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Biomedical subjects

F Porreca

Publications and source records attributed to F Porreca.

At least 253 records · Page 14Linked to original sources
PubMed1987

Role of mu and delta receptors in the supraspinal and spinal analgesic effects of [D-Pen2, D-Pen5]enkephalin in the mouse.

The opioid receptors involved in the supraspinal and spinal actions of [D-Pen2, D-Pen5]enkephalin (DPDPE) for production and/or modulation of analgesia were investigated in two thermal analgesic tests, the mouse warm water (55 degrees C) tail-withdrawal assay and the radiant heat tail-flick test. Two approaches were used at supraspinal and spinal sites: determination of possible cross-tolerance between morphine and a variety of receptor selective/nonselective agonists (DPDPE, [D-Pen2, L-Pen5]enkephalin (DPLPE), [D-Ala2, MePhe4, Gly-ol]enkephalin, [D-Ala2, Met5]enkephalin amide, [D-Ser2, Leu5, Thr6]enkephalin and [D-Thr2 Leu, Thr6]enkephalin) and possible potentiation of morphine (mu) analgesia by proposed delta agonists (DPDPE, DPLPE and [D-Ala2, D-Leu5]enkephalin) in naive and morphine-tolerant mice. Additionally, proposed mu (morphine) and delta (DPDPE) agonists were evaluated for their i.c.v. analgesic effectiveness in the absence, and in the presence, of the proposed delta antagonist ICI 174,864. The present communication now reports that after i.c.v. administration analgesic cross-tolerance could be demonstrated between morphine and a variety of relatively selective or nonselective opioids but not to the highly delta selective DPDPE and DPLPE. This result was consistent with direct antagonism of i.c.v. DPDPE, but not morphine analgesia, by ICI 174,864. Furthermore, i.c.v. DPDPE and DPLPE were able to potentiate morphine analgesia in either naive or morphine-tolerant mice. In contrast, after intrathecal administration, cross-tolerance could be demonstrated between DPDPE or DPLPE and morphine, and no potentiation of morphine by DPDPE could be observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1986

Estimation of the affinity of naloxone at supraspinal and spinal opioid receptors in vivo: studies with receptor selective agonists.

The apparent affinity of naloxone at cerebral and spinal sites was estimated using selective mu [D-Ala2, Gly-o15]-enkephalin (DAGO) and delta [D-Pen2, D-Pen5]enkephalin] (DPDPE) opioid agonists in the mouse warm water tail-withdrawal test in vivo; the mu agonist morphine was employed as a reference compound. The approach was to determine the naloxone pA2 using a time-dependent method with both agonist and antagonist given intracerebroventricularly (i.c.v.) or intrathecally (i.th.); naloxone was always given 5 min before the agonist. Complete time-response curves were determined for each agonist at each site in the absence, and in the presence, of a single, fixed i.c.v. or i.th. dose of naloxone. From these i.c.v. or i.th. pairs of time-response curves, pairs of dose-response lines were constructed at various times; these lines showed decreasing displacement with time, indicative of the disappearance of naloxone. The graph of log (dose ratio-1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this plot, the apparent pA2 and naloxone half-life was calculated at each site and against each agonist. The affinity of naloxone was not significantly different when compared between agonists after i.c.v. administration. A small difference was seen between the affinity of i.th. naloxone against DPDPE and DAGO; the i.th. naloxone pA2 against morphine, however, was not different than that for DPDPE and DAGO. The naloxone half-life varied between 6.6 and 16.9 min, values close to those previously reported for this compound. These results suggest that the agonists studied may produce their i.c.v. analgesic effects at the same receptor type or that alternatively, the naloxone pA2 may be fortuitously similar for mu and delta receptors in vivo. Additionally, while the affinity of naloxone appears different for the receptors activated by i.th. DAGO and DPDPE, further work may be necessary before firm conclusions regarding the nature of the spinal analgesic receptor(s) can be drawn.

Analgesia↗
PubMed1986

Evidence for a role of conditioning in the development of tolerance to morphine-induced inhibition of gastrointestinal transit in rats.

Groups of rats were administered s.c. saline or morphine for 14 consecutive days and received morphine, saline or no treatment on day 15. Significant and consistent environmental cues were established through the treatment and test periods. Transit of a charcoal meal along the gastrointestinal tract, measured on day 15, was significantly greater in rats conditioned to daily morphine, followed by saline on day 15, than in any other group. This enhanced transit was approximately equal in magnitude to the amount of developed tolerance to morphine. These results support the hypothesis that tolerance to opiates may be partly explained by a compensatory conditioned physiological response opposing the acute effect.

Animals↗
PubMed1986

Intrathecal FMRFamide (Phe-Met-Arg-Phe-NH2) induces excessive grooming behavior in mice.

The molluscan neuropeptide Phe-Met-Arg-Phe-NH2 (FMRFamide) was administered intrathecally (i.t.) to mice and their behavior was monitored for 30 min. FMRFamide induced a dramatic and dose-related (5-12 micrograms) increase in grooming-related activities compared to saline-treated controls. The grooming behavior produced by 8 micrograms FMRFamide was not blocked by simultaneous i.t. administration of 10 micrograms of the following antagonists: atropine, phentolamine, methysergide, naloxone or spantide; peripheral administration of naloxone (3.5 mg/kg, s.c.) also failed to antagonize FMRFamide grooming. These data constitute the first report that FMRFamide produces behavioral changes in mammals.

Animals↗
PubMed1986

Centrally-administered opioid selective agonists inhibit drinking in the rat.

The effects of intracerebroventricular injection of mu (morphine), kappa (dynorphin-(1-13), ethylketocyclazocine, and U50,488H), and delta ([D-Pen2, D-Pen5]enkephalin) opioid agonists on water intake of 14 hr water deprived rats was studied. All agonists caused a dose related decrease in time spent drinking, with a rank order potency of dynorphin-(1-13) greater than morphine greater than ethylketocyclazocine greater than [D-Pen2, D-Pen5]enkephalin = U50, 488H. With the exception of morphine, all of the compounds increased the latency to begin drinking, but only at the highest doses tested. The rank order potency for this endpoint was dynorphin-(1-13) = ethylketocyclazocine greater than [D-Pen2, D-Pen5]enkephalin greater than U50, 488H. The potent inhibition of drinking following centrally-given dynorphin-(1-13), at doses that did not affect the latency to begin drinking, supports a role for endogenous dynorphin in the homeostatic control of water balance. This function may not be primarily mediated through activation of a kappa opioid receptor since dynorphin-(1-13) was 80-230 times more potent than the selective kappa agonist, U50,488H or ethylketocyclazocine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Intrathecal bombesin-induced inhibition of gastrointestinal transit: requirement for an intact pituitary-adrenal axis.

The role of the pituitary-adrenal axis in the inhibition of gastrointestinal transit caused by intrathecal administration of bombesin was examined. Bombesin (0.3-10 micrograms) slowed transit by this route in a dose-related manner. Either hypophysectomy or adrenalectomy prevented the inhibition of gastrointestinal transit associated with bombesin (10 micrograms, i.th.). The inhibitory gut effects of this peptide were not prevented in sham-operated rats. Intrathecal bombesin-induced inhibition of gastrointestinal transit is thus dependent upon an intact pituitary-adrenal axis.

Adrenal Glands↗
PubMed1986

Evidence for delta receptor mediation of [D-Pen2,D-Pen5]-enkephalin (DPDPE) analgesia in mice.

Possible involvement of cerebral delta opioid receptors in antinociceptive processes was studied in a test utilizing heat as the noxious thermal stimulus. The investigation focused on selective agonists and antagonists for mu and delta opioid receptors. Morphine and [D-Ala2,NMPhe4, Gly-ol]enkephalin (DAGO) were used as agonists for the mu receptor while [D-Pen2,D-Pen5]enkephalin (DPDPE) was the agonist for the delta receptor. Two approaches were employed: first, the intracerebroventricular (i.c.v.) analgesic activity of the agonists was determined in the absence, and in the presence of graded i.c.v. doses of the selective delta antagonist, ICI 174,864 (N,N diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is alpha-aminoisobutyric acid); second, acute tolerance to morphine was produced and the possible presence of acute cross-tolerance between subcutaneous (s.c.) morphine and the delta agonist investigated. ICI 174,864 antagonized the analgesia produced by DPDPE, but not that resulting from morphine or DAGO. Morphine pretreatment resulted in the development of acute tolerance to i.c.v. morphine, and acute cross-tolerance to i.c.v. DAGO, but not to i.c.v. DPDPE. These results provide evidence that both cerebral delta and mu opioid receptors are responsible for the mediation of analgesia in tests utilizing heat as the nociceptive stimulus.

Analgesia↗
PubMed1986

Centrally administered bombesin affects gastrointestinal transit and colonic bead expulsion through supraspinal mechanisms.

Effects of bombesin on gastrointestinal transit and colonic bead expulsion (CBE) were studied in male, ICR mice. Mice received graded doses of bombesin or saline by either the i.c.v., intrathecal (i.t.) or i.p. routes; morphine was studied as the reference compound. Both compounds slowed gastrointestinal transit in a dose-dependent manner by these routes. Intracerebroventricular bombesin was 13.5 and 3406 times more potent than the i.t. and i.p. peptide, respectively. Intracerebroventricular or i.t. bombesin or morphine also produced dose-related inhibition of CBE. Intracerebroventricular bombesin was 1.54 times more potent than i.t. bombesin, whereas i.p. bombesin at doses 11,000 times greater (10 micrograms/kg; 25-g mouse) had no effect on CBE. Gastrointestinal transit and CBE were also studied in spinally transected (second thoracic vertebra) mice in which brain-spinal cord communication (neural and cerebrospinal fluid) had been interrupted. Cord transection eliminated the inhibition of gastrointestinal transit by i.t., but not i.c.v., bombesin. In contrast, morphine was effective by either route in normal or spinally transected mice. The CBE effects of i.t., but not i.c.v., bombesin were eliminated by spinal transection, whereas morphine was still effective by either the i.c.v. or i.t. route. These results suggest that 1) centrally administered bombesin acts at a central site to produce inhibition of gastrointestinal transit and CBE, 2) morphine inhibits gastrointestinal transit and CBE at both spinal or supraspinal sites, independent of an intact brain-cord axis and 3) i.t., but not i.c.v., bombesin requires communication between these two central sites. Intrathecal bombesin requires activation of supraspinal sites to produce its gut effects.

Animals↗
PubMed1985

Intrathecal morphine slows gastrointestinal transit in rats.

Intrathecal (i.th.) (by direct lumbar puncture) and intraperitoneal (i.p.) administration of morphine (30-100 micrograms/rat) caused a dose-related inhibition of gastrointestinal transit in the rat. Pretreatment with i.th. naloxone (5 micrograms at -5 min) reversed the effects of i.th., but not i.p., morphine. These results suggest that the spinal cord appears to be a target site for the inhibitory effects of morphine on gastrointestinal transit in the rat.

Animals↗
PubMed1985

Bombesin stimulates small intestinal motility after intracerebroventricular administration to rats.

The frequency and amplitude of contractions occurring in the duodenum and the jejunum of freely-moving, unanesthetized, female Sprague-Dawley rats were determined by continuously recording intestinal intraluminal pressure. Intracerebroventricular (i.c.v.) administration of saline did not significantly alter the frequency of contractions in either small bowel region when compared with activity observed during a preinjection control period. I.c.v. administration of bombesin (0.1-10 micrograms) produced a dose-related increase in the frequency of duodenal contractions of up to 583% of control. While an increase in jejunal motility was consistently seen with doses of 1 and 10 micrograms, the lowest bombesin dose tested (0.1 microgram) produced a significant decrease in the frequency of contractions in this intestinal area. The intestinal motor effects were seen within the first 30 min after the peptide, and lasted for at least 1 h. Intraperitoneal administration of bombesin, at doses 200 times higher than those given centrally, failed to significantly alter intestinal motility at either recording site. Whether all of the complex intestinal motor effects of bombesin can be directly related to its centrally initiated inhibitory transit effect is unclear; however, the stimulation of contraction frequency in the duodenum at all doses tested suggest that the antitransit effects of bombesin may be, in part, the result of either an increase in the frequency of non-propulsive contractions or a disruption of the normal coordinated propulsive motility pattern of the duodenum.

Animals↗
PubMed1985

Centrally-mediated bombesin effects on gastrointestinal motility.

