UMLS:C0043167 - FACTA Search

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

Picomol doses of the acetylated derivative of beta-endorphin-(1-31), injected intracerebroventricularly (icv) in mice, reduced the analgesic activity of morphine, etorphine and beta-endorphin-(1-31), while the efficiency of DAGO and DADLE in producing analgesia was enhanced. The effects of the delta agonists DPDPE and [D-Ala2]-Deltorphin II were not altered by this treatment. After alpha N-acetyl beta-endorphin-(1-31) injection, morphine antagonized the analgesia of DAGO. The regulatory effect of alpha N-acetyl beta-endorphin-(1-31) was exhibited when giving the peptide both before (up to 24 h) and after the opioids. Naloxone did not prevent or reverse that modulatory activity; moreover, pretreatment with the acetylated peptide did not change the pA2 value displayed by the antagonist at the mu receptor. The antinociceptive activity of the alpha 2-adrenoceptor agonist clonidine was also increased in mice treated with alpha N-acetyl beta-endorphin-(1-31). The reducing activity of alpha N-acetyl beta-endorphin-(1-31) upon morphine- and beta-endorphin-induced analgesia was not exhibited in mice undergoing treatment with pertussis toxin or N-ethylmaleimide, agents known to impair the function of Gi/Go transducer proteins. However, the enhancing activity displayed by this peptide upon DAGO- DADLE and clonidine-evoked antinociception was still manifested. These results confirm and strengthen the idea of alpha N-acetyl beta-endorphin-(1-31) acting as a non-competitive regulator of mu opioid- and alpha 2-adrenoceptor-mediated supraspinal antinociception. A neural substrate acted on by both receptors (likely Gi/Go transducer proteins) appears to be involved in the effects of that neuropeptide.
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PMID:Further characterization of alpha N-acetyl beta-endorphin-(1-31) regulatory activity, I: Effect on opioid- and alpha 2-mediated supraspinal antinociception in mice. 131 89

Human beta-endorphin 1-31 (beta-END) stimulated low-Km GTPase activity in a concentration-dependent and saturable manner in membranes prepared from the delta opioid receptor-containing hybrid cell line NG108-15 and from the mu opioid receptor-enriched human neuroblastoma cell line SK-N-SH. Naloxone and the delta-selective antagonist, ICI 174,864, blocked the stimulation of the GTPase activity produced by beta-END in NG108-15 cell membranes, whereas only naloxone inhibited the beta-END-induced stimulation in SK-N-SH cell membranes, suggesting that beta-END was acting through both mu and delta opioid receptors. Treatment of the cells with Bordetella pertussis toxin before the preparation of membranes blocked the stimulation of low-Km GTPase by beta-END in both cell lines. Activation of NG108-15 and SK-N-SH low-Km GTPase by beta-END was sodium-dependent, and lithium and potassium were poor promoters of this activation. These results demonstrate that beta-END stimulates the interaction of both mu and delta opioid receptors with B. pertussis toxin-sensitive G-proteins in SK-N-SH and NG108-15 cell membranes, respectively.
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PMID:Effects of beta-endorphin on mu and delta opioid receptor-coupled G-protein activity: low-Km GTPase studies. 132 14

In homogenate of rat olfactory bulb, the opioid receptor agonists beta-endorphin, Leu-enkephalin, and dynorphin A stimulated adenylate cyclase activity in a concentration-dependent manner, with half-maximal effects displayed at 22, 63, and 176 nM, respectively. The maximal stimulation of the enzyme activity corresponded to about a 40% increase of basal activity for all three peptides. Naloxone antagonized the stimulation of beta-endorphin, Leu-enkephalin, and dynorphin A, with pA2 values of 8.0, 7.7, and 8.1, respectively. Kinetic analysis performed with Leu-enkephalin showed that the opioid peptide increased the Vmax of the enzyme, without changing the Km for the substrate Mg-ATP. Moreover, the opioid stimulation was associated with a significant increase of the affinity of the enzyme for Mg2+ activation and occurred in membranes incubated in a Ca2(+)-free medium. Addition of exogenous GTP at micromolar concentrations was absolutely necessary for the detection of the opioid effect. Treatment of olfactory bulbs with cholera toxin did not alter the stimulation of adenylate cyclase by Leu-enkephalin. However, the opioid stimulation disappeared in membranes obtained from bulbs injected with pertussis toxin. These results demonstrate the presence in the brain of a new functional class of opiate receptors coupled to stimulation of adenylate cyclase via a transduction mechanism that is Ca2+ independent and seems to involve a pertussis toxin-sensitive GTP-binding protein.
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PMID:Naturally occurring opioid receptor agonists stimulate adenylate cyclase activity in rat olfactory bulb. 167 23

