Action of peptides and other algesic agents on paravascular pain receptors of the isolated perfused rabbit ear

Juan, H.; Lembeck, Fred

doi:10.1007/bf00501142

Cited by 175 publications

(88 citation statements)

References 22 publications

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“…Since the drug has practically no inhibitory activity on arachidonic acid metabolism (Brune, unpublished results; Darius & Schror, 1985), it is unlikely that a non-steroidal antiinflammatory drug-like mechanism would be involved in its antinociceptive action. Moreover, on the isolated perfused ear of rabbits, flupirtine inhibited the pain reaction (fall in blood pressure) (Juan & Lembeck, 1974) to bradykinin over a concentration range far greater than the blood levels observed to reduce nociception in vivo (Schweizer, unpublished results;Hlavica & Niebch, 1985). All previous experimental and human pharmacodynamic results suggest that flupirtine acts centrally and that its mode of action clearly differs from that of opioids.…”

Section: Discussionmentioning

confidence: 99%

Mode of antinociceptive action of flupirtine in the rat

Szelenyi¹,

Nickel²,

Borbe³

et al. 1989

British J Pharmacology

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1 Flupirtine is a novel, centrally acting, non-opioid analgesic agent. The present investigation was undertaken to ascertain which neuronal systems might be responsible for its antinociceptive effect in rodents. The antinociceptive responses to the test compounds were examined in the tail-flick test. 2 The selective destruction of noradrenergic pathways by 6-hydroxydopamine considerably reduced the flupirtine-induced inhibition of nociceptive responses but not the clonidine-induced antinociception which was significantly enhanced. Depletion of spinal 5-hydroxytryptaminergic pathways by pretreatment with 5,7-dihydroxytryptamine failed to affect the action of flupirtine and clonidine.3 The depletion of neurotransmitters by reserpine totally abolished the antinociceptive action of flupirtine. By contrast, clonidine-induced inhibition of nociceptive responses remained unchanged. 4 Inhibition of the synthesis of noradrenaline by a-methyl-L-p-tyrosine attenuated the antinociception induced by flupirtine. In contrast, inhibition of the synthesis of 5-hydroxytryptamine by (±)6-fluorotryptophan did not influence the antinociceptive activity of flupirtine. 5 Inhibition of noradrenaline uptake by imipramine led to a significant augmentation of flupirtine-induced antinociception. 6 Selective antagonists at a-adrenoceptors significantly decreased the antinociceptive action of flupirtine. Antinociception induced by clonidine was significantly diminished by idazoxan but not by prazosin. 7 The 5-hydroxytryptamine (5-HT) antagonist, ketanserin diminished the antinociceptive activity of flupirtine, probably due to its additional a,-adrenoceptor antagonist activity. The antinociceptive effect of clonidine was not influenced by ketanserin.8 Cholinoceptor antagonists such as mecamylamine and pirenzepine did not alter the antinociceptive action of flupirtine. Flupirtine-induced antinociception also remained unchanged after pretreatment with haloperidol. 9 Flupirtine has no pharmacologically relevant affinity for ac-, CX2-adrenoceptors, 5-HT1-and 5-HT2-receptors as shown in direct binding studies. 10 The present results indicate that the antinociceptive action induced by flupirtine depends on the descending noradrenergic pain-modulating system.

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Section: Discussionmentioning

confidence: 99%

Mode of antinociceptive action of flupirtine in the rat

Szelenyi¹,

Nickel²,

Borbe³

et al. 1989

British J Pharmacology

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“…In the preparation used here, the reflex fall in systemic blood pressure depends on the dose of the algogene injected and allows a quantification of the intensity of nociceptor stimulation (Juan & Lembeck, 1974). In the present experiments responses to effective doses of bradykinin (0.024-0.24 nmol) were blocked when injected during an infusion of B43 10 (50 or 500 nM).…”

Section: Pge2mentioning

confidence: 62%

“…Among numerous endogenous substances, bradykinin had by far the highest potency, followed by acetylcholine (Juan & Lembeck, 1974). In the preparation used here, the reflex fall in systemic blood pressure depends on the dose of the algogene injected and allows a quantification of the intensity of nociceptor stimulation (Juan & Lembeck, 1974).…”

