RP 67580, a non-peptide substance P antagonist, inhibits neurogenic inflammation and possesses antinociceptive activities in rodents

Moussaoui, Saliha; Carruette, A.; Montier, F.; Garret, C.

doi:10.1016/0143-4179(92)90455-6

Cited by 8 publications

(6 citation statements)

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“…Racemic RP67580 exhibited a selective antinociceptive profile in writhing and formalin paw tests but was not active in thermal or mechanical screens. These findings confirm and extend those of Garret et al (1991) and Moussaoui et al (1992). The doses required to induce antinociceptive effects in the mouse writhing and formalin paw tests in the present study were somewhat higher (10mgkg-', s.c.) than those reported by previous investigators (0.07-3.5 mg kg-'; Garret et al, 1991).…”

Section: Discussionsupporting

confidence: 93%

Antinociceptive activity of NK₁ receptor antagonists: non‐specific effects of racemic RP67580

Rupniak

Boyce

Williams

et al. 1993

British J Pharmacology

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1 Release of substance P in the dorsal horn is considered a primary event in the perception of pain. The profile of racemic RP67580, a non-peptide antagonist at the NK, (substance P) receptor, was examined in a range of antinociception tests on rodents.2 At doses up to 30 mg kg-', s.c. racemic RP67580 exhibited antinociceptive activity in writhing and formalin paw tests in mice and gerbils. Acetic acid induced writhing and the licking response to formalin were reduced to 40-50% of the level observed in vehicle-treated animmls (P <0.05). However, this agent was not. active in mouse tail flick, rat paw pressure or rat and giea-pig formalin paw tests.3 Like racemic RP67580, the calcium channel blockers nifedipine (30 mg kg-', i.p.) and verapamil (10 or 20mg kg-', s.c.) inhibited the response to formalin by approximately 60% in gerbils (P<0.05 compared with vehicle-treated animals). 4 Evidence for calcium channel antagonist activity of RP67580 was obtained in itro. Racemic RP67580 inhibited calcium entry into depolarized strips of guinea-pig ileum longitudinal muscle myenteric plexus (apparent KB = 587 ± 115 nM), inhibited [3H]-diltiazem binding to rabbit skeletal membranes (ICy, = 298 nM) and depressed high threshold calcium curren-ts in neurones cultured from rat cortex (10% inhibition at 10riM).5 These findings indicate that the acute antinociceptive effects of RP67580 may not be attributable to a specific interaction with NK, receptors and may be mediated via calcium channel blockade.

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Section: Discussionsupporting

confidence: 93%

Antinociceptive activity of NK₁ receptor antagonists: non‐specific effects of racemic RP67580

Rupniak

Boyce

Williams

et al. 1993

British J Pharmacology

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“…Recently, RP 67580, a perhydroisoindolone derivative, and CP-96,345, a quinuclidine derivative, were reported to be non-peptide NKI-receptor antagonists that both act competitively on NK,-receptors (Garret et al, 1991;Snider et al, 1991). Moreover, RP 67580 (3aR, 7aR) and CP-96,345 were reported to be antinociceptive agents in rodents (Garret et al, 1991;Yamamoto & Yaksh, 1991;Moussaoui et al, 1992a). We previously showed that RP 67580, but not its enantiomer RP 68651 (3aS, 7aS), inhibits plasma extravasation induced in rat skin by electrical stimulation of the saphenous nerve (Garret et al, 1991), and induced by NKI-receptor agonists in rat urinary bladder (Moussaoui et al, 1992a Lembeck & Holzer (1979).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, RP 67580 (3aR, 7aR) and CP-96,345 were reported to be antinociceptive agents in rodents (Garret et al, 1991;Yamamoto & Yaksh, 1991;Moussaoui et al, 1992a). We previously showed that RP 67580, but not its enantiomer RP 68651 (3aS, 7aS), inhibits plasma extravasation induced in rat skin by electrical stimulation of the saphenous nerve (Garret et al, 1991), and induced by NKI-receptor agonists in rat urinary bladder (Moussaoui et al, 1992a Lembeck & Holzer (1979). Plasma extravasation was visualized with Evans blue as previously described (Garret et al, 1991 20) was given s.c. to 2-day-old rats, and 2 months later, the male rats (200-250 g) were used for neurogenic inflammation studies.…”

Section: Introductionmentioning

confidence: 99%

A non‐peptide NK₁‐receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically

Moussaoui

Montier

Carruette

et al. 1993

British J Pharmacology

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1 The non-peptide neurokinin NKI-receptor antagonist, RP 67580 (3aR, 7aR), a perhydroisoindolone derivative, powerfully reduced plasma extravasation in rat hind paw skin induced by local application of xylene (ID50 = 0.03 mg kg ', i.v.) or capsaicin (ID50 = 0.06 mg kg-', i.v.), or by i.v. injection of exogenous substance P (SP) or septide ([pGlu6,) (IDm = 0.04-0.05 mg kg ', i.v.). RP 67580 (1 mg kg-', i.v.) also abolished capsaicin-induced nasal fluid hypersecretion (by 82 ± 5%). These effects were found to be stereospecific, the enantiomer, RP 68651 (3aS, 7aS), being inactive at lmgkg-', i.v. 2 In rats neonatally treated with capsaicin (50 mg kg-', s.c.), plasma extravasation induced by SP was significantly increased (by 43 ± 7%). RP 67580 (1 mg kg-', i.v.) completely inhibited the SP-induced plasma extravasation in capsaicin neonatally treated-animals, as it did in control animals. This result suggests that RP 67580 acts at the postsynaptic level for the inhibition of plasma extravasation.3 Opioid receptor agonists, ft-(morphine) and ic-(PD-117302) at 10mgkg-', s.c., in contrast to NKI-receptor antagonists, did not inhibit plasma extravasation induced by exogenous SP. They were, however, partially effective against plasma extravasation induced by electrical nerve stimulation (74 ± 4% and 48 ± 9% inhibition at 10 mg kg', s.c. of morphine and PD-1 17302, respectively, compared to 90 ± 3% inhibition obtained with RP 67580, 3 mg kg-', s.c.). These results indicate the presynaptic action of opioid receptor agonists, in contrast to the postsynaptic action of NK,-receptor antagonists for the inhibition of plasma extravasation. 4 Ligature of the saphenous nerve distal to the point of electrical stimulation, local application of lignocaine to the saphenous nerve, neonatal capsaicin pretreatment, and colchicine at very low doses (120 jig kg' day-' given for 3 days) were found to prevent plasma extravasation elicited by electrical nerve stimulation. 5 The foregoing results demonstrate that the non-peptide NK,-receptor antagonist, RP67580, is a potent inhibitor of plasma extravasation induced in skin by NK,-receptor agonists, by local application of chemical irritants (capsaicin or xylene) or by electrical nerve stimulation. Moreover, opioid receptor agonists and colchicine inhibit plasma extravasation induced by electrical nerve stimulation but not that elicited by exogenous SP. Therefore, it is possible to inhibit neurogenic inflammation either at the presynaptic level with opioid receptor agonists and colchicine, or at the postsynaptic level with NK,-receptor antagonists, and that the new non-peptide NK,-receptor antagonists may have a great potential for alleviation of inflammation in various pathological syndromes in man.

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“…Neurogenic inflammation occurs secondary to neuropeptide (substance P [SubP] and calcitonin gene related polypeptide [CGRP]) release from antidromically activated sensory endings (axon reflexes) and is manifested as redness, warmth, and swelling due to increased vascular permeability. The primary receptor for SubP is the NK 1 receptor and great promise appears to exist for NK 1 receptor antagonists based on nonhuman animal assays of nociception 103 . Unfortunately, human trials of NK 1 antagonists have been disappointing with little or no analgesia noted 104 .…”

Section: Agents Blocking Modulation Processesmentioning

confidence: 99%

Pharmacology of Peripheral Analgesia

Ness

2001

Pain Practice

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Pain may begin in the periphery with activation of nociceptor transducers. The present article reviews the pharmacology of drug action at the level of the primary afferent by discussing the following: [1] agents which block transduction processes (vanilloids, sodium ion channel blockers, antiserotonergic agents, antipurinergic agents); [2] agents inhibiting the transducer site (opioids, cannabinoids, alpha adrenergic agents); [3] agents blocking transducer-based modulation processes (anti-inflammatories, antikinin agents, antitachykinins); and [4] agents which block primary afferentrelated modification processes (antineurotrophins). There is a clear role for many of these agents in the treatment of inflammatory pain and they have potential benefits for neuropathic pain with peripheral triggers.

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RP 67580, a non-peptide substance P antagonist, inhibits neurogenic inflammation and possesses antinociceptive activities in rodents

Cited by 8 publications

References 0 publications

Antinociceptive activity of NK₁ receptor antagonists: non‐specific effects of racemic RP67580

Antinociceptive activity of NK₁ receptor antagonists: non‐specific effects of racemic RP67580

A non‐peptide NK₁‐receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically

Pharmacology of Peripheral Analgesia

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RP 67580, a non-peptide substance P antagonist, inhibits neurogenic inflammation and possesses antinociceptive activities in rodents

Cited by 8 publications

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Antinociceptive activity of NK1 receptor antagonists: non‐specific effects of racemic RP67580

Antinociceptive activity of NK1 receptor antagonists: non‐specific effects of racemic RP67580

A non‐peptide NK1‐receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically

Pharmacology of Peripheral Analgesia

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Product

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Antinociceptive activity of NK₁ receptor antagonists: non‐specific effects of racemic RP67580

Antinociceptive activity of NK₁ receptor antagonists: non‐specific effects of racemic RP67580

A non‐peptide NK₁‐receptor antagonist, RP 67580, inhibits neurogenic inflammation postsynaptically