[Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist.

BACKGROUND AND PURPOSE: Intrathecally (i.t.) administered nociceptin/orphanin FQ (N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide (NOP) and µ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ µ opioid receptor agonist. EXPERIMENTAL APPROACH: The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [(35)S]-GTPγS binding, [(35)S]-GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. KEY RESULTS: From calcium mobilization studies [Dmt(1)]N/OFQ(1-13)-NH(2) was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt(1)]N/OFQ(1-13)-NH(2) was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [(35)S]-GTPγS binding studies, at rat spinal cord receptors in [(35)S]-GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt(1) ]N/OFQ(1-13)-NH(2) was able to elicit robust and long-lasting antinociceptive effects. CONCLUSIONS AND IMPLICATIONS: Collectively, these results demonstrate that [Dmt(1)]N/OFQ(1-13)-NH(2) behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics.

[tBu-D-Gly5]NPS, a pure and potent antagonist of the neuropeptide S receptor: in vitro and in vivo studies.

Neuropeptide S (NPS) regulates various biological functions by selectively activating the NPS receptor (NPSR). Recently, the NPSR ligand [(t)Bu-D-Gly(5)]NPS was generated and in vitro characterized as a pure antagonist at the mouse NPSR. In the present study the pharmacological profile of [(t)Bu-D-Gly(5)]NPS has been investigated. [(t)Bu-D-Gly(5)]NPS activity was evaluated in vitro in the calcium mobilization assay at the rat NPSR and in vivo in the locomotor activity and righting reflex tests in mice and in the elevated plus maze and defensive burying assays in rats. In vitro, [(t)Bu-D-Gly(5)]NPS was inactive per se while it inhibited the calcium mobilization induced by 30 nM NPS (pK(B) 7.42). In Schild analysis experiments [(t)Bu-D-Gly(5)]NPS (0.1-10 µM) produced a concentration-dependent rightward shift of the concentration-response curve to NPS, showing a pA(2) value of 7.17. In mouse locomotor activity experiments, supraspinal injection of [(t)Bu-D-Gly(5)]NPS (1-10 nmol) dose dependently counteracted NPS (0.1 nmol) stimulant effects. In the mouse righting reflex assay [(t)Bu-D-Gly(5)]NPS (0.1-10 nmol) fully prevented the arousal-promoting action of the natural peptide (0.1 nmol). Finally, [(t)Bu-D-Gly(5)]NPS (3-30 nmol) was able to completely block NPS (1 nmol) anxiolytic-like actions in rat elevated plus maze and defensive burying assays. Collectively, the present results demonstrated that [(t)Bu-D-Gly(5)]NPS behaves both in vitro and in vivo as a pure and potent NPSR antagonist. This compound represents a novel and useful tool for investigating the pharmacology and neurobiology of the NPS/NPSR system.

Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor.

Neuropeptide S (NPS) is the endogenous ligand of a previously orphan receptor now named NPSR. In the brain NPS regulates several biological functions including anxiety, arousal, locomotion, food intake, learning and memory, pain and drug abuse. Mice lacking the NPSR gene (NPSR(-/-)) represent an useful tool to investigate the neurobiology of the NPS/NPSR system. NPSR(-/-) mice have been generated in a 129S6/SvEv genetic background. In the present study we generated CD-1 congenic NPSR(+/+) and NPSR(-/-) mice and investigated their phenotype and sensitivity to NPS in various behavioural assays. The phenotype analysis revealed no locomotor differences between NPSR(+/+) and NPSR(-/-) mice. The behaviour of NPSR(+/+) and NPSR(-/-) mice in the righting reflex test was superimposable. No differences were recorded between the two genotypes in the elevated plus maze, open field and stress-induced hyperthermia tests, with the exception of rearing behaviour that was reduced in knockout animals. Moreover the behaviour of NPSR(+/+) and NPSR(-/-) mice in the forced swimming, novel object recognition and formalin assays was similar. The stimulatory effects of NPS in the locomotor activity test and its anxiolytic-like actions in the elevated plus maze and open field assays were evident in NPSR(+/+) but not NPSR(-/-) animals. In conclusion, the present study indicates that the NPS/NPSR system does not tonically control locomotion, sensitivity to diazepam, anxiety, depressive-like behaviours, memory and pain transmission in mice. Furthermore our results clearly show that the product of the NPSR gene represents the mandatory protein for all the NPS biological effects so far described.

Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice.

BACKGROUND AND PURPOSE: Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice. EXPERIMENTAL APPROACH: Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice. KEY RESULTS: NPS (0.01-1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg(-1)). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg(-1)) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively. CONCLUSIONS AND IMPLICATIONS: We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders.

Endogenous nociceptin/orphanin FQ signalling produces opposite spinal antinociceptive and supraspinal pronociceptive effects in the mouse formalin test: pharmacological and genetic evidences.

Nociceptin/orphanin FQ (N/OFQ) has been demonstrated to modulate nociceptive transmission via selective activation of N/OFQ peptide (NOP) receptors. Despite huge research efforts, the role(s) of the endogenous N/OFQ-NOP receptor system in pain processing remains incompletely understood. In the present study, we investigated the role of endogenous N/OFQ in the processing of tonic nociceptive input. To address this issue the effects of NOP-selective antagonists [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) and J-113397 on nociceptive behaviour, and the nociceptive phenotype of NOP receptor-deficient mice were tested in the mouse formalin test. Twenty microliters of 1.5% formalin solution was injected subcutaneously into the right hind paw causing a characteristic pattern of nociceptive behaviours (licking, biting and lifting of the injected paw). In control mice, the injection of formalin resulted in a classical biphasic nociceptive response with the first phase lasting from 0 to 10 min and the second phase from 15 to 45 min. UFP-101 at 10 nmol/mouse (but not at 1 nmol/mouse) produced antinociceptive action when injected intracerebroventricularly and a pronociceptive action when given intrathecally. Systemic administration of J-113397 (10 mg/kg, intravenously) and the genetic ablation of the NOP receptor gene both produced a significant increase of mouse nociceptive behaviour. Collectively, these results demonstrate that endogenous N/OFQ-NOP receptor signalling is activated during the mouse formalin test producing spinal antinociceptive and supraspinal pronociceptive effects. The overall effect of blocking NOP receptor signalling, by either systemic pharmacological antagonism or genetic ablation, indicates that the spinal antinociceptive action prevails over supraspinal pronociceptive effects.

Antidepressant-like effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice.

Receptor antagonist and knockout studies have demonstrated that blockade of signalling via nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) has antidepressant-like effects in mice submitted to the forced swimming test (FST). The aim of the present study was to explore further the antidepressant-like properties of the NOP antagonist UFP-101 in different species (mouse and rat) and using different assays [FST and tail suspension test (TST)], and to investigate the mechanism(s) involved in its actions.UFP-101 (10 nmol i.c.v.) reduced immobility time of Swiss mice in the TST (mean+/-SEM) from 179+/-11 to 111+/-10 s. N/OFQ (1 nmol i.c.v.) was without effect per se, but fully prevented the effect of UFP-101. The spontaneous immobility time of NOP(-/-) CD1-C57BL/6J-129 mice in the TST was much lower than that of wild-type (NOP(+/+)) littermates (75+/-11 vs. 144+/-17 s) or of Swiss mice. UFP-101 (10 nmol i.c.v.) decreased immobility time (-65%) and increased climbing time (71%) in rats submitted to the FST. In rat brain slices, N/OFQ (100 nM) triggered robust K(+)-dependent hyperpolarizing currents in locus coeruleus and dorsal raphe neurons. UFP-101 (3 microM) fully prevented N/OFQ-induced currents, but was inactive per se. Fluoxetine, desipramine (both 30 mg/kg i.p.) and UFP-101 (10 nmol i.c.v.) reduced immobility time of mice in the FST. The serotonin synthesis inhibitor p-chlorophenylalanine methylester (PCPA, 4 x 100 mg/kg per day i.p.) prevented the antidepressant-like effects of fluoxetine and UFP-101 (but not desipramine), whereas N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine (DSP-4, neurotoxic for noradrenergic neurons; 50 mg/kg i.p., 7 days beforehand), suppressed only the effect of desipramine. Neither pretreatment affected spontaneous immobility time per se.Thus, UFP-101 exhibits pronounced antidepressant-like effects in different species and animal models, possibly by preventing the inhibitory effects of endogenous N/OFQ on brain monoaminergic (in particular serotonergic) neurotransmission. Participation of the N/OFQ-NOP receptor system in mood modulation sets new potential targets for antidepressant drug development.

Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test.

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor, regulates several central functions such as pain transmission, learning and memory, fear and anxiety and feeding and locomotor activity. It has been recently reported that NOP receptor antagonists induce antidepressant-like effects in the mouse forced swimming test (FST), i.e. reduce immobility time. This assay was used in the present study for further investigating the involvement of the NOP receptor in depression states. In male Swiss mice, intracerebroventricular injection (i.c.v) of the novel NOP receptor antagonist, UFP-101 (1-10 nmol) dose-dependently reduced the immobility time (control 192 +/- 14 s, UFP-101 91 +/- 15 s). The effect of 3 or 10 nmol UFP-101 was fully or partially reversed, respectively, by the coadministration of 1 nmol N/OFQ, which was inactive per se. NOP receptor knockout mice showed a reduced immobility time compared with their wild-type littermates (wild-type 215 +/- 10 s, knockout 143 +/- 12 s). Moreover, i.c.v. injected UFP-101 (10 nmol) significantly reduced immobility time in wild-type mice but not in NOP receptor knockout animals. In conclusion, these results, obtained using a combined pharmacological and genetic approach, indicate that blockade of the N/OFQ-NOP receptor signalling in the brain produces antidepressant-like effects in the mouse FST. These findings support the NOP receptor as a candidate target for the development of innovative antidepressant drugs.

Endogenous nociceptin signaling and stress-induced analgesia.

Nociceptin/orphanin FQ (NC) and its receptor (OP4) have been implicated in pain transmission. The aim of the present study was to investigate the role of the NC/OP4 system in stress-induced analgesia (SIA). The tail-withdrawal assay was performed in mice stressed by forced swimming in water at 15 degrees C (high severity swims) or 32 degrees C (low severity swims). High severity swims produced a naloxone-insensitive antinociceptive effect which was blocked by supraspinal NC (1 nmol). The selective OP4 receptor antagonist, [Nphe1]NC(-13)NH2 (30 nmol), was inactive by itself, but prevented the effect of NC. Low severity swims produced a milder analgesic effect that was partially antagonized by naloxone, completely blocked by NC and potentiated by [Nphe1]NC(-13)NH2. These findings confirm the anti-analgesic role of supraspinal NC and suggest that endogenous NC signaling counteracts the opioid component of SIA.

Characterization of the locomotor activity-inhibiting effect of nociceptin/orphanin FQ in mice.