Section: Pge2mentioning

confidence: 97%

“…The most suitable of them was then used to measure its inhibitory activity on bradykinin-induced venoconstriction (Guth et al, 1966;Goldberg et al, 1976) and prostaglandin E2 (PGE2) release (Lembeck et al, 1976;Juan, 1977), two actions which contribute to the plasma extravasation caused by bradykinin. In further experiments the specific stimulation of nociceptive sensory neurones by bradykinin (Juan & Lembeck, 1974) was used to investigate the specificity, potency and reversibility of the action of this bradykinin antagonist. Ueda et al (1984) showed, that bradykinin acts directly on the trigeminal substance P-ergic nerve and causes a release of substance P which contracts the isolated iris sphincter.…”

Section: 'Author For Correspondencementioning

confidence: 99%

“…One ear was separated from the head with the exception of the auricular nerve which remained connected to the body. The ear was perfused via the central artery with Tyrode solution to which PGE, was added (final concentration 10 lM) to augment the vascular responses to bradykinin and acetylcholine (Juan & Lembeck, 1974). The infusion rate was 5 ml min-'.…”

Section: Nociceptor Stimulationmentioning

confidence: 99%

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Effect of bradykinin antagonists on bradykinin‐induced plasma extravasation, venoconstriction, prostaglandin E₂ release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit

Griesbacher

Lembeck

1987

British J Pharmacology

100

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Austria1 The inhibition of the bradykinin-induced plasma extravasation by six bradykinin (Bk) antagonists was tested on rabbit skin. All of them showed inhibitory effects without an agonistic action in the doses used. B4310 (Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk) was the most active antagonist and was therefore used in the subsequent experiments. 2 B43 10 (5-500 nM) antagonized the bradykinin-induced reduction of the venous outflow from the rabbit isolated ear in a dose-dependent manner without affecting the arterial vasoconstriction induced by angiotensin II. 3 The bradykinin-induced release of prostaglandin E2 (PGE2) from the perfused rabbit ear was reduced by 63% when B4310 (800 nM) was infused before, during and after the bradykinin injection. 4 Bradykinin was injected into the ear artery of anaesthetized rabbits and the reflex hypotensive response was used as indicator of the nociception. The response was antagonized by a local infusion of B4310 (50 and 500 nM). The antagonism was dose-dependent and reversible. The parallel shift of the dose-response curve to bradykinin suggests a competitive inhibition. However, B4310 did not antagonize acetylcholine-induced nociceptor stimulation. 5 B4310 inhibited bradykinin-induced stimulation of the trigeminal nerve which results in a substance P-mediated contraction of the iris sphincter muscle. A pA2 of 7.59 was calculated. B4310 did not inhibit capsaicin-induced contractions. 6 It is concluded that B4310 inhibits specifically five different actions of bradykinin which are related to its possible pathophysiological role.

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Kinins in the brain

Figueroa

Worthy

Bhoola

1990

Human Psychopharmacology

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Action of peptides and other algesic agents on paravascular pain receptors of the isolated perfused rabbit ear

Cited by 175 publications

References 22 publications

Mode of antinociceptive action of flupirtine in the rat

Mode of antinociceptive action of flupirtine in the rat

Effect of bradykinin antagonists on bradykinin‐induced plasma extravasation, venoconstriction, prostaglandin E₂ release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit

Kinins in the brain

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Action of peptides and other algesic agents on paravascular pain receptors of the isolated perfused rabbit ear

Cited by 175 publications

References 22 publications

Mode of antinociceptive action of flupirtine in the rat

Mode of antinociceptive action of flupirtine in the rat

Effect of bradykinin antagonists on bradykinin‐induced plasma extravasation, venoconstriction, prostaglandin E2 release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit

Kinins in the brain

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Effect of bradykinin antagonists on bradykinin‐induced plasma extravasation, venoconstriction, prostaglandin E₂ release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit