Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of i.c.v. treatment with pertussis toxin (PTX) on the motivational effect of opioid agonists were examined in mice. Morphine (0.1-10 nmol, i.c.v.), [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAGO, 0.001-0.1 nmol, i.c.v.), a selective mu-opioid receptor agonist, and [D-Pen2, D-Pen5]enkephalin (DPDPE, 1-15 nmol, i.c.v.), a selective delta-opioid receptor agonist, produced a dose-related place preference in mice. Administration of PTX (0.5 micrograms, i.c.v.) to mice resulted in no preference for either the drug- or vehicle-associated place. Pretreatment with PTX abolished the place preferences induced by DAGO (0.1 nmol), morphine (10 nmol) and DPDPE (15 nmol). These findings demonstrate that the appetitive effects of opioids result from the activation of central mu- and delta-receptors, and suggest that PTX-sensitive GTP-binding proteins in the central nervous system may be involved in the motivational effects of mu- and delta-opioid agonists.
 ...
PMID:Pertussis toxin abolishes mu- and delta-opioid agonist-induced place preference. 166 84

The present study evaluates the effect of pertussis toxin (PTX) on morphine-induced analgesia and lethality. Mice were injected with 0.2 microgram PTX intracerebroventricularly (i.c.v.) and 0.2 micrograms PTX intrathecally (i.t.) or saline. Mice were tested for morphine-induced analgesia (tail flick) and lethality 16 days later; mice were also examined for pentobarbital-induced mortality. Morphine analgesic potency was decreased by approximately 4-fold in PTX-treated mice compared to controls. Conversely, the lethal potency of morphine was increased by 10-fold in PTX-treated mice compared to controls. PTX treatment did not alter the lethal potency of pentobarbital. Morphine-induced analgesia and lethality were dose-dependently antagonized by naloxone in both PTX and saline-treated groups. The results of this study suggest that morphine analgesia is mediated through PTX-sensitive G proteins. On the other hand, morphine-induced lethality appears to be limited by PTX-sensitive factor(s) since PTX treatment enhanced morphine's lethal potency. The increase in lethal potency of morphine may be due to unmasking of an excitatory opioid receptor mediated effect by PTX.
 ...
PMID:Modification of morphine-induced analgesia and toxicity by pertussis toxin. 203 36

The intradermal injection of mu (morphine, Tyr-D-Ala-Gly-NMe-Phe-Gly-ol and morphiceptin), kappa (trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl) cyclohexyl]benzeneactemide) and delta ([D-Pen2.5]-enkephalin and [D-Ser2]-[Leu]enkephalin-Thr) selective opioid-agonists, by themselves, did not significantly affect the mechanical nociceptive threshold in the hindpaw of the rat. Intradermal injection of mu, but not delta or kappa opioid-agonists, however, produced dose-dependent inhibition of prostaglandin E2-induced hyperalgesia. The analgesic effect of the mu-agonist morphine was dose-dependently antagonized by naloxone and prevented by co-injection of pertussis toxin. Morphine did not, however, alter the hyperalgesia induced by 8-bromo cyclic adenosine monophosphate. We conclude that the analgesic action of opioids on the peripheral terminals of primary afferents is via a binding site with characteristics of the mu-opioid receptor and that this action is mediated by inhibition of the cyclic adenosine monophosphate second messenger system.
 ...
PMID:Involvement of the mu-opiate receptor in peripheral analgesia. 255 56

Pertussis toxin, a substance known to inactivate the inhibitory guanine nucleotide regulatory unit of adenylate cyclase, was injected into the lateral cerebral ventricle of rats; intracellular recordings were made from locus coeruleus neurons in brain slices 1-3 days later. Morphine (an opiate agonist) and clonidine (an alpha 2-agonist) produced the expected outward currents (and associated hyperpolarization and inhibition of firing) in controls whereas the effects of both agonists were blocked in animals pretreated with pertussis toxin. These results are consistent with the hypothesis that opiate and alpha 2-agonists may depress the firing of locus coeruleus neurons by inhibiting adenylate cyclase via a guanine nucleotide regulatory protein.
 ...
PMID:Pertussis toxin blocks the outward currents evoked by opiate and alpha 2-agonists in locus coeruleus neurons. 369 68

The influence of pertussis toxin (PTX) injected intracerebroventricularly (i.c.v., 0.5 micrograms) on the analgesic effect induced in the rat by i.c.v. injection of morphine (5 micrograms) was studied. Morphine analgesia was unaffected 24 h after toxin administration, but there was a significant decrease after 6 days. Therefore a PTX-sensitive substrate, probably a guanine nucleotide regulatory protein could be involved in the coupling of opiate receptors to cellular effectors responsible for the expression of the antinociceptive action of morphine.
 ...
PMID:Pertussis toxin inhibits the antinociceptive action of morphine in the rat. 373 84

Opioid sensitivity of a catecholaminergic cell line (CATH.a) of brainstem origin was examined using whole-cell voltage-clamp techniques. Morphine produced a preferential and concentration-dependent decrease of the amplitude of voltage-activated potassium current, IK (ED50 = approximately 4 microM, maximum inhibition 52%, n = 33). The mu-selective opiate agonist [D-Ala2, MePhe, Gly-ol5] enkephalin (2-20 microM; n = 6) and the delta-selective agonist [D-Pen2, D-Pen5] enkephalin (2-20 microM; n = 7) produced no effect. However, the kappa-selective agonist trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)ben zene-acetamide reduced IK in a concentration-dependent manner (EC50 = 2.3 microM, maximum inhibition 44%, n = 40). The kappa receptor antagonist nor-binaltorphimine (10 nM) blocked the effect of either morphine (10 microM, n = 6) or U50,488 (10 microM, n = 7). Kappa agonist-mediated IK reduction was prevented by intracellular dialysis with an inactive form of guanosine diphosphate, guanosine 5'-O-(2-thio)diphosphate (100-200 microM; n = 10) but was unchanged by incubation with pertussis toxin (500 ng/ml, 24-48 h, n = 10). These results suggest that opioid suppression of IK is mediated by kappa-opioid receptors coupled to a pertussis toxin-insensitive G-protein.
 ...
PMID:Kappa opioid receptor-mediated suppression of voltage-activated potassium current in a catecholaminergic neuronal cell line. 775 97

Morphine, the opioid-agonist, and the antagonists naloxone and levallorphan exerted direct effects on spontaneously-contracting cultures of cardiac myocytes from neonatal rats. Naloxone and levallorphan induced an increase in the amplitude of systolic cell motion (ASM) and in the size of [Ca2+]i-transients, measured as indo-1 fluorescence ratio (IFR), whereas morphine caused an increase in IFR with no change in ASM. Both morphine and naloxone caused a transient increase in 45Ca2+ influx into the cardiomyocytes. Analysis of the relationship between changes in ASM and IFR indicated dual action of the drugs: (a) An increase in [Ca2+]i-transients elicited by morphine and the antagonists, apparently resulting from a transient increase of Ca2+ influx. (b) Altered myofibril responsiveness to Ca2+; the agonists decreased it, and the antagonists increased it. Intracellular pHi measurements in cardiomyocytes loaded with the fluorescent indicator BCECF revealed that morphine caused acidosis and the antagonists caused alkalosis. These pH changes were inhibited by pertussis-toxin, protein kinase inhibitor K323a, phorbol-ester and ethylisopropyl-amiloride, indicating pathways mediated by GTP-binding proteins and altered activities of protein kinase C and Na+/H+ exchanger. Preincubation with pertussis toxin prior to the addition of morphine prevented the decrease in the myofibril responsiveness to Ca2+ as well as the decrease in pHi but did not affect the increase in [Ca2+]i-transients and the increase in the rate of Ca2+ influx. As a result, addition of morphine after preincubation with pertussis toxin caused a positive inotropic effect. Our results indicate that morphine acts by two different pathways distinguishable by their sensitivity to pertussis toxin (1), increased Ca2+ influx leading to increased Ca(2+)-transients and (2) decreased intracellular pH leading to reduced myofibril responsiveness to Ca2+.
 ...
PMID:Opioid effects on contractility, Ca(2+)-transients and intracellular pH in cultured cardiac myocytes. 837 18

Using CHO cells stably transfected with rat mu-opioid receptor cDNA, we show that the mu-agonists morphine and [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin are negatively coupled to adenylylcyclase and inhibit forskolin-stimulated cAMP accumulation. Chronic exposure of cells to morphine leads to the rapid development of tolerance. Withdrawal of morphine or [D-Ala2,N-methyl-Phe4,Gly-ol5]enkephalin following chronic treatment (by wash or addition of the antagonist naloxone) leads to an immediate increase in cyclase activity (supersensitization or overshoot), which is gradually reversed upon further incubation with naloxone. Phosphodiesterase inhibitors do not affect the overshoot, indicating that it results from cyclase stimulation rather than phosphodiesterase regulation. Morphine's potency to inhibit cAMP accumulation is the same before and after chronic treatment, suggesting that the apparent tolerance results from cyclase activation, rather than from receptor desensitization. The similar kinetics of induction of tolerance and overshoot support this idea. Both the overshoot and acute opioid-induced cyclase inhibition are blocked by naloxone and are pertussis toxin-sensitive, indicating that both phenomena are mediated by the mu-receptor and Gi/G(o) proteins. The supersensitization is cycloheximide-insensitive, indicating that it does not require newly synthesized proteins. This is supported by the rapid development of supersensitization. Taken together, these results show that mu-transfected cells can serve as a model for investigating molecular and cellular mechanisms underlying opiate drug addiction.
 ...
PMID:Adenylylcyclase supersensitization in mu-opioid receptor-transfected Chinese hamster ovary cells following chronic opioid treatment. 853 Mar 63

The hypothesis that mu-opioid agonists having low antinociceptive efficacy might be more susceptible to interference with G-protein coupling than mu-opioid agonists having higher antinociceptive efficacy was tested. Supraspinal antinociceptive efficacy for the three mu-opioid agonists morphine, [D-Ala2, NMePhe4, Gly5-ol]-enkephalin (DAMGO) and sufentanil in the mouse 55 degrees C warm-water tail-flick test was evaluated 18-24 h after intracerebroventricular (i.c.v.) administration of beta-funaltrexamine (beta-FNA). The beta-FNA pretreatment (0.2-2.0 nmol) attenuated antinociception in the order morphine > DAMGO > sufentanil, consistent with previous reports of their relative antinociceptive efficacy. The association of efficacy with G-protein coupling was then assessed by determining sensitivity to i.c.v. (0.1-3.0 micrograms) pertussis toxin (PTX) or cholera toxin (CTX). The effect of PTX on equiantinociceptive doses was in the inverse order of agonist efficacy. CTX augmented sufentanil-induced antinociception. Morphine- and DAMGO-induced antinociception were unaffected by CTX. These data suggest that: (i) highly efficacious mu agonists (viz., sufentanil) couple more efficiently to PTX-sensitive inhibitory Gi-proteins than do agonists of lower efficacy (viz., morphine, DAMGO) and (ii) highly efficacious mu agonists have greater capacity to utilize CTX-sensitive stimulatory Gs-proteins than do mu-agonists with lower efficacy.
 ...
PMID:An examination of the relationship between mu-opioid antinociceptive efficacy and G-protein coupling using pertussis and cholera toxins. 904 82

Microglia are important immune effector cells within the brain. The phagocytosis of nonopsonized Cryptococcus neoformans by swine microglia was used as an in vitro model for studies on cellular mechanisms of opiate-mediated immunomodulation in the brain. Morphine inhibited potently (IC50 approximately 10(-16) M) the phagocytosis of C. neoformans by primary cultures of neonatal pig microglia. The mu opioid agonist Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) also suppressed phagocytosis but with a much lower potency than morphine (IC50 approximately 10(-8) M). The inhibitory effects of morphine and DAMGO were blocked by equimolar concentrations of naloxone and by the selective mu opiate receptor antagonist beta-funaltrexamine. Pertussis toxin but not cholera toxin reversed the inhibitory effects of both morphine and DAMGO. Our data suggest that morphine inhibits phagocytosis of C. neoformans by swine microglia via a mechanism involving mu opiate receptors coupled to a pertussis toxin-sensitive Gi/G(o) protein signaling pathway.
 ...
PMID:Inhibition of swine microglial cell phagocytosis of Cryptococcus neoformans by femtomolar concentrations of morphine. 911 3


1 2 3 Next >>