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F Porreca

Publications and source records attributed to F Porreca.

At least 217 records · Page 12Linked to original sources
PubMed1990

Modulation of the potency and efficacy of mu-mediated antinociception by delta agonists in the mouse.

Previous reports have shown that [Leu5]enkephalin or [Met5] enkephalin, endogenous delta receptor agonists, or synthetic analogues of these substances, can respectively produce a positive (i.e., increase) or negative (i.e., decrease) modulation of the antinociceptive potency of mu agonists such as morphine; such modulation is believed to be the result of interactions between delta and mu receptors. In spite of these studies showing modulation of mu agonist potency, it is unclear whether delta agonists can similarly modulate the antinociceptive efficacy of mu agonists. This question was addressed by using several levels of nociceptive stimulus intensity in mice. As the nociceptive stimulus intensity increased, the i.c.v. morphine dose-response line was shown to be displaced progressively to the right with decreasing maximal effect (i.e., decreased efficacy) a pattern typical of partial agonists. In contrast, the antinociceptive potency and efficacy of i.c.v. etorphine was unaffected by increasing the stimulus intensity, suggesting that this compound has higher efficacy than morphine in this nociceptive assay. Coadministration of delta opioid agonists produced leftward ([D-Pen2, D-Pen5] enkephalin) or rightward ([Met5]enkephalin) displacement of the morphine dose-response line (i.e., changes in potency). When the delta agonists were coadministered with morphine under conditions of high stimulus intensity, the maximal antinociceptive effects of i.c.v. morphine were increased or decreased from studies with morphine alone (i.e., change in efficacy). Both changes in potency and efficacy produced by the delta agonists, but not the direct antinociceptive effects of morphine, were blocked by the delta antagonist, ICI 174,864, suggesting that modulation occurred via the delta receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1990

Opioid agonist and antagonist antinociceptive properties of [D-Ala2,Leu5,Cys6]enkephalin: selective actions at the deltanoncomplexed site.

The present study used the irreversibly binding enkephalin analog, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) in an effort to determine whether selective agonist and antagonist properties could be demonstrated at hypothesized types of opioid delta receptors previously termed the deltanoncomplexed and the deltacomplexed sites. These putative subtypes of delta receptors have been functionally distinguished on the basis of involvement (i.e., deltacomplexed) in the modulation of mu-mediated effects such as antinociception. Intracerebroventricular administration of DALCE or the reference delta and mu agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and morphine, to mice all produced antinociception in the warm-water tail-flick test in a dose- and time-related manner. Maximal effects with DALCE were seen at +10 min and significant antinociception could be detected for approximately 1 hr; DALCE was 3- and 90-fold more potent than i.c.v. morphine and DPDPE, respectively. The antinociceptive effects of i.c.v. DALCE and DPDPE, but not those of morphine, were antagonized by the selective delta antagonist, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH, suggesting that the antinociception associated with the peptides was mediated through a delta receptor. DALCE pretreatment up to 24 hr before testing, a time at which this compound did not produce antinociception, significantly blocked the i.c.v. DPDPE antinociceptive effect as well as that of DALCE itself, but not that of morphine, suggesting long-lasting DALCE antagonism at a delta receptor. Modulation of morphine antinociception was demonstrated with subeffective doses of i.c.v. DPDPE or [Met5]enkephalin, but not with subeffective doses of i.c.v. DALCE.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1990

Effects of nerve stimulation on ion transport in mouse jejunum: responses to Veratrum alkaloids.

Veratrum alkaloids were used to examine the effect of neural stimulation on intestinal ion transport in full-thickness (intact) and serosally stripped (mucosal) preparations of mouse jejunum. When applied to the serosal media of mucosal preparations, veratrine or veratridine evoked a biphasic increase in transmural potential difference and short-circuit current, consisting of phasic and tonic increases of both bioelectric parameters without a change of tissue conductance; these responses were blocked by pretreatment with tetrodotoxin, but unaffected by pretreatment with atropine, naloxone or yohimbine. In ion flux experiments, neural stimulation of mucosal tissues produced changes of unidirectional fluxes that corresponded with an increase in net Cl- secretion and a reduction of net Na+ absorption, supporting a net secretory role for neurons that were associated with the intestinal mucosa. In intact jejunal preparations, neural stimulation by veratrine or veratridine caused a tetrodotoxin-sensitive reduction of basal transmural potential difference and short-circuit current and a significant increase of tissue conductance. Flux studies on intact tissues failed to reveal the ionic basis for the effects of nerve stimulation by veratridine in these tissues. Nonetheless, the neurally evoked reduction of short-circuit current was attenuated by yohimbine pretreatment, but unaffected by naloxone or atropine, suggesting an involvement of alpha-2 adrenoceptors in the mediation of this effect. These findings demonstrate the existence of endogenous neurotransmitter systems that play opposing roles in the regulation of mucosal ion transport in the small intestine of the mouse.

Action Potentials↗
PubMed1990

Opioid regulation of mucosal ion transport in the mouse isolated jejunum.

Opioid control of mucosal ion transport was examined in intact, full thickness preparations of mouse jejunum in vitro, using standard Ussing chamber techniques. DPDPE and DAMGO were used as selective agonists for delta and mu subtypes of opioid receptors, respectively, whereas U50,488H [trans-(+-)-3,4-dichloro-N-Me-N-[2-(1-pyrrolidinyl]-benzene-acedamid+ ++ e- methanesulfonate] and U69,593 [(5 alpha, 7 alpha, 8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidiny)-1- oxa-spiro-(4,5)-dec-8-yl]-benzeaneacetamide] were used as selective agonists at the kappa-opioid receptor. When added to the serosal medium of intact tissues, DPDPE, DAMGO, U50,488H and morphine, but not U69,593, produced a concentration-dependent reduction of basal transmural potential difference and short-circuit current (Isc), and an increase in tissue conductance. DPDPE was 41-, 341- and 476-fold more potent than DAMGO, U50,488H and morphine, respectively, in producing these effects, although all these compounds were equiefficacious. DPDPE, but not DAMGO, U50,488H or U69,593, caused a similar effect on basal Isc when added to the mucosal medium. Naloxone produced a rightward shift in the concentration-effect curve for DAMGO and DPDPE, yielding distinct Ke values for naloxone of 9.7 +/- 0.5 and 42.9 +/- 7.9 nM, respectively. In contrast, ICI 174,864, a delta-selective antagonist, blocked the Isc response induced by DPDPE but not DAMGO. The Isc response of U50,488H, however, was neither blocked nor reversed by naloxone or ICI 174,864, nor blocked by norbinaltorphimine, suggesting that the response was not mediated via opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Modulation of mu-mediated antinociception by delta agonists: characterization with antagonists.

The functional interactions between supraspinal mu and delta receptors were characterized in the mouse using mu receptor-selective antagonists. The effects of pretreatment with the mu opioid antagonists, beta-funaltrexamine (beta-FNA) and naloxonazine on the modulation of morphine antinociception by the delta agonists [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2,Met5]enkephalinamide (DAMA) were studied. When co-administered in the same i.c.v. injection, a sub-antinociceptive dose of DPDPE consistently and significantly increased the antinociceptive potency of morphine in control animals, while a sub-effective dose of DAMA decreased morphine antinociception; both the respective increase and the decrease of morphine potency by DPDPE and DAMA had been previously shown to be blocked by ICI 174,864, a delta antagonist. Pretreatment of mice with the non-equilibrium mu antagonist beta-FNA 4 h prior to testing, a pretreatment which had no effect on i.c.v. DPDPE or DAMA antinociception, prevented the modulation of morphine antinociception by both DPDPE and DAMA. Pretreatment with the long acting mu 1 antagonist naloxonazine, 24 h prior to testing, failed to affect the modulation of morphine antinociception by either DPDPE or DAMA; such a pretreatment had no effect on the antinociceptive effects of DPDPE or DAMA when given alone. These results provide further support for the concept of a functionally coupled mu-delta receptor complex which is sensitive to antagonism by beta-FNA, but not naloxonazine, and support the notion that subtypes of opioid mu and delta (i.e. complexed and non-complexed) receptors may exist.

Analgesics↗
PubMed1989

Modulation of mu-mediated antinociception by delta agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2,D-Pen5]enkephalin.

The effect of the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) on the antinociception produced by intracerebroventricular (i.c.v.) administration of the mu agonists morphine, [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAGO), [NMePhe3,D-Pro4]morphiceptin (PLO17), beta-endorphin, phenazocine, etorphine and sufentanil was studied in mice. Only the antinociceptive effects of morphine and normorphine were modulated by i.c.v. coadministration of a dose of DPDPE which did not produce any significant antinociception alone. Both the morphine and normorphine dose-response lines were displaced to the left in the presence of DPDPE. The delta-selective antagonist ICI174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH) (where Aib is alpha-aminoisobutyric acid) blocked the modulation of morphine antinociception by DPDPE. ICI 174,864 alone failed to produce either a significant increase or decrease of morphine, phenazocine, etorphine or beta-endorphin antinociception. The results of the present study provide support for the hypothesis that the enkephalins may function to modulate antinociception produced at the mu receptor; such modulation may come about via the existence of an opioid mu-delta receptor complex. The mu receptors existing in such a complex may be selectively activated by morphine and normorphine, but not the other mu agonists studied here. Thus, the enkephalins may function both to directly initiate, as well as to modulate, some forms of supraspinal mu receptor-mediated antinociception.

Animals↗
PubMed1989

Statistical analysis of drug-drug and site-site interactions with isobolograms.

The use of more than one drug to achieve a desired effect has been a common practice in pharmacologic testing and in clinical practice. For example, combinations of analgesics are frequently prescribed with a view to enhancing pain relief and reducing adverse effects. It is also well established that administration of more than one drug may give effects that are greater than, or less than, the additive effect of each drug given individually. A non-mechanistic method of characterizing the effect resulting from the administration of two compounds is the isobologram. It is relatively simple to draw and interpret isobolograms. However, this graphical technique, which employs equieffective concentrations of individual drugs and combinations of these, obtains the concentrations as random variables from concentration-effect data, usually transformed to a parallel line assay. Thus, statistical confidence limits from such assays, as well as from non-parallel designs, must be expressed on the isobologram if this diagram is to establish superadditive, subadditive, or merely additive effects. We now present a detailed statistical analysis of the isobolographic method illustrated with examples of the statistical procedures, a rational basis for selecting proportions of each drug in the combination, and a relatively novel application of the isobolographic concept, i.e., interactions involving different anatomical sites.

Animals↗
PubMed1989

Thermodynamic analysis of the drug-receptor interaction.

Thermodynamic analysis of pharmacologic data potentially offers an insight into the molecular events underlying drug-receptor interactions not obtainable by other techniques. Embodied in thermodynamics are the laws governing the interconvertibility of heat and work and, hence, it is a particularly apt framework for the analysis of the transduction of information from ligand to biological tissue during the initiation of a drug effect. Implicit in thermodynamic analysis of pharmacologic data is quantitative measurement of the driving forces involved in the drug-receptor interaction (in place of less precise terms such as "affinity"). In addition, the cautious interpretation of thermodynamic analysis can give clues to the underlying mechanisms of the drug-receptor interaction that is beyond the resolving power of other parameters, such as the dissociation constant. The present review is an attempt to identify representative reports that have overtly analyzed pharmacologic data with thermodynamic analysis, to summarize the findings within and across studies (particularly regarding enthalpy- versus entropy-driven binding of agonists and antagonists), to point out and address some apparent inconsistencies that can arise, and to consider the application of thermodynamic analysis to data obtained using isolated tissue preparations.

Animals↗
PubMed1989

Can equal pA2 values be compatible with receptor differences?

Situations exist in which pA2 analysis leads to conclusions about receptor differentiation that conflict with those drawn from other convincing lines of evidence. Robert Raffa and colleagues address this issue in its broadest context, particularly in relationship to the concept of accessory binding sites, using the controversy of delta-opioid receptor-mediated antinociception as an example. When the possibility of accessory binding sites is considered, it becomes clear that the finding of equal pA2 values does not necessarily mean action at the same receptor, and that the finding of unequal pA2 values does not necessarily confirm action at different receptors.

Chemical Phenomena↗
PubMed1989

Differential modulation by [D-Pen2, D-Pen5]enkephalin and dynorphin A-(1-17) of the inhibitory bladder motility effects of selected mu agonists in vivo.

The possibility that the delta agonist, [D-Pen2, D-Pen5]enkephalin (DPDPE) and the putative endogenous kappa agonist, dynorphin A-(1-17) could differentially modulate the effects of a group of chemically diverse mu agonists was evaluated using inhibition of volume-induced contractions of the rat urinary bladder as a model of central nervous system opioid receptor function in vivo. Intracerebroventricular administration of equieffective doses of the mu agonists [D-Ala2, NMPhe4, Gly-ol]enkephalin (DAMGO), [N-MePhe3, D-Pro4]enkephalin (PL017), morphine, normorphine, sufentanil, etorphine, phenazocine, meperidine and methadone inhibited spontaneous bladder contractions for approximately 20 to 30 min. Low doses of DPDPE or dynorphin A-(1-17) failed to affect spontaneous bladder contractions; higher doses of DPDPE (greater than 15.5 nmol) and dynorphin A-(1-17) (i.e., greater than 3.7 nmol), inhibited bladder contractions. When coadministered i.c.v., DPDPE displaced the morphine dose-response line to the left and also potentiated the effects of normorphine and etorphine. In contrast, DPDPE failed to alter the actions of equieffective doses of DAGO, PL017, meperidine, methadone, phenazocine or sufentanil. The potentiation of the effects of morphine by DPDPE were prevented by i.c.v. coadministration of the delta antagonist, ICI 174,864 (N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH); at the dose tested, the delta antagonist had no agonist effects alone and did not antagonize the effects of morphine directly. Furthermore, the agonist effects of morphine were potentiated by several different doses of DPDPE. Administration of i.c.v. dynorphin A-(1-17) produced a rightward displacement of the morphine dose-response line and also antagonized the effects of normorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1989

Pharmacological characterization of neural mechanisms regulating mucosal ion transport in mouse jejunum.

Neural regulation of electrolyte transport in mouse jejunum was investigated in vitro using: 1) a full-thickness intestinal segment (intact preparation) and 2) a mucosal preparation, consisting of only mucosa, basement membrane and muscularis mucosa. In Ussing chambers, intact tissues exhibited high- and low-frequency oscillations of basal transmural potential difference (PD) and short-circuit current (Isc), whereas mucosal tissues exhibited only low-frequency oscillation of these parameters. High-frequency oscillations of PD and Isc were found to originate from muscle activity. Under basal conditions, intact tissues exhibited net Na+ absorption and net Cl- secretion, whereas mucosal tissues displayed greater net Na+ absorption and net Cl- absorption. When applied to the serosal medium of intact tissues, tetrodotoxin, a neurotoxin, and chlorisondamine, a ganglionic blocking agent, caused a concentration-dependent reduction of basal PD and Isc, whereas atropine produced no significant effect; these agents were without effect in mucosal tissues. Furthermore, in intact tissues, tetrodotoxin caused significant increases in net Na+ absorption and net residual flux, attaining values that were comparable to those seen in mucosal tissues. Carbachol, a muscarinic agonist, and 1,1-dimethyl-4-phenylpiperizinium, a ganglionic stimulant, elicited concentration-dependent, transient increases of basal PD and Isc when applied to the serosal medium of intact tissues; in mucosal preparations, carbachol elicited greater changes of basal PD and Isc, whereas 1,1-dimethyl-4-phenylpiperizinium produced no significant effect. In intact tissues, Isc responses elicited by carbachol were antagonized by atropine, but not tetrodotoxin or chlorisondamine; Isc responses induced by 1,1-dimethyl-4-phenylpiperizinium, however, were blocked by tetrodotoxin or chlorisondamine, but not atropine. These results support the existence of a multisynaptic, and tonically active neural pathway which serves to limit intestinal Na+ transport at some point below the maximal absorptive capacity of the mucosa. Furthermore, cholinergic muscarinic and nicotinic receptors are present in distinct neural pathways that influence intestinal electrolyte transport in the small intestine of the mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1988