Nociceptin/orphanin FQ (NC) modulates spontaneous locomotor activity (LA) in mice. NC applied intracerebroventricularly (i.c.v.) has been reported to stimulate LA at low doses (0.001-0.01 nmol) while inhibiting LA at higher doses (1-10 nmol). In the present study, the effects of NC on LA in mice were evaluated and the receptor involved characterized using NC receptor (OP4) agonists and antagonists. No significant differences were found in the LA (30-min observation period) between non-injected mice, mice injected with saline (2 microl/mouse, i.c.v.), or with low doses of NC (0.001 nmol and 0.01 nmol). In the 0.1-10 nmol range, NC caused a dose-dependent, naloxone-insensitive reduction of LA. The effects of the natural peptide were mimicked by NCNH2 and NC(1-13)NH2 while shorter fragments were inactive (NC(1-12)NH2, NC(1-9)NH2). [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2) was inactive at 0.1 nmol and 1 nmol, while causing a partial reduction of LA at 10 nmol. One nmol of the pseudopeptide also prevented the inhibitory effect of 1 nmol NC. Ten nmol [Nphe1]NC(1-13)NH2 did not modify LA per se, but fully prevented the inhibitory action of 1 nmol NC. Results indicate that [F/G]NC(1-13)NH2 and [Nphe1]NC(1-13)NH2 behave as a partial agonist and a pure antagonist of OP4 sites, respectively. Taken together, these data demonstrate that NC inhibits LA in mice by activating OP4 receptor sites.

The nociceptin/orphanin FQ receptor antagonist, [Nphe1]NC(1-13)NH2, potentiates morphine analgesia.

Nociceptin/orphanin FQ (NC) and its receptor (OP4) represent a novel peptide/receptor system which has been implicated in the regulation of various central functions, including pain. The aim of the present study was to explore the involvement of the endogenous NC/OP4 system in the modulation of opioid analgesia using the selective OP4 receptor antagonist [Nphe1]NC(1-13)NH2. Experiments were performed in mice exposed to acute as well as chronic treatment with morphine. [Nphe1]NC(1-13)NH2, injected i.c.v. at 30 nmol, strongly potentiated the analgesic effect of supraspinal morphine (1 nmol, i.c.v.) while it only slightly increased the antinociceptive activity of morphine given systemically (5 mg/kg, s.c.). [Nphe1]NC(1-13)NH, (30 nmol, i.c.v.) also potentiated morphine analgesia in mice made tolerant to the opiate (30 mg/kg/day for 4 days). These findings implicate the endogenous NC signaling as a modulator of morphine analgesia and tolerance.

Characterization of [Nphe(1)]nociceptin(1-13)NH(2), a new selective nociceptin receptor antagonist.

1.. Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a specific G-protein coupled receptor. However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states. As part of a broader programme of research, geared to the identification and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe(1)]nociceptin(1-13)NH(2) acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity. 2. [Nphe(1)]nociceptin(1-13)NH(2) binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pK(i) 8.4) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA(2) 6.0) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea-pig with pA(2) values ranging from 6.0 to 6.4. 3. [Nphe(1)]nociceptin(1-13)NH(2) is also active in vivo, where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay. Moreover, [Nphe(1)]nociceptin(1-13)NH(2) produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine-induced analgesia. 4. Collectively our data indicate that [Nphe(1)]nociceptin(1-13)NH(2), acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics.

Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay.

1. The newly discovered neuropeptide nociceptin (NC) has recently been reported to be the endogenous ligand of the opioid-like orphan receptor. Despite its structural similarity to opioids, when injected intracerebroventricularly (i.c.v.) in the mouse, NC exerts a direct hyperalgesic effect and reverses opioid-induced analgesia. In the present investigation, these two effects of NC were evaluated under the same experimental conditions; in addition, a pharmacological characterization of the receptor mediating these central effects of NC was attempted. 2. NC caused a dose dependent (0.1-10 nmol/mouse), naloxone-insensitive reduction of tail withdrawal latency with a maximal effect of about 50% of the reaction time observed in saline injected mice. In the same range of doses, NC inhibited morphine (1 nmol/mouse) induced analgesia. 3. The effects of the natural peptide were mimicked by NCNH2 and NC(1-13)NH2 (all tested at 1 nmol/mouse) while 1 nmol NC(1-9)NH2 was found to be inactive either in reducing tail withdrawal latency or in preventing morphine analgesia. 4. [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2), which has been shown to antagonize NC effects in the mouse vas deferens, acted as an agonist, mimicking NC effects in both the experimental paradigms. In addition, when NC and [F/G]NC(1-13)NH2 were given together, their effects were additive. 5. These results demonstrate that both the direct hyperalgesic action and the anti-morphine effect of NC can be studied under the same experimental conditions in the mouse tail withdrawal assay. Moreover, the pharmacological characterization of the NC functional site responsible for these actions compared with the peripherally active site, indicates the existence of important differences between peripheral and central NC receptors.

