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Biomedical subjects

J Donnerer

Publications and source records attributed to J Donnerer.

At least 19 recordsLinked to original sources
PubMed1996

Stimulation by nerve growth factor of neuropeptide synthesis in the adult rat in vivo: bilateral response to unilateral intraplantar injections.

Unilateral intraplantar injections (1/day for 3 days) of 4 mu g nerve growth factor (NGF) into the rat hindpaw increased the expression of prepro-tachykinin (PPT)- and prepro-calcitonin gene-related peptide (ppCGRP)-mRNA in bilateral L5 dorsal root ganglia (DRGs). This was accompanied by an increase of CGRP-like immunoreactivity in the ipsi- and contralateral sciatic nerve but by no detectable change of CGRP-IR in other afferents. NGF injections into the skin of one ear or into the plantar side of one forepaw increased CGRP-IR in the respective afferents (trigeminal ganglion, or nerves arising from the brachial plexus, respectively), but had no effect on sciatic CGRP-IR. This suggests that the NGF-induced symmetrical increase of CGRP synthesis in L5 DRGs was not caused by systemic action of NGF, which, therefore, may be a useful tool to further investigate mechanisms which are responsible for contralateral effects of unilateral inflammation.

Animals↗
PubMed1995

Histamine-induced edema in the rat paw--effect of capsaicin denervation and a CGRP receptor antagonist.

Histamine is known to cause edema and excitation of small-diameter primary afferent neurons. In the present study we wanted to investigate to which extent afferent neurons participate in histamine-induced edema and, subsequently, determine possible inhibitory effects of a tachykinin NK1 receptor and CGRP receptor antagonist on the histamine response. Intraplantar injection of histamine (0.5 mumol) into the rat hind paw caused a 34% increase of paw volume. In capsaicin-denervated rats, this effect of histamine was nearly abolished. The calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37), but not the tachykinin NK1 receptor antagonist SR140333, caused significant inhibition of the edema response. Further indication that CGRP can promote the histamine action was obtained in capsaicin-denervated rats, where co-injection of CGRP (0.3 pmol) increased the edema response to intraplantar histamine. In additional experiments, plasma protein extravasation in the paw skin was evaluated after close arterial infusion of histamine. Also in these experiments CGRP-(8-37), but not SR140333, significantly reduced the histamine effect. The observation that in the rat hind paw a CGRP receptor antagonist, but not a tachykinin NK1 receptor antagonist, attenuates histamine-induced vascular leakage raises the possibility that in some tissues CGRP receptor antagonists may be superior to tachykinin NK1 receptor antagonists in reducing histamine-induced neurogenic inflammatory responses.

Animals↗
PubMed1995

The non-peptide NK1 receptor antagonist SR140333 produces long-lasting inhibition of neurogenic inflammation, but does not influence acute chemo- or thermonociception in rats.

In anaesthetized rats, the neurokinin (NK)1 receptor antagonist SR140333 (10-1000 micrograms/kg) stereo-selectively inhibited mustard oil-induced plasma protein extravasation in the dorsal skin of the hind paw. After s.c. administration of SR140333, inhibition of plasma protein extravasation was maximal 3 h after injection. A dose of 0.1 mg/kg i.v. or 1.0 mg/kg s.c. produced long-lasting inhibition which was still significant 24 h after treatment. Since systemic administration of SR140333 has been shown to inhibit nociceptive responses in anaesthetized rats, we wanted to evaluate a possible effect of SR140333 on chemo- and thermonociception in conscious rats. SR140333 (100 micrograms/kg s.c.) did not reduce the behavioral response of rats to the irritant effect of capsaicin in the wiping test, nor did it affect the thermal nociceptive threshold in the plantar test. Furthermore, the decrease in thermal nociceptive threshold which was produced by intraplanter injection of PGE2, and which has been shown to be entirely dependent on capsaicin-sensitive afferents, was not affected by treatment with this NK1 receptor antagonist. These results show that systemic administration of SR140333, at doses which cause inhibition of neurogenic inflammation, has no detectable effect on acute chemo- or thermonociception in conscious rats.