Administration of bombesin into the lateral cerebral ventricle (i.c.v.) of rats results in a dose-related delay in gastric emptying and small intestinal transit. Recordings of intestinal intraluminal pressure in this species show that the i.c.v. peptide produces a dose-related increase in the frequency of duodenal contractions, and a complex inhibitory/excitatory jejunal effect at low and high doses, respectively. Intrathecal (i.th.) or i.c., but not intraperitoneal (i.p.), bombesin produces a dose-related slowing of gastrointestinal and colonic transit in mice. I.c.v. bombesin is 13.5 and 3406 times more potent in inhibition of gastrointestinal transit than when given by the i.th. or i.p. routes, respectively. Similarly, the i.c.v. peptide is 1.54 and over 11000 times more potent in slowing mouse colonic transit than when given by the i.th. or i.p. routes, respectively. The substance P analogue, D-Arg1, D-Pro2, D-Trp7,9, Leu11-Substance P (DAPTL-SP)(a reported bombesin antagonist in vitro) was not effective in blocking the gastrointestinal transit effects of the peptide in vivo. Transection of the spinal cord at the level of the second thoracic vertebra (T2) eliminates the gastrointestinal and colonic effects of i.th., but not i.c.v. bombesin. Thus, bombesin can affect motor function of the gut via activity within the brain or spinal cord of rats and mice; the activity of the peptide when given at the supraspinal level depends on an intact vagus nerve and adrenal-pituitary axis, while the activity of the peptide given at the spinal level appears to depend on the integrity of ascending spinal-supraspinal pathways.

Animals↗
PubMed1985

The proenkephalin A fragment, peptide E: central processing and CNS activity in vivo.

The proenkephalin A derivative, peptide E, delayed gastrointestinal transit in mice and inhibited the micturition reflex in anesthetized rats after intracerebroventricular (i.c.v.) administration. BAM22P, BAM12P and [Met5]enkephalin, possible processing fragments of peptide E, were also compared in the two test systems. Of these peptides, peptide E and BAM 22P were found to have the greatest potency and activity. Studies in vitro of peptide E metabolism by enzyme homogenates of mouse brain using HPLC techniques revealed that peptide E is bound to the membrane homogenate avidly for an extended period of time. The total formation of BAM22P, BAM12P, [Met5]enkephalin and all other peptide fragments during a 40 min incubation period accounted for only 8% of the total peptide E added to the homogenates. Thus, peptide E, rather than one of its known metabolites, appears to be of primary importance in the initiation of CNS-mediated effects. Further, these effects are probably the result of mu-opioid receptor activation.

Animals↗
PubMed1985

Mu, but not kappa, opioid agonists induce contractions of the canine small intestine ex vivo.

The proposed kappa opioid receptor agonists ethylketocyclazocine (EK), nalorphine, bremazocine and U-50,488H were evaluated for their ability to produce contractions of isolated, vascularly perfused canine small intestinal segments. Responses to these agonists were compared to those of morphine and phenazocine, a mu benzomorphan. Morphine (0.04-25 micrograms) and phenazocine (0.01-3.0 micrograms) both produced naloxone-reversible contractions, suggesting that the responses were mediated largely by mu opioid receptors. In contrast, the proposed kappa agonists were ineffective in producing intestinal stimulation, with only EK (1-100 micrograms) showing minimal but significant activity at very high doses. We suggest that the effects of EK may be mediated through mu opioid receptors and that kappa receptors appear not to be involved in the contractile response of the dog small intestine to opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

Studies in vivo with ICI 174864 and [D-Pen2, D-Pen5]enkephalin.

We studied the in vivo pharmacology of a selective agonist (DPDPE) and a selective antagonist (ICI 174864) at delta opioid receptors. ICI 174864 (10 micrograms icv) caused postural abnormalities, barrel rotation and hypothermia in rats. DPDPE induced behavioural arousal (at 75 micrograms icv) and barrel rotation (at 125 micrograms) in rats. ICI 174864 (10 micrograms icv) attenuated acetic acid induced writhing in mice. This action was antagonized by naloxone (10 but not 2 mg/kg s.c.). A lower, non-agonist dose of ICI 174864 (5 micrograms) antagonized DPDPE (3 micrograms icv) in this test without affecting DAGO (0.0006 micrograms icv), a selective agonist at mu receptors. In the mouse tail flick test, ICI 174864 (10-50 micrograms icv) did not significantly antagonize the agonist actions of DPDPE (40 micrograms icv) or DAGO (0.3 micrograms icv). At 10-50 micrograms icv, ICI 174864 had no marked effect on gastrointestinal transit in mice. ICI 174864 (25 micrograms icv or 20 mg/kg s.c.) did not interact with mu opioid receptors in mice rendered physically dependent on morphine.

Analgesics↗