Post-ischemic recovery of acetylcholine release in vitro: influence of different excitatory amino acid receptor subtype antagonists.

The release of endogenous acetylcholine was measured in electrically (5-20 Hz) stimulated guinea pig cerebral cortex and caudate nucleus slices under ischemic (hypoxic and glucose-free) conditions. Ischemia reduced acetylcholine release by 40-90%; the inhibition depended on the duration of ischemia (10-30 min) while the extent of post-ischemic recovery was inversely related to it. Caudate nucleus slices displayed a higher sensitivity to ischemia than did cortical slices. To test the effects of excitatory amino acid receptor antagonists on the ischemia-induced reduction of acetylcoline release and on its post-ischemic recovery, the following drugs were used: 5-methyl-10,11-dihydro-5-H-dibenzo-[a,b]-cyclohepten-5,10-imine (MK-801,-a blocker of the N-methyl-D-aspartate [NMDA] receptor-linked channel), 7-chloro-kynurenic acid (7-Cl-KYN) and (E)-3-[2(phenylcarbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt (GV150526A, blockers of the glycine site of the NMDA receptor), eliprodil, (an antagonist at the polyamine site of the NMDA receptor), and 6-cyano- 7-nitro-quinoxalin-2,3-dione (CNQX, a D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid [AMPA] receptor antagonist). These did not modify the time-course and the extent of ischemia-induced inhibition but improved post-ischemic recovery in a concentration dependent manner. GV 150526A and CNQX appeared to be more effective in the cerebral cortex. Only eliprodil was devoid of any effect in both areas. The evaluation of acetylcholine release from brain slices represents a suitable in vitro model to quantify the effectiveness of drugs in favouring recovery from the cholinergic presynaptic failure induced by ischemic conditions. The different effects of the excitatory amino acid receptor antagonists cited above, depending on the brain areas considered and the receptor subtypes involved, may be of interest in view of their therapeutic potential.

Conversion of enkephalin and dermorphin into delta-selective opioid antagonists by single-residue substitution.

The properties of di- and tri-peptides containing 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in second position suggest that the message domain of opioid peptides can be composed of only two residues [Temussi, P. A., Salvadori, S., Amodeo, P., Guerrini, R., Tomatis, R., Lazarus, L. H., Picone, D. & Tancredi, T. (1994) Biochem. Biophys. Res. Commun. 198, 933-939]. As a crucial test of the possibility that the Tyr-Tic segment be a message domain in longer peptide sequences, we have inserted it in the sequences of two typical opioid peptides: [Leu]enkephalin, a non-selective agonist, and dermorphin, a selective mu agonist. Here we report the synthesis and biological activity of [L-Tic2]enkephalin, [L-Tic2]dermorphin, [L-Tic2]dermorphin carboxylic acid and [D-Tic2]dermorphin: all [L-Tic2]peptides were converted from agonists to delta-selective antagonists. The NMR conformational study in a dimethylsulfoxide/water cryoprotective mixture at low temperature shows diagnostic side-chain--side-chain NOEs in the spectra of all [L-Tic2]peptides and hints that the 90 degrees arrangement of the the two aromatic rings found in the cis-Tyr-L-Tic moiety, typical of N-methyl naltrindole and other delta-selective opiate antagonists, is responsible for the antagonist activity of all these peptides.