Animals↗
PubMed1995

Stereoselective increase of plasma concentrations of the enantiomers of propranolol and atenolol during exercise.

OBJECTIVE: In vitro studies have shown that, like catecholamines, both propranolol and atenolol are taken up by and released from adrenergic cells. We performed this study to investigate whether this may also play a role in humans and whether stereoselective aspects are important. METHODS: This was a randomized, double-blind, placebo-controlled, crossover study of two groups of 12 healthy volunteers. Subjects received single oral doses of 80 mg (R,S)-, 40 mg (R)-, and 40 mg (S)-propranolol; 100 mg (R,S)-, 50 mg (R)-, and 50 mg (S)-atenolol; and placebo at intervals of 1 week. Exercise was performed at 4 and 9 hours after drug intake, and blood samples were taken before and at the end of each exercise period. The plasma concentrations of the (R)- and (S)-enantiomers of propranolol and atenolol, as well as those of epinephrine and norepinephrine, were determined by HPLC. RESULTS: Effects of exercise on the plasma levels of the enantiomers of propranolol and atenolol were similar. When the optically pure enantiomers were administered, exercise caused a marked and significant increase of the plasma concentrations of the (S)- but not of the (R)-enantiomers. When the drugs were administered in the racemic form, the plasma levels of both the (R)- and (S)-enantiomers were elevated to the same extent. The increase of norepinephrine levels during exercise was more pronounced than that of epinephrine and paralleled that of the (S)-enantiomers of the beta-blockers. CONCLUSION: Bearing the in vitro data in mind, we conclude that (S)-propranolol and (S)-atenolol are taken up into and released from adrenergic cells together with norepinephrine during exercise. The reason why the plasma concentrations of (R)-propranolol and (R)-atenolol are increased only during exercise in the presence of the corresponding (S)-enantiomers remains to be determined.

Administration, Oral↗
PubMed1995

Neuroantibodies: ectopic expression of a recombinant anti-substance P antibody in the central nervous system of transgenic mice.

Recombinant antibodies are efficiently secreted by cells of the nervous system. Thus, their local expression in the CNS of transgenic mice could be used to perturb the function of the corresponding antigen. As a first application of this approach, we have generated transgenic mice that express antibodies against the neuropeptide substance P, under the transcriptional control of the promoter of the neuronal gene vgf. The transgenic antibodies are expressed in a tissue-specific and developmentally regulated manner and are effective in competing with the endogenous substance P, as demonstrated by a marked inhibition of neurogenic inflammation and by motor deficits. This phenotypic knockout approach may provide a complementary alternative to gene knockout by homologous recombination.

Animals↗
PubMed1994

Human and rat primary C-fibre afferents store and release secretoneurin, a novel neuropeptide.

Secretoneurin is a recently discovered neuropeptide derived from secretogranin II (SgII). Since this peptide could be detected in the dorsal horn of the spinal cord we studied whether it is localized in and released from primary afferent neurons. Secretoneurin was investigated with immunocytochemistry and radioimmunoassay in spinal cord, dorsal root ganglia and peripheral organs. SgII mRNA was determined in dorsal root ganglia. Normal rats and rats pre-treated neonatally with capsaicin to destroy selectively polymodal nociceptive (C-) fibres were used. Slices of dorsal spinal cord were perfused in vitro for release experiments. Immunocytochemistry showed a distinct distribution of secretoneurin-immunoreactivity (IR) in the spinal cord and, lower brainstem. A particularly high density of fibres was found in lamina I and outer lamina II of the caudal trigeminal nucleus and of the spinal cord. This distribution was qualitatively identical in rat and human post-mortem tissue. Numerous small diameter and some large dorsal root ganglia neurons were found to contain SgII mRNA. Capsaicin treatment led to a marked depletion of secretoneurin-IR in the substantia gelatinosa, but not in other immunopositive areas of the spinal cord and to a substantial loss of small (< 25 microns) SgII-mRNA-containing dorsal root ganglia neurons. Radioimmunoassay revealed a significant decrease of secretoneurin-IR in the dorsal spinal cord, the trachea, heart and urinary bladder of capsaicin-treated rats. Perfusion of spinal cord slices with capsaicin as well as with 60 mM potassium led to a release of secretoneurin-IR. In conclusion, secretoneurin is a neuropeptide which is stored in and released from capsaicin-sensitive, primary afferent (C-fibre) neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Neonatal capsaicin treatment does not prevent splanchnic vasodilatation in portal-hypertensive rats.

