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Biomedical subjects

F Porreca

Publications and source records attributed to F Porreca.

At least 235 records · Page 13Linked to original sources
PubMed1988

Regulation of gastrointestinal function by multiple opioid receptors.

Agonist and antagonist drugs possessing selectivity for individual types of opioid receptors have been employed in vitro and in vivo to determine the mechanisms by which opioids regulate gastrointestinal functions. Selective mu opioid agonists given by intracerebroventricular (i.c.v.) injection, by intrathecal (i.t.) injection, or by peripheral (s.c. or i.v.) injection in rats or mice decreased gastrointestinal transit and motility, inhibited gastric secretion, and suppressed experimentally-induced diarrhea. Selective delta agonists, by contrast, inhibited gastrointestinal transit after i.t., but not after i.c.v. or s.c. administration. Delta agonists also did not alter gastric secretion after i.c.v. or s.c. injection. However, delta agonists exhibited antidiarrheal effects after i.c.v., i.t., or s.c. administration. Kappa agonists given i.c.v. had no effect on gastrointestinal transit in rats or mice or on gastric secretion in rats, but exhibited antidiarrheal effects in mice. The kappa agonist U-50, 488H given peripherally increased gastric acid secretion. Different types of opioid receptors in different anatomical sites influence differently gastrointestinal motility and propulsion, gastric secretion, and mucosal transport. Brain, spinal cord, enteric neural and smooth muscle opioid receptors represent chemosensitive sites for regulation of gastrointestinal function.

Animals↗
PubMed1988

Methodological refinements to the mouse paw formalin test. An animal model of tonic pain.

The formalin tonic pain test has recently been adapted for use in mice. We have observed two problems with this procedure. First, compared to a vehicle control group, the majority of mice injected in a hind paw with dilute formalin exhibited a significant nociceptive response (paw licking), including peaks of activity, well beyond the end of the recommended observation period; and, second, an unacceptably wide variation in response occurred. We report two modifications that eliminate these difficulties: a) extending the observation period to 20-45 min postformalin injection, and b) lightly anesthetizing the mice with ether before injection of formalin into the paw. The modified protocol was tested by evaluating morphine, pentazocine and zomepirac (analgesic A50 values were 2.1, 23.8, and greater than 100 mg/kg, s.c., respectively). An intrathecal or intracerebroventricular injection of saline, given to the lightly anesthetized mouse, did not interfere with the nociceptive behavior; this finding widens the applicability and usefulness of the test. Collectively, these refinements significantly improve the mouse formalin model of tonic pain.

Animals↗
PubMed1988

Dissociation of opioid antinociception and central gastrointestinal propulsion in the mouse: studies with naloxonazine.

The effect of pretreatment with naloxonazine on opioid-mediated antinociception against a thermal stimulus (55 degrees C warm-water tail-flick test) and inhibition of gastrointestinal transit at supraspinal and spinal levels was studied in unanesthetized mice. The mu-selective agonist [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin (DAGO), the delta-selective agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) and the reference mu-acting agonist morphine, all produced antinociception after either i.c.v. or intrathecal(ly) (i.t.) administration. Morphine and DAGO, but not DPDPE, inhibited gastrointestinal transit after i.c.v. administration, whereas all three agonists slowed gut propulsion when given i.t. A single s.c. naloxonazine pretreatment, 35 mg/kg given 24 hr earlier, failed to displace the dose-response line for i.c.v. DPDPE antinociception but produced a marked rightward displacement of the i.c.v. morphine and DAGO dose-response lines for antinociception. In contrast, naloxonazine (35 mg/kg) pretreatment did not alter the antinociceptive effects of i.t. morphine, DAGO or DPDPE. The effects of naloxonazine pretreatment on inhibition of gut propulsion were the converse of those observed for antinociception at supraspinal and spinal sites; naloxonazine had no effect on the antitransit properties of i.c.v. morphine and DAGO but inhibited the antitransit properties of all three agonists when they were given i.t. These results support the view that opioids may produce their supraspinal antitransit effects at a receptor different from that mediating antinociception; morphine and DAGO mediate their antitransit effects at a naloxonazine-insensitive site, whereas their antinociceptive effects are produced at the naloxonazine-sensitive receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Direct dependence studies in rats with agents selective for different types of opioid receptor.

The objective of this study was to describe, quantitate and compare naloxone-induced abstinence syndromes in rats infused centrally (Sylvian aqueduct) with agonists that are currently the most selective for mu [( D-Ala2, MePhe4, Gly-ol5]enkephalin), delta [( D-Pen2, D-Pen5]enkephalin) and kappa (3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]benzeneacetamide) (U-50,488H) opioid receptors, respectively. Morphine, ethylketazocine and dynorphin A served as reference compounds. After 70 hr of infusion from s.c. implanted osmotic minipumps, three levels of abstinence were associated with the injection of naloxone (3 mg/kg s.c.): 1) negligible syndromes (scores of less than 21) were obtained in rats on water or the kappa-directed ligands, U-50,488H and dynorphin A; 2) a low-to-moderate abstinence score (37-38) was recorded with rats receiving [D-Pen2, D-Pen5]enkephalin and ethylketazocine; and 3) a high abstinence score (64-73) was obtained with rats on morphine and DAGO. These results reinforce the concept of developing selective, nonbenzomorphan kappa agonists as clinically useful analgesics and emphasize that, when evaluating new analgesics, high selectivity for delta receptors does not, in itself, guarantee freedom from physical dependence.

Analgesics↗
PubMed1987

Differential antagonism of mu agonists by U50,488H in the rat.

Agonist, and antagonist effects of the proposed kappa opioid agonist, U50,488H (U50) have been studied in an experimental model of seizure activity (flurothyl-induced seizure threshold) (ST) and in the central modulation of spontaneous, volume-induced micturition contractions (bladder motility) (BM) in rats. Intracerebroventricular (i.c.v.) administration of U50 (at the doses tested) did not produce any agonist effect in either ST or in BM. In contrast, i.c.v. administration of [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAGO) or etorphine, agonists with activity at mu opioid receptors, produced an elevation of ST and inhibition of BM. The elevation in ST produced by etorphine (0.004 nmol) was prevented by prior treatment with U50. In contrast, the approximately equieffective elevation in ST resulting from DAGO was not affected by U50 pretreatment. Similarly, pretreatment of rats with U50 antagonized the approximately equieffective BM effects of etorphine, but not those of DAGO. As both DAGO and etorphine are thought to exert their effects via the opiate mu receptor, the results may be consistent with the view that subpopulations of mu receptors exist within the central nervous system; these sites may be differentially associated with the kappa receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

A comparison of the central gastrointestinal antitransit effects of morphine and bombesin in the mouse.

The gastrointestinal motor effects of centrally-given morphine and bombesin were compared in mice. Both compounds produced a dose-related decrease in the propulsion of a marker along the gut when given by the intracerebroventricular (i.c.v.) or intrathecal (i.th.) routes. Co-administration of the same compound by both routes was found to produce a marked increase in potency for morphine, but only a slight increase in potency for bombesin. Isobolographic analysis of the gut effects of these compounds revealed a multiplicative brain-spinal cord interaction for morphine, but an additive interaction for bombesin. These results are consistent with the interpretation that morphine can act at either the level of the brain or the spinal cord, activating independent pathways which ultimately converge to alter gut propulsion. In contrast, spinal bombesin requires communication to supraspinal sites in order for its gut effects to occur, suggesting activation of a common outflow pathway from the central nervous system.

Animals↗
PubMed1987

Opioid delta-receptor involvement in supraspinal and spinal antinociception in mice.

The possibility that the opioid delta-receptor mediates antinociception in tests where heat is the noxious stimulus was investigated using highly selective mu- and delta-agonist and -antagonists. Antinociceptive dose-response curves were constructed for mu ([D-Ala2,NMePhe4,Gly-ol]enkephalin, DAGO; morphine) and delta ([D-Pen2,D-Pen5]enkephalin, DPDPE)-agonists in the absence, and in the presence of the mu non-surmountable antagonist, beta-funaltrexamine (beta-FNA) or the delta-antagonist ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, where Aib is alpha-amino-isobutyric acid). Agonists and ICI 174,864 were given alone in the same intracerebroventricular (i.c.v.) or intrathecal (i.th.) injection to mice 20 min prior to testing in the warm-water (55 degrees C) tail-withdrawal test (+10 min for i.th. DPDPE); beta-FNA was given as a single i.c.v. or i.th. pretreatment dose (20 and 0.01 nM, respectively) 4 h prior to testing. I.c.v. pretreatment with beta-FNA resulted in a rightward displacement of the DAGO and morphine antinociceptive dose-response lines, but failed to displace the i.c.v. DPDPE curve. Similarly, i.th. pretreatment with beta-FNA displaced the i.th. morphine dose-response curve to the right without affecting the i.th. DPDPE antinociceptive dose-response line. ICI 174,864 (1 and 3 micrograms) produced a dose-related antagonism of i.c.v. or i.th. DPDPE, but did not alter the antinociceptive effects of DAGO or morphine given by the same routes. Co-administration of ICI 174,864 (3 micrograms) with i.c.v. morphine in beta-FNA pretreated (but not control) mice resulted in a further rightward displacement of the morphine dose-response line.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Mu antagonist properties of kappa agonists in a model of rat urinary bladder motility in vivo.