U50,488H differentially antagonizes the bladder effects of mu agonists at spinal sites.

The mu antagonist property of the kappa agonist U50,488H was studied at the spinal level, using motility of the rat urinary bladder as an endpoint in vivo. Intrathecal (i.th.) administration of the mu agonists [D-Ala2,NMePhe4,Gly-ol]enkephalin (DAGO), [N-MePhe3,D-Pro4]enkephalin (PL017), morphine and normorphine, as well as the delta agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), resulted in an equieffective inhibition of volume-initiated contractions of the urinary bladder. In contrast, i.th. administration of U50,488H, a highly selective kappa agonist, had no effect on bladder motility. Pretreatment of rats with i.th. U50,488H prior to agonist administration, blocked the suppression of spontaneous bladder activity induced by equieffective i.th. does of morphine and normorphine, but failed to alter the inhibitory effect of the mu agonists DAGO and PL017, or that of the delta agonist DPDPE. The finding that U50,488H differentially antagonized the identical bladder effects of several mu agonists suggests the presence of mu receptor subtypes (mu isoreceptors) in the rat spinal cord, which may be involved in the regulation of bladder function.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Sites of clonidine action to inhibit gut propulsion in mice: demonstration of a central component.

The role of central (supraspinal and spinal) and peripheral alpha-adrenoceptors in the regulation of gastrointestinal propulsion in the mouse was studied using clonidine, an alpha 2-adrenoceptor agonist. Clonidine produced a dose-dependent inhibition of propulsion when given intracerebroventricularly, intrathecally, or subcutaneously, but was most potent when given intracerebroventricularly. The antitransit effects of centrally given clonidine were antagonized by intracerebroventricular (i.c.v.) yohimbine, but higher doses were required when this antagonist was given peripherally. Whereas i.c.v. and s.c. administration of clonidine were effective in inhibiting gut transit in spinally transected mice, intrathecal (i.th.) administration of this agonist was not. A supraspinal site of clonidine action is suggested based upon (a) the higher central to peripheral potency of clonidine; (b) the greater potency of i.c.v., compared with s.c., administration of yohimbine in blocking i.c.v. clonidine; (c) the lack of effect of i.th. administration of clonidine in spinally transected mice; and (d) the reduced potency of i.c.v., but not s.c., administration of clonidine in spinally transected mice. Additionally, a peripheral site of clonidine action is suggested by (a) the lower potency of i.c.v. yohimbine in blocking s.c., compared with i.c.v., clonidine; (b) the lower potency of i.c.v. yohimbine in blocking i.c.v. clonidine in transected mice (compared with normal mice); (c) the equal potency of s.c. clonidine in slowing propulsion in normal and spinally transected mice; and (d) the equal potency of i.c.v. yohimbine in blocking s.c. clonidine in normal and spinally transected mice. These data in mice would thus support the concept that normal (peripheral) therapeutic administration of clonidine would affect gut motor function by interactions within the brain and directly at the level of the gut.

Animals↗