrease in the spinal release of CGRPLM release could be evoked by the combined addition of U 50488 H (10 microM) plus DAGO (10 microM) to the perfusing medium, indicating that the simultaneous stimulation of both kappa and mu receptors is required for this negative control to occur. This could notably be achieved with morphine (10 microM) in the presence of naltrindole (10 microM) which also produced a significant reduction in the spinal release of CGRPLM. In conclusion, morphine per se did not change CGRPLM release because this drug triggers opposite positive (through the stimulation of delta receptors) and negative (through the concomitant stimulation of both kappa and mu receptors) control mechanisms within the rat spinal cord.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Calcitonin Gene-Related Peptide; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Spinal; Iodine Radioisotopes; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord

The possible opioid control through delta, mu and kappa receptors of the spinal release of Met-enkephalin-like material (MELM) was investigated in halothane-anaesthetized rats. The intrathecal perfusion of the delta agonist DTLET (10 microM) or the mu agonist DAGO (10 microM) resulted in a marked inhibition of MELM release, which could be prevented by the selective antagonists naltrindole and naloxone, respectively. Although the kappa agonist U 50488 H (10 microM) was inactive per se, it completely suppressed the inhibitory effect of DAGO, without affecting that of DTLET. As the selective kappa antagonist norbinaltorphimine blocked the action of U 50488 H, it can be concluded that kappa receptors modulate the mu- (but not the delta-) mediated feed back control of spinal enkephalinergic neurones.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Methionine; Enkephalins; Indoles; Injections, Spinal; Male; Morphinans; Naloxone; Naltrexone; Neurons; Oligopeptides; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord

Opioid-cholecystokinin (CCK) interactions at the spinal level were investigated by looking for possible modulations by various opioid agonists of the release of cholecystokinin-like material (CCKLM) from slices of the dorsal zone of the rat lumbar enlargement. K(+)-evoked CCKLM overflow was reduced by 0.1-10 microM of the mu agonist DAGO or 10 nM to 3 microM of the delta agonist DTLET. By contrast, at a higer concentration (10 microM), the latter drug as well as morphine enhanced CCKLM overflow. Although inactive alone, the kappa opioid agonist U 50488 H (1 microM) prevented the inhibitory effect of DAGO without affecting that of DTLET. These data suggest that an opioid acting through the stimulation of mu, delta and kappa receptors (such as morphine) should produce a net increase in the spinal release of CCK.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Cholecystokinin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; In Vitro Techniques; Male; Narcotic Antagonists; Oligopeptides; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord

1. The effects of three opioid receptor agonists on the blood pressure and heart rate of anaesthetized normotensive, spontaneously hypertensive and renal hypertensive rats were measured. 2. Mu agonist morphiceptin i.c.v. induced a pressor response and increase in heart rate in hypertensive rats, but hypotension in normotensive rats. After intravenous (i.v.) injection, morphiceptin produced a hypotensive response in all three groups of rats. 3. In contrast, the delta agonist DTLET i.c.v. decreased blood pressure and heart rate in hypertensive rats, but increased both pressure and beat rate in normotensive rats. After i.v. injections DTLET produced a hypertensive response and increase in heart rate in all groups of rats. 4. Kappa agonist U-50, 488H given i.c.v. induced effects similar to morphiceptin: an increase in blood pressure and heart rate in hypertensive and a decrease in normotensive rats. After i.v. injections U-50, 488H produced decreases in blood pressure and heart rate in all treated groups of rats. 5. Pretreatment with naloxone antagonized the activity of morphiceptin but prevented only the stimulating effect of DTLET in normotensive rats. Cardiovascular actions of U-50, 488H were not blocked by naloxone. 6. The results suggest that opioid agonists exert similar changes in cardiovascular function at central and peripheral sites in both models of experimental hypertension and these effects are different in normotensive rats.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Amino Acid Sequence; Analgesics; Animals; Blood Pressure; Endorphins; Heart Rate; Hemodynamics; Hypertension, Renal; Injections, Intraventricular; Male; Molecular Sequence Data; Naloxone; Oligopeptides; Pyrrolidines; Rats; Rats, Inbred SHR; Rats, Inbred Strains

A previous study has implicated central mu opioid receptors in the preference for salt solutions. Because mu, kappa and delta receptors are all thought to play a role in food intake and/or the mediation of palatability, we performed a series of experiments to determine whether preferential agonists at kappa and delta receptors might also stimulate the intake of salt solutions. When injected centrally into nondeprived rats, two selective agonists at delta receptors caused increases in the intake of 0.6% saline; the intake of concurrently available water was either unchanged or slightly increased. The selective kappa agonist U-50,488H had no effect on water or saline intake, whereas the preferential kappa agonist DAFPHEDYN caused a delayed increase in saline intake. These results indicate a role for central delta receptors in the preference for salt solutions, and are consistent with the suggestion that opioids play a role in the mediation of palatability.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Drinking; Dynorphins; Eating; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Food Preferences; Hypotonic Solutions; Injections, Intraventricular; Male; Oligopeptides; Peptide Fragments; Pyrrolidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Taste