The possibility that the kappa agonists, U50,488H, ethylketazocine and tifluadom, might act as opioid antagonists was studied using the inhibition of the anesthetized rat micturition reflex in vivo as a pharmacological endpoint. Intracerebroventricular administration of equieffective doses of the mu agonists [D-Ala2, NMePhe4, Gly-ol]enkephalin (0.01 nmol), [N-MePhe3, D-Pro4]enkephalin (0.03 nmol), morphine (0.08 nmol), normorphine (0.3 nmol), sufentanil (0.002 nmol), etorphine (0.004 nmol), phenazocine (17 nmol) and meperidine (176 nmol) inhibited spontaneous bladder contractions for a duration of approximately 20 to 30 min. Similarly, i.c.v. administration of the delta-selective agonist (D-Pen2, D-Pen5]enkephalin (15 nmol) inhibited the micturition reflex for approximately the same duration. The kappa agonists U50,488H (22 nmol), ethylketazocine (3 nmol) and tifluadom (3 nmol) did not alter bladder activity after i.c.v. administration. Higher doses of ethylketazocine (10 nmol) or tifluadom (20 nmol), but not U50,488H, produced consistent suppression of bladder contractions. Pretreatment of rats (-15 min, i.c.v.) with doses of U50,488H, ethylketazocine or tifluadom which did not produce an agonist effect consistently blocked the inhibitory actions of the mu agonists morphine and normorphine on bladder motility, but failed to antagonize the similar actions of the mu agonists [D-Ala2, NMePhe4, Gly-ol]enkephalin, [N-MePhe3, D-Pro4]enkephalin, phenazocine, meperidine or those of the delta agonist [D-Pen2, D-Pen5]enkephalin. Centrally initiated bladder effects of the mu agonists etorphine and sufentanil were antagonized by U50,488H but unaffected by ethylketazocine or tifluadom. In addition, administration of U50,488H (i.c.v.) during a morphine-induced bladder shutdown resulted in either an immediate recovery of bladder activity or a shortened duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: identification of mu receptor-related functions.

We have shown previously that D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP) produces selective antagonism of mu, but not delta or kappa, opioid receptor-selective ligands in the guinea pig ileum and mouse vas deferens bioassays, and in radioligand binding assays using homogenized rat brains. In the present study we characterized the agonist and opioid antagonist profile of CTP in analgesic (hot-plate test, abdominal stretch test) and in gastrointestinal assays (transit time test) in mice. CTP was a potent antagonist of the supraspinal and spinal analgesic effects of the mu selective agonist [MePhe3, D-Pro4]morphiceptin (PL017) in both assays. The gastrointestinal antitransit actions of PL017 were also antagonized by CTP at both supraspinal and spinal sites. CTP did not alter the effects of the kappa agonist trans-3,4-dichloro-N-methyl-N-(2-(1-pyrolidinyl)cyclohexyl)benz eneacetamine in any test. Surprisingly, CTP also antagonized the analgesia produced by i.c.v. and intrathecal administration of [D-Pen2, D-Pen5]enkephalin (DPDPE), a highly delta selective agonist, in both analgesic tests. Differential antagonism of DPDPE, but not PL017, by the delta selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH in the hot-plate test indicates that PL017 and DPDPE may act at separate receptors to produce analgesia (mu and delta, respectively). In contrast, CTP did not reverse the gastrointestinal antitransit effects of intrathecal DPDPE. Schild analysis of the interactions of CTP with supraspinal mu and delta agonists in the hot-plate test indicated that although CTP antagonized PL017 in a competitive fashion (Schild slope = -1.0), the interaction of CTP with DPDPE was not competitive (Schild slope = -0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1987

Supraspinal and spinal potency of selective opioid agonists in the mouse writhing test.

Three agonists with the highest degree of selectivity available for mu ([D-Ala2,NMePhe4,Gly-ol]enkephalin, DAGO), delta ([ D-Pen2,D-Pen5]enkephalin, DPDPE) and kappa (U-50,488H, U50) opioid receptors were compared for their activity in inhibiting acetic acid-induced writhing in mice. Additionally, three reference agonists for mu (morphine), delta ([ D-Ala2,D-Leu5]enkephalin, DADLE) and kappa (ketocyclazocine, KC) receptors were also studied in this test. The agonists were given directly into the lateral cerebral ventricle (i.c.v.) or into the lumbar spinal subarachnoid space (intrathecal), and the potency of each compound was compared across injection sites and with data previously obtained in a thermal analgesic test (mouse hot-plate test). The rank order of potency for inhibition of writhing after i.c.v. administration was DAGO greater than DADLE greater than morphine greater than DPDPE; KC and U50 showed no significant activity by this route. After intrathecal administration, the compounds inhibited writhing with a rank potency order of DAGO greater than KC greater than morphine = DADLE greater than DPDPE greater than U50. All compounds were more potent in inhibiting writhing at spinal sites than at supraspinal sites; DPDPE and DAGO were 15 and 24 times more potent after intrathecal than after i.c.v. administration, respectively. The proposed delta agonists DPDPE and DADLE inhibited writhing at both spinal and supraspinal sites. Further, although the proposed kappa-acting compounds KC and U50 were effective at relatively low doses at spinal levels, these compounds lacked activity at supraspinal sites at doses not causing sedation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