Spontaneous rupture of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent malignant tumour of the liver. HCC has an incidence that changes with geographic areas (1.2-2.5% in western countries and 13-53% in Asia and Africa) as the risk of tumour bleeding. The patient arrives to the surgeon in emergency with no possibility of radical resection because of the patient's general conditions, the tumour's stage and the cirrhosis. Palliative treatments are: resection, direct suture of the bleeding tumour, artery embolization and selective binding of the hepatic artery. The Authors describe two cases of spontaneous rupture of HCC observed in the surgical department of Venice Hospital. A review of the literature is also reported.

Synthesis and activity profiles of new dermorphin-(1-4) peptide analogues.

A new series of 12 dermorphin tetrapeptides, W-Tyr-D-MetO-Phe-Xaa-Y (W = H, H2NC = (NH); Xaa = Gly, Sar, D-Ala; Y = OH, OCH3, NH2) were prepared by traditional methods in solution and tested for opioid activity. In binding studies based on displacement of mu, delta, and kappa opioid receptor selective radiolabels from guinea pig brain membranes, the new analogues showed a negligible affinity for the kappa binding site and a preference for mu- over delta-receptors with an evident dependence on N- and/or C-terminal modifications; H-Tyr-D-MetO-Phe-Gly-OCH3 was shown to be one of the most selective mu-receptor ligands reported to date. All these tetrapeptides display dose-related naloxone-reversible antinociceptive effects following intracerebroventricular (icv) or subcutaneous (sc) administrations in mice. In comparison to morphine, H-Tyr-D-MetO-Phe-Sar-NH2 and the guanidino derivative H2NC = (NH)-Tyr-D-MetO-Phe-Gly-NH2 showed lower affinity for mu, delta, and kappa sites but exceptionally stronger analgesia: respectively they are 560 and 1550 times as potent an analgesic as morphine. Among analogues tested after sc administration, H-Tyr-D-MetO-Phe-Sar-NH2 and H-Tyr-D-MetO-Phe-D-Ala-OH displayed the highest activities; they were respectively 22 and 30 times more potent than morphine on a molar basis. These results indicate that N- or C-terminal modifications and substitution at position 2 or 4 of dermorphin-(1-4) peptide do not only influence the affinity of the resulting analogues to opioid receptors but also may favorably alter their pharmacokinetic properties.

[CA-50: evaluation of a new tumor marker in the diagnosis of neoplastic pathologies of the gastrointestinal tract]. / CA-50: valutazione di un nuovo marcatore tumorale nella diagnostica delle patologie neoplastiche del tratto gastro-enterico.

In order to assess the diagnostic value of CA-50, a new tumour marker, a series of 226 patients with gastroenteric tumours, 152 healthy controls and 175 patients with benign gastrointestinal pathologies, was examined. CEA, CA 19-9, Alphafetoprotein and CA-50 were assayed in all subjects and the results subjected to statistical analysis in order to discover the sensitivity, specificity and diagnostic value of the new marker. Studies conducted to date indicate that CA-50 assays may be of some value in the diagnosis of pancreatic and liver tumours but are no improvement on existing markers in clinical use, for the diagnosis of gastroenteric tumours. Indeed CA-50 gives a very large number of false positive especially in cirrhosis and to a lesser extent in chronic pancreatitis.

Gastric cancer in the elderly: results of surgical treatment.

Some relevant data on 290 patients (151 under 65 and 139 over 65 years of age) operated on for gastric carcinoma, have been analysed. The age, the stage and location of the neoplasm, the type of surgery and the post-operative mortality have been studied. The mortality in the 113 patients (64 under and 49 over the age of 65 years) who had had total or partial gastrectomies performed, was evaluated at one year, from one to three years and from three to five years. The survival was evaluated according to the age of the patients, the stage and site of the tumour and the type of operation performed. The most frequent location in the elderly patient is the distal third or two-thirds of the stomach. There is no difference between the mortality in elderly or younger patients except following partial gastrectomy. The survival analysed on the basis of the absolute value, the relationship to the stage, the site of the tumour and the type of operation, is longer in the elderly.