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Biomedical subjects

F Porreca

Publications and source records attributed to F Porreca.

At least 199 records · Page 11Linked to original sources
PubMed1991

Differential antagonism of opioid delta antinociception by [D-Ala2,Leu5,Cys6]enkephalin and naltrindole 5'-isothiocyanate: evidence for delta receptor subtypes.

The present study has investigated the direct opioid delta receptor-mediated antinociception produced by i.c.v. administration of the highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II, as well as that of the less delta-selective [D-Ser2,Leu5,Thr6]enkephalin (DSLET), by using two novel nonequilibrium opioid antagonists, [D-Ala2,Leu5,Cys6] enkephalin (DALCE) and naltrindole 5'-isothiocyanate (5'-NTII). At times ranging from 8 to 48 hr after a single i.c.v. pretreatment of mice with 5'-NTII, the antinociceptive effects of [D-Ala2] deltorphin II were significantly antagonized. In contrast, 5'-NTII pretreatment at times between 10 min and 24 hr failed to antagonize the antinociceptive effects of DPDPE. Previous studies have shown that pretreatment with i.c.v. DALCE produces a dose- and time-related antagonism of DPDPE, but not morphine, antinociception. However, pretreatment with i.c.v. DALCE failed to antagonize the antinociceptive effects of [D-Ala2]deltorphin II. Similarly, i.c.v. administration of DSLET produced time- and dose-related antinociception which was partially antagonized by either beta-funaltrexamine (beta-FNA) or by ICI 174,864 (N,N-dialyl-Tyr-Aib-Aib-Phe-Leu-OH), suggesting mixed activity at mu and delta receptors. ICI 174,864 produced essentially complete antagonism of DSLET antinociception in beta-FNA-pretreated mice. Pretreatment with 5'-NTII (at -8 to -48 hr), blocked the antinociception produced by DSLET in control or in beta-FNA-pretreated mice. In contrast, pretreatment with DALCE failed to antagonize the antinociception produced by i.c.v. DSLET in either control or in beta-FNA-pretreated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1991

Differential antagonism of U69,593- and bremazocine-induced antinociception by (-)-UPHIT: evidence of kappa opioid receptor multiplicity in mice.

The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1-pyrrol idinyl) cyclohexyl]benzeneacetamide), on U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5) dec-8-yl)benzeneacetamide]- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2, NMePhe4, Gly-ol]enkephalin- (mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significantly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, beta-funaltrxamine (mu antagonist) and ICI 174,864 [N,N,-diallyl-Tyr-(alpha-aminoisobutyric acid)2-Phe-Leu-OH] (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2, NMePhe4, Gly-ol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinociception produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.

Analgesics↗
PubMed1991

Lack of antinociceptive cross-tolerance between [D-Pen2, D-Pen5]enkephalin and [D-Ala2]deltorphin II in mice: evidence for delta receptor subtypes.

This study has investigated the development of antinociceptive tolerance to, and cross-tolerance between, two highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2] deltorphin II as well as to [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO), a highly selective mu agonist, in mice. Intracerebroventricular administration of DPDPE, [D-Ala2]deltorphin II and DAMGO each produced an antinociceptive effect. Pretreatment with i.c.v. DPDPE twice daily for 3 days resulted in tolerance to DPDPE as shown by a 4.8-fold rightward shift in the dose-response curve. In contrast, in DPDPE pretreated mice, the dose-response lines for [D-Ala2]deltorphin II and DAMGO were not altered when compared to those obtained in naive animals. The development of tolerance was also shown by pretreating mice with i.c.v. [D-Ala2]deltorphin II; following this pretreatment, the [D-Ala2]deltorphin II dose-response line was displaced to the right by more than 37-fold. In contrast, in [D-Ala2]deltorphin II-pretreated mice, the dose-response lines for DPDPE and DAMGO were not altered compared to those obtained in naive animals. Finally, pretreatment with i.c.v. DAMGO produced a rightward displacement of the DAMGO dose-response line of 47-fold, indicating the development of antinociceptive tolerance. In DAMGO-pretreated mice, however, the dose-response lines for DPDPE and [D-Ala2]deltorphin II were not altered compared to those obtained in naive mice. Thus, the data indicate that antinociceptive tolerance develops to DPDPE, [D-Ala2]deltorphin II and DAMGO but that there is no cross-tolerance between these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1991

Prostaglandin E2-induced diarrhea in mice: importance of colonic secretion.

