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Biomedical subjects

F Porreca

Publications and source records attributed to F Porreca.

At least 271 records · Page 15Linked to original sources
PubMed1985

Studies in vitro with ICI 174,864, [D-Pen2, D-Pen5]-enkephalin (DPDPE) and [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO).

The interactions of a proposed, selective delta receptor antagonist (ICI 174,864) and selective agonists at mu and delta receptors, [D-Ala2, NMePhe4, Gly-ol]-enkephalin (DAGO) and [D-Pen2, D-Pen5]-enkephalin (DPDPE), respectively, have been studied using the electrically-stimulated mouse isolated vas deferens (MVD) and the guinea-pig isolated ileum (GPI). Incubation of increasing concentrations of ICI 174,864 (10,30,100 and 300 nM) produced a dose-related and parallel rightward displacement of the DPDPE dose-response curve in the MVD. In contrast, ICI 174,864 (300-3000 nM) failed to affect the DAGO dose-response curve in the same tissue. Analysis of the DPDPE-ICI 174,864 interaction in the MVD using the pA2 method revealed a Schild plot slope of -0.68 suggesting the involvement of more than one population of receptors. ICI 174,864 (300 nM) failed to antagonize DPDPE in the GPI at doses up to 30 microM. These results suggest that (a) ICI 174,864 acts as a selective delta antagonist in the MVD; (b) DPDPE interacts with mu receptors in the MVD but only at very high concentrations, and (c) delta receptors appear not to be of functional importance in the GPI.

Animals↗
PubMed1985

Regulation of gastric emptying.

Studies carried out in the years since William Beaumont's direct observations of gastric motility have provided increased understanding of the physiological roles of the stomach and of the mechanisms for the regulation of gastric motility. Tonic contractions of the proximal stomach are of primary importance for transfer of liquids from the stomach to the duodenum. Peristaltic contractions of the distal stomach are of primary importance for reducing the size of solid food particles and for transfer of solids to the duodenum. Because gastric emptying requires a net antral-duodenal pressure gradient, contractions of the duodenum also influence the rate of gastric emptying. Gastrointestinal hormones, including gastrin, cholecystokinin, secretin, somatostatin, and others, are released by contact of chyme with the intestinal mucosa, and affect contractions of the proximal stomach, distal stomach, and duodenum. Neural reflexes that arise from the stomach act through autonomic motor nerves to allow regulation by the central nervous system of gastric motility. gamma-Aminobutyric acid, opioids, and bombesin may serve as central neurochemical regulators of gastric motility.

Afferent Pathways↗
PubMed1984

Motilin acts within the CNS to inhibit urinary bladder contractions.

Although peripheral actions have been shown for the brain-gut peptide, motilin, its localization in the CNS of mammals suggests some physiological role at this site. In the present experiments intracerebroventricular or intrathecal, but not peripheral, administrations of motilin produced a dose-related and naloxone reversible inhibition of the micturition reflex. Cross-tolerance was demonstrated between motilin and morphine in this respect. These data suggest a physiological role for motilin within CNS to alter urinary bladder motility, possibly through an enkephalinergic or naloxone-sensitive link.

Animals↗
PubMed1984

Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse.

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)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1983

Dissociation of analgesic and gastrointestinal effects of electroconvulsive shock-released opioids.

Activation of endogenous opioid systems by electroconvulsive shock (ECS) produced naloxone-reversible thermal analgesia (52 degrees C hot plate) 5 min after ECS administration. Although opioid peptides injected intracerebroventricularly have previously been found to inhibit gastrointestinal motility, ECS treatment did not affect gastric emptying, small or large intestinal transit. These results suggest that centrally-mediated opioid analgesia and changes in gastrointestinal motility are initiated through independent mechanisms.

Animals↗
PubMed1983

Studies in vivo with dynorphin-(1-9): analgesia but not gastrointestinal effects following intrathecal administration to mice.

Direct administration of dynorphin-(1-9) (10-100 micrograms) into the spinal subarachnoid space of mice produced a dose-related analgesic effect at 5 and 10, but not 35 min, in the tail-flick test using hot water as the nociceptive stimulus. By contrast, the same doses did not affect gastrointestinal transit at 5, 10, 15 or 35 min after injection. These results suggest that dynorphin-(1-9) is similar in this endpoint to ketazocine-type kappa opioid agonists in naive animals while confirming that intrathecal administration of dynorphin is analgesic in mice.

Analgesia↗
PubMed1983

Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration.

The mu agonist, morphine, and the prototype kappa agonists, ketocyclazocine and ethylketocyclazocine (EK), were studied for their effects on gastrointestinal transit. Following s.c. administration, both morphine (0.3-3 mg/kg) and ketocyclazocine (0.3-10 mg/kg) antagonized transit of an opaque marker through the small intestines of mice. Morphine (0.1-1 microgram) was also effective after intracerebroventricular (icv) administration in mice whereas ketocyclazocine (0.3-30 micrograms) was not. Similarly, while both morphine (0.3-5 mg/kg) and EK (0.6-10 mg/kg) slowed transit after s.c. injection to rats, only morphine (1-10 micrograms), but not EK (0.3-300 micrograms), was active following icv administration. Icv infusion of the mu benzomorphan, phenazocine (10-100 micrograms), slowed transit in a dose-related manner. These results indicate that there may be an anatomically distinct distribution of receptors for benzomorphan kappa agonists in both the mouse and rat, with these opiate receptors not being located near the lateral cerebral ventricles. The difference in efficacy between morphine and ketazocines in slowing gastrointestinal transit after icv administration to rodents suggests that (a) inactivity in this endpoint is a characteristic of benzomorphan kappa compounds and (b) the model may serve as a useful screen when establishing in vivo profiles of kappa agonists in mice and rats.

Animals↗
PubMed1983

A comparison of the analgesic and gastrointestinal transit effects of [D-Pen2, L-Cys5]enkephalin after intracerebroventricular and intrathecal administration to mice.

Intrathecal (i.t.) administration of the highly delta selective peptide, [D-Pen2, L-Cys5]enkephalin (DPLCE) (1-10 micrograms), effectively inhibited gastrointestinal transit of an orally-given radiolabelled marker in mice. By contrast, the same doses did not affect marker transit after intracerebroventricular (i.c.v.) administration. I.c.v. or i.t. administration of the peptide effectively increased the latency to hindpaw lick using the 55 degrees C hot-plate as the nociceptive stimulus. Maximum analgesic effects were seen with 0.3 micrograms given i.t. or 10 micrograms given i.c.v. Time-response studies showed activity for as long as 20 min after administration by either route. The differential gastrointestinal effects of DPLCE after i.c.v. and i.t. administration to mice suggest that delta receptors in the brain may mediate analgesic but not gut effects while spinal cord receptors may be less functionally selective.

Analgesia↗
PubMed1983

Footshock produces analgesia but no gastrointestinal motility effects in the rat.

The effect of inescapable footshock was determined on gastrointestinal motility in unanesthetized rats. Inescapable footshock did not affect gastric emptying, small or large intestinal transit. Footshock produced a brief, naloxone-reversible thermal analgesia. These data indicate that gastrointestinal motility and analgesia are controlled by different central nervous system opioid mechanisms.

Analgesia↗
PubMed1983

Gastrointestinal drug receptors.

Drug receptors consist of recognition sites coupled to transducer and cellular amplifier mechanisms. Slight differences in receptor recognition sites can be exploited pharmacologically to provide drugs with a high degree of selectivity for activating or blocking individual receptor subtypes. For example, it may now be possible to block, selectively, subtypes of muscarinic cholinergic receptors in the gastrointestinal tract with pirenzepine and other drugs that discriminate between subtypes of muscarinic cholinergic receptors. The recognition of subtypes of adrenergic receptors may allow highly selective pharmacological activation and blockage of gastrointestinal neural and smooth muscle receptors. The development of nonpeptide receptor antagonists of gastrointestinal hormones and peptide neurotransmitters also offers promise for improved therapy of digestive diseases. Tremendous progress has occurred in recent years in defining multiple types of opioid receptors that alter gastrointestinal secretory, absorptive and motility functions. These receptors are located in the mucosa, nerves and muscle of the intestine and in the brain and spinal cord.

Animals↗
PubMed1983

Affinity of normorphine for its pharmacologic receptor in the naive and morphine-tolerant guinea-pig isolated ileum.