It has been suggested that the peripheral sensory neurons are involved in the splanchnic hemodynamic changes of portal hypertension. Therefore the influence of permanent ablation of sensory neurons by neonatal capsaicin pretreatment (50 mg/kg, subcutaneously) on the development of the hyperdynamic splanchnic circulation in portal-hypertensive rats was studied. In adulthood, portal hypertension was induced with partial portal vein ligation. In study 1, systemic and splanchnic hemodynamics were measured by means of a radiolabeled-microsphere technique in portal-hypertensive rats, under ketamine anesthesia, pretreated with capsaicin or vehicle. Mean arterial pressure, heart rate, cardiac index, systemic and splanchnic vascular resistance, portal pressure, portal venous inflow, portal-collateral resistance and portal-systemic shunting were not significantly different between capsaicin-pretreated and vehicle-pretreated rats. In study 2, gastric mucosal blood flow, measured by means of hydrogen gas clearance, and the hemoglobin and oxygen content of the gastric mucosa, as assessed with reflectance spectrophotometry, were not significantly different in the two groups of anesthetized portal-hypertensive rats pretreated with capsaicin or vehicle. In study 3, we confirmed the effectiveness of neonatal capsaicin pretreatment by measuring calcitonin gene-related peptide content of the gastric corpus wall. Capsaicin pretreatment caused a depletion of calcitonin gene-related peptide by at least 98% compared with that in vehicle-pretreated rats. These results do not support a role of capsaicin-sensitive sensory neurons that innervate the gastrointestinal tract in the development of the splanchnic vasodilatation characteristically observed in chronic portal hypertension.

Animals↗
PubMed1994

Bradykinin-induced sensitization of afferent neurons in the rat paw.

Determination of the thermal nociceptive threshold in the rat hind paw was used to investigate the participation of postganglionic sympathetic neurons and of capsaicin-sensitive afferent neurons to bradykinin-induced thermal hyperaesthesia. Intraplantar injection of 0.5 microgram bradykinin or of 0.3 microgram prostaglandin E2 significantly lowered paw withdrawal latencies, whereas injection of [des-Arg9]bradykinin was ineffective. The B-2 receptor antagonist HOE 140 (0.1 mg/kg) prevented bradykinin- but not prostaglandin E2-induced thermal hyperaesthesia. While morphine (1 mg/kg) antagonized the effect of bradykinin and prostaglandin E2, indomethacin (10 mg/kg) reduced only bradykinin-induced sensitization. Although this can be taken as indication that bradykinin-induced sensitization of heat-sensitive fibres is mainly mediated via local prostanoid formation, we failed to obtain evidence for an involvement of sympathetic postganglionic fibres in this process: chemical sympathectomy, which lowered the tissue concentration of noradrenaline by more than 90%, did not influence the ability of bradykinin to induce a decrease in thermal nociceptive threshold. The target of bradykinin/prostaglandin E2 action seemed to be capsaicin-sensitive afferents, since in rats which had been treated with capsaicin to destroy this group of afferents, both substances were completely ineffective in producing sensitization. We suggest therefore that in the rat paw, bradykinin, independently from sympathetic postganglionic neurons, lowers the thermal nociceptive threshold mainly via B-2 receptor-mediated formation of cyclo-oxygenase products which, in turn, act exclusively on capsaicin-sensitive afferent neurons.

Animals↗
PubMed1992

Time-course of capsaicin-evoked release of calcitonin gene-related peptide from rat spinal cord in vitro. Effect of concentration and modulation by Ruthenium Red.