The present study has investigated the basis for induction of diarrhea by prostaglandin (PG)E2 in mice. When given i.p., PGE2 induced a dose- and time-dependent diarrhea; the shortest post-treatment time for diarrhea onset was approximately 7 min, at a PGE2 dose of 200 micrograms/kg. At this dose, PGE2 also produced accumulation of fluid in the small intestine and in the colon (enteropooling). The enteropooling reached its maximum by 9 min and did not decrease until approximately 11 min (i.e., 2 to 4 min after the mean time for diarrhea onset). PGE2 treatment altered neither gastric emptying nor gastrointestinal propulsion, but strongly enhanced the expulsion of a glass bead from the colon (i.e., decreased the time to bead expulsion). The shortest time to expulsion of the glass bead was observed at 200 micrograms/kg i.p. The induction of diarrhea by PGE2 was unaffected by cecectomy, or sham-cecectomy, but the dose-response curve for time to onset of diarrhea by i.p. PGE2 was displaced to the right in animals with ligations of the ileo-ceco-colonic (ICC) junctions. The intraluminal fluid accumulation in the colon, evaluated in mice with ICC ligations, was increased by PGE2 administration within 2 min and remained greater than in vehicle-treated animals until the onset of diarrhea. The stimulation of colonic bead expulsion produced by i.p. PGE2 in control mice was not observed in animals with acute ICC ligations, even at i.p. doses up to 800 micrograms/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Bombesin differentially affects gastric emptying in suckling, weanling and adult rats.

The gastric effect of bombesin, a homolog of the mammalian peptide found in breast milk, was studied in suckling, weanling and adult rats (11, 30 and 90 days old, respectively). Control gastric emptying was not different in the three age groups. When bombesin was given orogastrically in a saline vehicle, 30 min before a nonabsorbable radiolabeled marker (used to assess gastric emptying), a significant and dose-related inhibitory effect was observed in sucklings. In contrast to the data with orogastric peptide in saline, when bombesin was given orogastrically in rat milk 30 min before the marker, there was no effect on gastric emptying in sucklings. Inhibition of gastric emptying was again demonstrated in the sucklings when bombesin (0.6-30 micrograms) was given with an artificial rat milk substitute 30 min before the marker. In contrast, orogastric bombesin in rat milk or rat milk substitute had no effect on gastric emptying in weanlings or adults. While s.c. bombesin in saline did not alter gastric emptying in sucklings, s.c. administration of the peptide produced a significant and dose-related increase in gastric emptying in both weanlings and adults. These results support the concept that milk-borne peptides, such as gastrin releasing peptide, may be involved in regulation of gastric function in suckling rats.

Administration, Oral↗
PubMed1990

Selective modulation of morphine antinociception, but not development of tolerance, by delta receptor agonists.

Co-administration of delta opioid agonists at doses which do not produce measurable antinociception were demonstrated to produce an increase in the antinociceptive potency of morphine in the mouse tail-flick test. In contrast, co-administration of equi-antinociceptive combinations of a delta agonist plus morphine for three days resulted in the development of less tolerance to morphine antinociceptive actions. The data indicate that while acute antinociceptive effects of opioid mu agonists are modulated by delta agonists, the development of antinociceptive tolerance is not.

Analgesics↗
PubMed1990

Modulation of morphine antinociception by peripheral [Leu5]enkephalin: a synergistic interaction.

This study determined whether the modulation of morphine antinociception by [Leu5]enkephalin, a compound which does not produce detectable antinociception when given i.p., was additive or synergistic. Co-administration of graded i.p. doses of morphine and [Leu5]enkephalin 20 min before testing resulted in a progressive leftward and parallel displacement of the i.p. morphine dose-response line. The increase in potency produced by i.p. [Leu5]enkephalin, but not the antinociception of i.p. morphine alone, was blocked by i.c.v. ICI 174,864. The data demonstrate strong and dose-related synergism between the two compounds, supporting the view that (a) peripheral administration of [Leu5]enkephalin can modulate morphine antinociception, apparently at the level of the brain and (b) that the interaction between mu and delta opioid agonists is not the result of simple additive action at the same (i.e., mu) receptor. Further evidence is thus provided for the existence of functional mu-delta interactions.

Analgesics↗
PubMed1990

Gastrointestinal motor effects of corticotropin-releasing factor in mice.

The present investigation examined the effects of centrally and peripherally administered corticotropin-releasing factor on gastric emptying and gastrointestinal transit in mice. Corticotropin-releasing factor, given either intracerebroventricularly or intrathecally, caused a dose-dependent inhibition of gastric emptyping and gastrointestinal transit. Intravenous or intraperitoneal administration of corticotropin-releasing factor, while 5- to 7-fold less potent than after central injection, produced an equivalent level of effect. alpha-Helical corticotropin-releasing factor, a corticotropin-releasing factor receptor antagonist, blocked the effects of intracerebroventricularly administered corticotropin-releasing factor when the antagonist was given concurrently by the intracerebroventricular, but not by the intraperitoneal, route. Conversely, corticotropin-releasing factor, when given peripherally, was antagonized equally well by intracerebroventricular or intraperitoneal administration of the antagonist. The inhibition of gastric emptying induced by corticotropin-releasing factor was reduced by pretreatment with the ganglionic blocking agent, chlorisondamine, and in adrenalectomized mice, but this effect was not antagonized by naloxone. These findings provide evidence for an action of corticotropin-releasing factor within the central nervous system, as well as a peripheral site of action, to inhibit gastric emptying in the mouse. The gastrointestinal motor effects of corticotropin-releasing factor are not mediated through opioid mechanisms although their full expression may require intact autonomic innervation and adrenal function.

Adrenalectomy↗
PubMed1990

Opioid agonist affinity in the guinea-pig ileum and mouse vas deferens.

The affinity of morphine, normorphine, methadone, Tyr-D-Ala-Gly-MePhe-NH(CH2)2(N-O)(CH3)2 (RX 783030), [D-Ala2,D-Leu5]enkephalin (DADLE), ketazocine and ethylketocyclazocine (EKC) were determined for their pharmacological receptors in two bioassay tissues, the guinea-pig ileum and the mouse vas deferens (MVD). The method involved the use of the irreversible antagonist, beta-chlornaltrexamine (beta-CNA), and the method of partial receptor blockade. The agonist concentration-effect curves were displaced to the right with decreasing maximum effect, a pattern typical of partial, irreversible blockade of receptors. The concentrations of beta-CNA required to produce a rightward displacement in the concentration-effect curves for different agonists, ranged between 2 and 3000 nM. No similarity was found between the IC50 and the dissociation constant (KA), values predicted to be equivalent only if a linear relationship exists between receptor occupation and observed effect; the dissociation constant for the agonists were between 3 and 218 times larger than the IC50 values. When methadone was used as the agonist in the guinea-pig ileum, beta-CNA produced parallel displacement of the concentration-effect curve, regardless of the blocking concentration chosen, preventing the determination of KA for this agonist, in this tissue; this problem was not encountered in the mouse vas deferens. The KA of morphine, RX 783030 and ketazocine were found not to differ in the guinea-pig ileum and mouse vas deferens. As expected, DADLE had significantly different affinity in the two tissues, showing 117-fold lower affinity in the guinea-pig ileum. Surprisingly, the normorphine affinity was found to be 7-fold higher in the guinea-pig ileum. While the difference in affinity of DADLE may be due to the suggested lack of functional delta receptors in the guinea-pig ileum, the difference in affinity seen with normorphine, but not morphine, in the two tissues is difficult to explain. Taken together with the insensitivity of methadone to beta-CNA blockade in the guinea-pig ileum, but not mouse vas deferens, the difference in the affinity of normorphine in these tissues may suggest the possibility of differences in local milieu of mu receptors or of mu receptor subtypes in the two tissues. The results provide fundamental information regarding opioid agonist affinity in two standard bioassays in vitro, and support the view of (1) a difference in receptors activated by DADLE in the guinea-pig ileum (mu) and mouse vas deferens (delta), as well as (2) possible differences in mu-receptors in these tissues.

Animals↗
PubMed1990

Antinociceptive effects of [D-Ala2]deltorphin II, a highly selective delta agonist in vivo.