Endogenous opioid peptides are thought to play a role in mediating the pleasurable or rewarding aspects of the ingestion of certain foods and liquids. We therefore measured the effects of central administration of selective opioid agonists and naloxone on the intake of two concentrations of saccharin solution. All tests were performed on nondeprived rats, such that the taste of the solutions provided the primary incentive to consume. Intracerebroventricular (ICV) administration of the selective mu agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAGO) and the selective delta agonist Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET) (3 nmol) increased intake of a 0.15% saccharin solution by approximately 10 ml over 3 hr. Water was available simultaneously, but intake was minimal. The selective kappa agonist U-50,488H did not increase intake of the saccharin solution. Naloxone (30 and 100 micrograms, ICV) caused a 44% reduction in saccharin solution intake in the first hour; two- and three-hour cumulative intakes were not different from control. DAGO and DTLET were also tested when rats were given a weaker saccharin solution (0.006%) along with water. Both agonists caused small increases in saccharin and water intake, but the increases above baseline were much smaller than those observed with the more palatable 0.15% saccharin solution. These results are consistent with reports by others which suggest that endogenous opioids influence taste preferences or palatability. Further, they indicate a role for central mu and delta opioid receptors in the mediation of this influence.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Dose-Response Relationship, Drug; Drinking Behavior; Eating; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Food Preferences; Male; Naloxone; Oligopeptides; Pyrrolidines; Rats; Rats, Inbred Strains; Saccharin; Time Factors

The kappa nature of opioid binding sites in a brush border membrane (BBM) fraction from human placenta has been confirmed: these sites display considerably higher apparent affinity (KI = 1.2 nM) for the kappa selective ligand U-50488 than they do for the mu and delta selective ligands [D-Ala2, MePhe4, Glyol5] enkephalin (KI = 1.5-2 microM) and [D-Thr2, Leu5] enkephalyl-Thr (KI = 10-15 microM), respectively. The BBM fraction from human placenta was incubated either with the agonist 3H-etorphine or with the antagonist 3H-diprenorphine and subsequently solubilized with digitonin. The solubilized macromolecular radioactivity was found to behave as a homogeneous entity both in molecular exclusion chromatography (app. rs = 6.1 nm) and in linear sucrose gradients (app. S20.w = 12 S). Two lines of evidence indicated that the placental kappa opioid receptor is capable of interacting with a guanine nucleotide regulatory (G) protein: (i) equilibrium binding of the agonist 3H-etorphine in the BBM fraction was clearly inhibited by 5'-guanylylimidodiphosphate (Gpp(NH)p), especially in the presence of Na+ ions while binding of the antagonist 3H-diprenorphine was significantly less so and (ii) the sedimentation velocity of the kappa opioid receptor was decreased down to about 10 S when the BBM fraction was prelabeled with radioligand in the presence of Gpp(NH)p prior to its solubilization with digitonin. The G protein that mediates the effect of Gpp(NH)p might be neither Gs nor Gi since no adenylate cyclase activity could be demonstrated in the BBM fraction from human placenta.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adenylyl Cyclases; Binding, Competitive; Centrifugation, Density Gradient; Chromatography, Gel; Diprenorphine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Etorphine; Female; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Humans; Microvilli; Oligopeptides; Placenta; Pregnancy; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Sodium Chloride

The opioid receptors involved in the mediation of thermal analgesia (55 degrees C hot-plate) and inhibition of gastrointestinal transit at the spinal and supraspinal levels were studied in unanesthetized mice. Five receptor-selective compounds were evaluated for effectiveness in eliciting analgesia and inhibiting transit after both i.c.v. and intrathecal administration; these included the proposed mu agonist, [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAGO), the proposed delta agonists, [D-Pen2, L-Pen5]enkephalin (DPLPE), [D-Pen2, D-Pen5]enkephalin (DPDPE) (conformationally constrained delta selective enkephalin analogs) and [D-Thr2, Thr6, Leu5]enkephalin (DTTLE), and the proposed kappa agonist, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate (U-50,488H), as well as the nonselective mu-acting agonist, morphine. All compounds were found to produce analgesia after i.c.v. administration; the rank order of potency by the i.c.v. route was DAGO greater than DTTLE greater than morphine greater than DPLPE greater than DPDPE greater than U-50,488H. The analgesic effectiveness of most of these agonists given i.c.v. was evident for up to 40 min, with only DTTLE and U-50,488H having briefer time courses. Similarly, all the compounds produced analgesic responses after intrathecal administration, with the rank order of potency by this route being DTTLE greater than morphine greater than DAGO greater than DPLPE greater than DPDPE greater than U-50,488H, and all compounds (except U-50,488H) had durations of action of up to 20 to 40 min. These agonists also inhibited gastrointestinal transit after intrathecal administration, with a rank order of potency of DAGO greater than DTTLE greater than DPLPE greater than morphine greater than DPDPE greater than U-50,488H.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Animals; Digestive System Physiological Phenomena; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Hot Temperature; Injections, Intraventricular; Injections, Spinal; Male; Mice; Morphine; Narcotics; Oligopeptides; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Spinal Cord