The affinity of normorphine for its pharmacologic receptor was determined using the longitudinal muscle-myenteric plexus preparation of naive and morphine-tolerant guinea pigs and the method of partial blockade of a fraction of the receptor population with the novel, irreversible opiate antagonist, beta-chlornaltrexamine. The normorphine concentration-response curve was antagonized by beta-chlornaltrexamine in a nonsurmountable fashion, at antagonist concentrations ranging from 6.0 to 15.0 nM in both naive and tolerant tissues. The dissociation constant (KA; reciprocal of affinity) of normorphine was found to be 1.54 (+/- 0.22) X 10(-6) M in naive and 2.30 (+/- 0.66) X 10(-6) M in morphine-tolerant ilea, values that did not differ significantly. The IC50 of normorphine was approximately one-sixth as large as KA in the naive, but was approximately equal to KA in the tolerant preparation. The stimulus-effect relation was nonlinear in both naive and tolerant ilea, but differed markedly in range in the two states. This study represents a direct pharmacological determination of the normorphine dissociation constant using concentration-response data; the values obtained agree well with those based on brain concentration in vivo and with data obtained in radioligand binding studies performed in the presence of sodium chloride. Furthermore, these results suggest that affinity changes may not be of major importance in the development of tolerance to opiates in this tissue and that the phenomenon of tolerance is probably related to changes in the postreceptor chain of events that lead to the measured effect.

Animals↗
PubMed1983

The spinal cord as a site of opioid effects on gastrointestinal transit in the mouse.

Intrathecal (i.t.) administration of morphine (1, 3 or 10 micrograms) effectively inhibited the passage of a radiolabeled marker through the gastrointestinal tract of mice. This effect was reversed by pretreatment with naloxone (2 mg/kg s.c.). Transection of the spinal cord at the level of the second thoracic vertebra (T2) slowed control transit when measured after 4 hr; nevertheless, i.t. morphine inhibited transit in these paralyzed animals. Similarly, i.c.v. administration of morphine (1, 3 or 10 micrograms) inhibited transit regardless of whether the spinal cord was transected at T2. Lower efficacy was seen with i.p. (10-300 micrograms/kg) or i.v. (10 micrograms) morphine than with comparable doses given i.t. (10 micrograms). Intrathecal administration (1, 3 or 10 micrograms) of the proposed selective delta opioid agonist peptides, D-Ala2-D-Leu5-enkephalin, D-Pen2-L-Cys5-enkephalin or i.t. administration of D-Ser2-Leu-enkephalin-(Thr6) (10 micrograms) were effective in inhibiting gastrointestinal transit. In contrast, the proposed kappa agonists, ketocyclazocine (1, 3 or 10 micrograms) or dynorphin-(1-13) (1, 10 or 100 micrograms), did not affect transit after i.t. administration. Dynorphin-(1-13) (10, 30 or 100 micrograms) or dynorphin-(1-9) (10, 30 or 100 micrograms) similarly did not affect transit after i.c.v. administration. Whereas D-Ala2-D-Leu5-enkephalin (1, 3 or 10 micrograms) and D-Ser2-Leu-enkephalin-(Thr6) (10 micrograms) were also efficacious in inhibiting transit by the i.c.v. route, the more delta selective D-Pen2-L-Cys5-enkephalin (1, 3, 10 or 20 micrograms) was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Centrally administered bombesin affects gastric emptying and small and large bowel transit in the rat.

The effects of intracerebroventricular bombesin on gastric emptying and small and large bowel transit were evaluated in female rats using radioactive marker techniques. Gastric emptying was studied by determining the rate of emptying of tritium-labeled polyethylene glycol from the stomach after intracerebroventricular saline or bombesin, while intestinal transit was determined after the direct instillation of radiochromium into the small and large bowels. Dose- and time-response studies were conducted. Bombesin (0.01-1.0 microgram, intracerebroventricularly) slowed gastric emptying in a dose-related manner. Time-course studies of gastric emptying after administration of the peptide concurrently with, or 10 or 20 min before the marker, showed maximum effects 20 min after bombesin. This effect was blocked by subdiaphragmatic vagotomy. Small intestinal transit was also delayed by intracerebroventricular bombesin (0.01-3.0 microgram); when studied by giving the peptide concurrently with, or 10 or 20 min before the marker, maximal effects were seen 20 min after bombesin. In contrast, transit in the large intestine was stimulated when bombesin (1 microgram, intracerebroventricularly) and the marker were given concurrently, while a small (nonsignificant) delay of transit occurred at 20 min after doses of 0.01-1.0 microgram. Fed rats showed a significant (p less than 0.05, Student's t-test) increase in fecal boli within the first 30 min after intracerebroventricular bombesin (1 microgram) (3.66 +/- 0.49, bombesin; 1.16 +/- 0.54, saline). Peripherally administered bombesin (20 micrograms/kg, intraperitoneally) had no effect on gastric emptying. These results indicate that bombesin exerts profound effects on the mammalian gastrointestinal tract via the central nervous system, probably through a vagally mediated motor pathway. Furthermore, the qualitatively different effects of this peptide on the small and large bowels emphasize that these different organs respond to drugs in different manners and with different time-courses.

Animals↗