The present study has characterized the antinociceptive actions of [D-Ala2]deltorphin II following intracerebroventricular (i.c.v.) administration in the mouse tail-flick test. [D-Ala2]deltorphin II produced dose- and time-related antinociception, with maximal effects at +10 min and significant antinociception which lasted for 40-60 min. [D-Ala2]deltorphin II was 13-fold more potent than i.c.v. [D-Pen2, D-Pen5]enkephalin (DPDPE), a second highly selective delta agonist, and approximately equipotent with i.c.v. morphine in producing antinociception. The antinociceptive effects of i.c.v. [D-Ala2]deltorphin II and DPDPE, but not those of morphine, were antagonized by the selective delta antagonist, ICI 174,864. In contrast, pretreatment with the non-equilibrium mu antagonist, beta-funaltrexamine blocked morphine antinociception, but failed to antagonize [D-Ala2]deltorphin II and DPDPE antinociception. These data indicate that [D-Ala2]deltorphin II produced its antinociceptive effects at a supraspinal delta receptor. [D-Ala2]deltorphin II appears to be the most appropriate delta opioid agonist currently available for studies in vivo and support the involvement of delta receptors in supraspinal antinociception.

Analgesics↗
PubMed1990

Effects of bombesin on mucosal ion transport in the mouse isolated jejunum.

The effects of bombesin (BBS) on ion transport in the mouse isolated jejunum were studied in full thickness (intact) or serosal stripped (mucosal) sheets of jejunum mounted in Ussing chambers. Although serosal BBS (0.1-30 nM) induced a concentration-related increase in transmural potential difference (PD) and short-circuit current (Isc) without altering conductance in both preparations, the peptide was more potent and efficacious in mucosal than in intact tissues. In all preparations, pretreatment with BBS abolished the effects of a subsequent administration of BBS showing the rapid development of desensitization. In intact tissues, serosal pretreatment with either chlorisondamine (3 microM) or tetrodotoxin (0.1 microM) decreased, but did not abolish BBS action. Meanwhile, atropine pretreatment (3 microM) did not affect the BBS response. In these tissues, previous blockade of NaCl cotransport by furosemide (300 microM) decreased BBS (30 nM) stimulation of PD or Isc. In mucosal preparations, tetrodotoxin pretreatment (0.1 microM) similarly reduced but did not eliminate BBS (3 nM) stimulation of PD or Isc, whereas atropine pretreatment (1 microM) again had no effect on BBS action. In contrast in these mucosal tissues, furosemide pretreatment (300 microM) did not modify the BBS response. Furthermore, carbachol pretreatment (10 microM) prevented completely the tetrodotoxin-resistant action of BBS. These findings in vitro suggest that the increase of PD and Isc following BBS administration in isolated mouse jejunum is associated with three different levels of action of this peptide: BBS may act on noncholinergic nerves, at pre- and post-ganglionic levels, as well as directly on the enterocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Mu antagonist and kappa agonist properties of beta-funaltrexamine (beta-FNA) in vivo: long-lasting spinal analgesia in mice.

It is now well established that compounds classified as kappa opioids can, in circumstances where they produce no measurable agonist effects, antagonize the actions of mu opioids. Largely on the basis of studies in vitro, beta-funaltrexamine (beta-FNA) has been classified as a reversible kappa agonist and long acting mu antagonist. The present study investigated the possibility that the mu antagonist profile of this compound could be related to its kappa agonist actions. We used two tests of analgesia (the acetic acid writhing test and the hot-water tail-flick test) and selective kappa agonists and antagonists given at supraspinal and spinal sites in mice. Intrathecal (i.t.) administration of beta-FNA, but not the selective kappa agonist U50,488H, produced long-lasting and dose-related analgesia in the writhing test for periods up to 48 hr after a single dose. In contrast, i.t. beta-FNA had no agonist actions in the tail-flick test. The kappa antagonist, nor-binaltorphimine (nor-BNI) produced no agonist effects in either analgesic test when given i.t. In the writhing test, nor-BNI produced a rightward displacement of the beta-FNA dose-response line regardless of whether beta-FNA was given 10 min or 4 hr before testing, indicating that i.t. beta-FNA was acting as a kappa agonist in this test. As both i.t. morphine and beta-FNA are active in the writhing test, the antagonist actions of i.t. beta-FNA could be evaluated only in the tail-flick test. beta-FNA, but not nor-BNI, blocked the effects of i.t. morphine in the tail-flick test.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1990

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)

Analgesics↗