The capsaicin-evoked release of calcitonin gene-related peptide (CGRP) from rat superfused dorsal spinal cord slices was investigated during sustained capsaicin exposure thought to represent equilibrium conditions. The dose-effect relationship for total peptide release evoked by single capsaicin doses (26 min exposure) was very steep with a threshold at 0.06 microM and a maximum at 0.3 microM capsaicin. With concentrations of capsaicin within this range the slow decline of the peptide release in the presence of capsaicin was not a consequence of exhaustion of an available peptide pool nor of neuronal impairment because potassium depolarization was still able to release CGRP. In contrast, with concentrations of capsaicin at 1.5 microM and above, there was a much faster decay of the release after the peak, most probably due to a loss of the secretion capacity caused by neuronal inactivation. When cumulative dose regimens for capsaicin were employed, release of CGRP could be stimulated only up to a dose of 1-1.5 microM capsaicin; further increase in capsaicin concentration was ineffective. This was also most probably due to a loss of the secretion capacity caused by neuronal inactivation and not caused by depletion of a releaseable peptide pool. Release of CGRP evoked by capsaicin concentrations in the range of 0.1-0.3 microM in either dosage protocol was reduced in the presence of Ruthenium Red (RR, 2.5 microM). RR did not reduce neuropeptide release evoked by capsaicin concentrations at or above 1-1.5 microM, nor did it affect the inactivation of the release process at such high capsaicin concentrations. The results demonstrate that, upon sustained exposure to capsaicin, different ranges of concentration can be established at which either only stimulatory or a mixture of stimulatory and inhibitory effects determine the amount of neuropeptides released.

Animals↗
PubMed1992

CP-96,345, a non-peptide antagonist of substance P: II. Actions on substance P-induced hypotension and bronchoconstriction, and on depressor reflexes in mammals.

In order to extend the in vivo pharmacological profile of CP-96,345 ((2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl)- methyl)-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride), a non-peptide antagonist of substance P, the compound was tested against substance P-induced effects on blood pressure in rabbits and on respiration pressure in guinea-pigs. In addition, CP-96,345, and its inactive (2R,3R)-enantiomer, CP-96,344, were also tested in 2 models involving presumably substance P-mediated reflexes in the rat. The fall in blood pressure evoked by i.v. injections of substance P in the rabbit was inhibited by 0.3 mumol kg-1 CP-96,345 i.v. for at least 30 min, and almost abolished, for at least 2 h, by 3 mumol kg-1. In guinea-pigs, the bronchoconstriction induced by i.v. injections of substance P, but not that in response to histamine or bradykinin, was inhibited by CP-96,345 (0.6 and 6.0 mumol kg-1, i.v.) in a dose-dependent manner and this inhibition lasted for 40 min and 70 min, respectively. CP-96,345 (3-20 mumol kg-1, i.v.) reduced depressor reflexes in response to stimulation of peripheral capsaicin-sensitive neurones in the rat. However, the inhibition was not dose-dependent and was also seen with the inactive enantiomer, CP-96,344. This effect can hardly be attributed to receptor-specific effects of CP-96,345 and may be related to unspecific actions such as those involved in the cardiac depression exhibited by both enantiomers. The present results show that CP-96,345 is a potent antagonist of substance P in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

CP-96,345, a non-peptide antagonist of substance P. III. Cardiovascular effects in mammals unrelated to actions on substance P receptors.

The cardiovascular effects of CP-96,345, a non-peptide antagonist of substance P, were analyzed in vivo and in vitro. In the anaesthetized rat, the i.v. injection of 3 mumol kg-1 of CP-96,345 induced a fall in mean arterial blood pressure and a reduction in heart rate. Similar effects were obtained with the enantiomer CP-96,344 (2R,3R)-cis-isomer of CP-96,345) which does not interact with substance P receptors. Both enantiomers, at a concentration of 10 microM, decreased the beating frequency of the isolated atria and of the isolated perfused heart of the guinea-pig to a similar extent, and caused transient coronary dilatation. CP-96,345 (10 microM) decreased the spontaneous sinus rate, prolonged the atrioventricular-nodal conduction interval and the His-bundle conduction interval of the perfused guinea-pig heart. The intraventricular spread of conduction was markedly inhibited. During programmed stimulation 10 min after the beginning of the drug application, the effective refractory periods evaluated by stimulation with premature beats, as well as rate dependent effective refractory periods, of the atrioventricular node, of the atrial and of the ventricular myocardium, were prolonged. Sinus node recovery time was also prolonged. It was concluded that these cardiac effects of CP-96,345 were not caused by an action of the compound on substance P receptors.

Anesthesia↗
PubMed1992

Effect of noradrenergic denervation by neonatal DSP-4 on peptide neurotransmitter systems in the rat brain.

The specific effects of a neonatal treatment of rats with the noradrenergic neurotoxin DSP-4 were investigated in the adult rat by measuring monoamine and peptide transmitter levels in eight brain regions. When applied concomitantly with a 5-hydroxytryptamine uptake blocker, neonatal DSP-4 induced a selective depletion of noradrenaline (NA) in cortex, hippocampus and amygdala. An increase of NA was observed in the medulla and substantia nigra/ventral tegmental area and a decrease in dopamine was observed in the thalamus. The vasoactive intestinal polypeptide levels were markedly elevated in the DSP-4 treated rats in almost all CNS regions whereas those of three other neuropeptides remained unchanged. It is concluded that certain adaptational changes can be observed in the peptide systems of the CNS upon disruption of the development of the noradrenergic innervation.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo.

The responses of sensory neuropeptides during unilateral, Freund's adjuvant-induced, paw inflammation in the rat were examined. After five days of inflammation, the substance P and calcitonin gene-related peptide content in the sciatic nerve supplying the inflamed paw were increased by 60-75% when compared with the contralateral side. At this time-point, there was also a 30-40% increase in the substance P and calcitonin gene-related peptide content of the dorsal root ganglia (L4-L6), and a 40% increase in the calcitonin gene-related peptide content of the L4-L6 segments of the dorsal spinal cord on the inflammation side. In the dorsal root ganglia, calcitonin gene-related peptide content was also increased as early as 12 h and 48 h after induction of paw inflammation. On day 5 of inflammation, the axonal transport of both sensory neuropeptides towards the inflamed paw, as determined after sciatic nerve ligation, was also markedly increased as compared with the control side. Despite this increased transport, the amount of substance P and calcitonin gene-related peptide present in the inflamed paw itself was either reduced or remained unchanged from day 1 through to day 5 of inflammation pointing towards reduced storage and increased release of the peptides in the inflamed tissue. Nerve growth factor content was markedly increased in the sciatic nerve of the inflamed paw with a peak of +136% at time-point 24 h after induction of inflammation. When rats were systemically treated with anti-nerve growth factor serum, the increase in neuropeptide content in the sciatic nerve of the inflamed paw (day 5) was prevented. On the other hand, local injections of nerve growth factor for 5 days into a noninflamed paw were able to induce an increase in substance P and calcitonin gene-related peptide content in the supplying sciatic nerve. These findings point towards a regulatory function for nerve growth factor in vivo in the stimulation of sensory neuropeptide synthesis during prolonged inflammatory processes.

Animals↗
PubMed1992

The non-peptide tachykinin antagonist, CP-96,345, is a potent inhibitor of neurogenic inflammation.

1. Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C-fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP-96,345, a non-peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat. 2. Intravenously (i.v.) injected CP-96,345 (0.4-3.0 mumol kg-1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose- and time-dependent manner, but did not affect that elicited by the non-tachykinin peptides calcitonin gene-related peptide and vasoactive intestinal polypeptide. 3. Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP-96,345 (3.0-9.0 mumol kg-1, i.v.). Furthermore, CP-96,345 was orally active in blocking mustard oil-induced plasma extravasation with an ED50 of 10 mumol kg-1. 4. The inhibition of substance P-induced vasodilatation and of neurogenic plasma extravasation by CP-96,345 was stereospecific as the inactive isomer CP-96,344 (2R, 3R enantiomer of CP-96,345) had no effect. 5. Thus CP-96,345 is a specific, highly potent, long-acting and orally active inhibitor of tachykinin-mediated neurogenic inflammation.

Animals↗