The effect of intrathecal pertussis toxin on morphine dependence was studied in rats suffering from chronic pain (Freund's adjuvant-induced arthritis). Animals were rendered tolerant-dependent by subcutaneous implantation of 3 pellets of 75 mg morphine base each. In both, normal and arthritic animals, 1 microgram pertussis toxin reduced the analgesia induced by morphine in the tail-flick test. Naloxone (1 mg/kg, s.c.) precipitated a withdrawal syndrome in arthritic animals that was milder in respect to the one produced in normal rats. Pretreatment with pertussis toxin significantly diminished the incidence of withdrawal signs such as jumps, squeak on touch, chattering, ptosis, body shakes and diarrhoea in tolerant-dependent normal rats, while this effect could not be observed in animals suffering from chronic pain. This differential activity of the toxin could be due to the altered tonus of certain neurotransmitter systems that accompanies the chronic situation of pain.
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PMID:Intrathecal pertussis toxin attenuates the morphine withdrawal syndrome in normal but not in arthritic rats. 230 75

We studied the influence of opioid agonists on the release of serotonin (5-HT) elicited by K+ (20 mM) in superfused slices of rat hippocampus. K+-evoked outflow of serotonin was inhibited significantly up to 50% in the presence of the mu-selective agonist [D-Ala2,N-methyl-Phe4,Gly5-ol]enkephalin (DAGO) and of the delta-selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE). U50,488H a selective kappa agonist, at concentrations between 0.1 to 1 microM, produced an inhibition of 5-HT-release lower than that observed in the presence of mu and delta agonists. The delta antagonist ICI 174,864 (N,N-diallyl-Tyr1,Aib2,Aib3)Leu-enkephalin potently inhibited the effect of DPDPE but did not affect the inhibition produced by DAGO. In contrast, the mu-selective antagonist D-Phe-Cys-Tyr-D-Trp-Nle-Thr-Pen-Thr-NH2 at 1 microM significantly reversed the inhibitory effect produced by a maximal dose of DAGO (0.1 microM) but not the corresponding effect produced by a maximal dose of DPDPE (1 microM). Naloxone was a competitive antagonist of DAGO but noncompetitive antagonist of DPDPE. Treatment of hippocampal slices with pertussis toxin did not alter the K+-evoked release of 5-HT but abolished the inhibitory effect of both DAGO and DPDPE.
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PMID:Mu and delta opioid receptors inhibit serotonin release in rat hippocampus. 253 29

The longitudinal muscle-myenteric plexus preparation of the guinea-pig ileum has been employed for the study of the effect of pertussis toxin (IAP) on opioid dependence. Guinea-pigs were treated with IAP (120 micrograms/kg, i.p.) either prior to chronic administration of an opioid or after opioid dependence had been established. The isolated preparations were tested in vitro for dependence; that is, the naloxone-precipitated withdrawal contracture. Naloxone almost failed to evoke a sign of dependence in preparations treated with IAP prior to chronic exposure to an opioid. In contrast, IAP failed to affect the withdrawal contracture when applied to an animal after dependence has been established. It is concluded that the Ni-unit, the substrate for IAP, plays a critical function in the development of dependence. The continuous activation of the opioid receptor associated with the development of dependence may induce changes in Ni which in turn prevent the interaction of IAP with its substrate.
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PMID:Opioid dependence prevents the action of pertussis toxin in the guinea-pig myenteric plexus. 405 98

In freshly isolated spinal dorsal horn (DH) neurons (laminae I-IV) of the young rat, the effects of dynorphin A1-17, U-50,488H and U-69,593 on inward currents induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) were studied under whole-cell voltage-clamp conditions. When the cells were clamped to a holding potential of -60 mV, co-application of dynorphin A1-17 (10(-6) M) and AMPA (2 x 10(-5) M) reversibly decreased the peak amplitude of the initial transient component of the AMPA-induced current in 72% of the examined cells. In addition, dynorphin (10 microM) in perforated patch-recordings consistently produced a decrease in the steady-state component of the AMPA response. The depressant effect was concentration-dependent (IC50 = 86 nM) and reversible. The dynorphin A1-17-induced depression of the AMPA response was associated with slowing of the response kinetics, including both a 10-90% rise-time and time constant of decay. The AMPA-induced currents were modulated by dynorphin not only during the co-administration but also after the removal of the peptide. Dynorphin increased the initial peak AMPA current in 42% of the examined cells. Similar as with dynorphin A1-17, the peak amplitude of the AMPA-induced current was reversibly suppressed in the presence of 1 microM U-50,488H and U-69,593 in 75% and 86% of the examined cells, respectively. Naloxone and the kappa 1-selective antagonist norbinaltorphimine (nor-BNI) blocked the initial depressant but not late excitatory effects of dynorphin A1-17 and U-50,488H. This antagonistic effect of naloxone and norbinaltorphimine suggests that the depressant effect of dynorphin A1-17 on the AMPA-activated conductance is a true opioid, probably kappa 1-opioid receptor-mediated event. In contrast, the dynorphin-induced late potentiation of AMPA/KA responses appears to be a non-opioid effect since it was not inhibited by nor-BNI, CTAP and naltrindole, the selective kappa-, mu- and delta-opioid receptor blocking agents, respectively. Pretreatment of DH neurons with pertussis toxin blocked the depressant action of dynorphin A1-17, indicating that a Gi- or Go-type G protein was required for this effect on AMPA-activated currents. Intracellular dialysis with a highly specific peptide inhibitor (peptide 6-22) of the cAMP-activated protein kinase (PKA), and with Rp-cAMPS, prevented the depressant effect of dynorphin A1-17. In addition, staurosporine, a nonselective kinase inhibitor, blocked the dynorphin depression of the AMPA response.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The opioid peptide dynorphin modulates AMPA and kainate responses in acutely isolated neurons from the dorsal horn. 753 29

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+.
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PMID:Opioid effects on contractility, Ca(2+)-transients and intracellular pH in cultured cardiac myocytes. 837 18

This study examined the potential role of testicular opioids, a pertussis toxin (PT)-sensitive G-protein, and phosphodiesterase in mediating the inhibitory effect of immobilization stress on testicular steroidogenesis in adult rats. The experiments were initiated with enriched preparations of Leydig cells, but the stress effect was not sustained in vitro either as a result of the disruption of the morphology of the testis and/or the time required for Leydig cell isolation. Consequently, testicular fragments from control and stressed (3-hour immobilization) rats were used in these experiments. When fragments from stressed rats were incubated for 2 hours in the absence and presence of human chorionic gonadotropin (hCG) (0.1,1, or 10 mlU), testosterone (T) production in response to 1 and 10 mlU hCG was lower (P < 0.05 and 0.01, respectively) than that from control fragments. Basal T secretion did not differ between stressed and control fragments. Naloxone (1, 10, or 100 mu M), did not alter basal or hCG-stimulated T secretion from control fragments, but it normalized the T response to hCG from stressed fragments. Control fragments also showed a reduced T response (P < 0.05) to hCG in the presence of beta-endorphin (beta-E; 36 nM). Incubation of control fragments with PT (30 ng) did not alter basal or hCG-stimulated T production. However, PT normalized (P < 0.01) hCG-stimulated T secretion from stressed fragments. Methylisobutylxanthine (MIX; 0.125 mM) elevated (P < 0.01) hCG-stimulated T production from control fragments, but hCG-stimulated T secretion from stressed fragments remained subnormal in the presence of the phosphodiesterase inhibitor. The data suggest that acute immobilization stress inhibits gonadotropin-induced T production in adult male rats via a mechanism involving testicular opioids and a PT sensitive G-protein. We found no evidence to suggest that a stress induced increase in the activity of phosphodiesterase was involved in this mechanism.
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PMID:Mechanism of stress-induced attenuation of the testicular response to gonadotropin: possible involvement of testicular opioids, a pertussis toxin-sensitive G-protein, and phosphodiesterase. 883 36

Activation of kappa receptors inhibits adenylate cyclase, enhances K+ conductance and reduces Ca++ conductance via pertussis toxin-sensitive G proteins. We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined. The presence of GDP and Mg++ was essential for the kappa agonist (-)-U50,488H-induced increase in [35S]GTPgammaS binding to be observed and the optimal concentration was 3 microM and 5 mM, respectively. The presence of 100 mM Na+ was necessary to produce the maximal signal-to-background ratio. (-)U50,488H-induced increase in [35S]GTPgammaS binding was time- and tissue concentration-dependent. (-)U50,488H increased [35S]GTPgammaS binding in a dose-dependent manner with an EC50 of 3.1 nM. (+)-U50,488H had no effect, which indicates that this effect is stereospecific. Naloxone (1 microM) or norbinaltorphimine (10 nM) shifted the dose-response curve of (-)-U50,488H to the right by 100-fold. These results indicate that enhancement of [35S]GTPgammaS binding by (-)-U50,488H is a kappa receptor-mediated event. Pretreatment of the cells with pertussis toxin, but not cholera toxin, abolished the (-)-U50,488H-induced increase in [35S]GTPgammaS binding, which indicates the involvement of Gi and/or Go proteins. [35S]GTPgammaS binding induced by (-)-U50,488H had a Kd value of 0.34 +/- 0.08 nM and a Bmax value of 431 +/- 29 fmol/mg protein. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine. Dynorphin A 1-17, (+/-)-ethylketocyclazocine, (-)-U50,488H, tifluadom and beta-funaltrexamine were full agonists, but nalorphine and pentazocine were partial agonists producing maximal responses of 68% and 23% of those of full agonists, respectively. Nalbuphine and buprenorphine had low levels of agonist activities. Norbinaltorphimine and naloxone were antagonists devoid of activities. Enhancement of [35S]GTPgammaS binding by kappa agonists provides a simple functional measure for receptor activation and can be used for determination of potencies and efficacies of opioid ligands at the kappa receptor.
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PMID:Activation of the cloned human kappa opioid receptor by agonists enhances [35S]GTPgammaS binding to membranes: determination of potencies and efficacies of ligands. 926 30

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