Suppression of carrageenan-induced hyperalgesia, hyperthermia and edema by a bradykinin antagonist

doi:10.1016/0014-2999(89)90118-0

European Journal of Pharmacology

Volume 171, Issues 2–3, 21 November 1989, Pages 259-263

https://doi.org/10.1016/0014-2999(89)90118-0 Get rights and content

Abstract

Although bradykinin (BK) antagonists have antinociceptive effects, they have not been evaluated for anti-inflammatory activity. When administered with carrageenan into the rat hindpaw, NPC567 significantly blocke carrageenan-induced hyperalgesia, hyperthermia and edena. In addition, NPC567 did not alter the in vitro release of immunoreactive BK by plasma kallikrein. These results indicate that the antinociceptive activity of NPC567, a BK antagonist, may be related to its overall anti-inflammatory activity and that is mechanism of action does not include inhibition of plasma kallikrein.

References (10)

K.M. Hargreaves et al.
A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
Pain
(1988)
J. Joris et al.
Local production of immunoreactive bradykinin (iBK) in two models of inflammation
Pain
(1987)
J. Spragg et al.
The inhibition of glandular kallikrein by peptide analog antagonists of bradykinin
Peptides
(1988)
L.R. Steranka et al.
Antinociceptive effects of bradykinin antagonists
European J. Pharmacol.
(1987)
W. Dawson et al.
Inflammation: mechanisms and mediators

There are more references available in the full text version of this article.

Cited by (56)

Peripheral P2X7 receptor-induced mechanical hyperalgesia is mediated by bradykinin
2014, Neuroscience
Citation Excerpt :
Bradykinin is rapidly generated after tissue injury and modulates most of the events observed during the ensuing inflammatory process, including increased vascular permeability, cell migration, nociception and inflammatory hyperalgesia (Marceau et al., 1998; Calixto et al., 2000; Couture et al., 2001). In addition, bradykinin has been highlighted as a key target in models of inflammatory hyperalgesia, as blockade of B receptors inhibits the hyperalgesia induced by carrageenan (Costello and Hargreaves, 1989; Bryan et al., 2012; Gomis et al., 2013), complete Freund’s adjuvant (Ferreira et al., 2001; Fox et al., 2003) and zymosan (Belichard et al., 2000). However, to our knowledge, this is the first demonstration that peripheral activation of P2X7 receptor induces bradykinin-mediated mechanical hyperalgesia.
P2X7 receptors play an important role in inflammatory hyperalgesia, but the mechanisms involved in their hyperalgesic role are not completely understood. In this study, we hypothesized that P2X7 receptor activation induces mechanical hyperalgesia via the inflammatory mediators bradykinin, sympathomimetic amines, prostaglandin E₂ (PGE₂), and pro-inflammatory cytokines and via neutrophil migration in rats. We found that 2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate triethylammonium salt (BzATP), the most potent P2X7 receptor agonist available, induced a dose-dependent mechanical hyperalgesia that was blocked by the P2X7 receptor-selective antagonist A-438079 but unaffected by the P2X1,3,2/3 receptor antagonist TNP-ATP. These findings confirm that, although BzATP also acts at both P2X1 and P2X3 receptors, BzATP-induced hyperalgesia was mediated only by P2X7 receptor activation. Co-administration of selective antagonists of bradykinin B₁ (Des-Arg⁸-Leu⁹-BK (DALBK)) or B₂ receptors (bradyzide), β₁ (atenolol) or β₂ adrenoceptors (ICI 118,551), or local pre-treatment with the cyclooxygenase inhibitor indomethacin or the nonspecific selectin inhibitor fucoidan each significantly reduced BzATP-induced mechanical hyperalgesia in the rat hind paw. BzATP also induced the release of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1), an effect that was significantly reduced by A-438079. Co-administration of DALBK or bradyzide with BzATP significantly reduced BzATP-induced IL-1β and CINC-1 release. These results indicate that peripheral P2X7 receptor activation induces mechanical hyperalgesia via inflammatory mediators, especially bradykinin, which may contribute to pro-inflammatory cytokine release. These pro-inflammatory cytokines in turn may mediate the contributions of PGE₂, sympathomimetic amines and neutrophil migration to the mechanical hyperalgesia induced by local P2X7 receptor activation.
Antinociceptive effect of Nidularium procerum: A Bromeliaceae from the Brazilian coastal rain forest
2005, Phytomedicine
Nidularium procerum, a common plant of the Brazilian flora, has not yet been studied for its pharmacological properties. We report here that extracts of N. procerum show both analgesic and anti-inflammatory properties. Oral (p.o.) or intraperitoneal (i.p.) administration of an aqueous crude extract from leaves of N. procerum (LAE) inhibited the writhing reaction induced by acetic acid (ED₅₀ value=0.2 mg/kg body weight, i.p.) in a dose-dependent manner. This analgesic property was confirmed in rats using two different models of bradykinin-induced hyperalgesia; there was 75% inhibition of pain in the modified Hargreaves assay, and 100% inhibition in the classical Hargreaves assay. This potent analgesic effect was not blocked by naloxone, nor was it observed in the hot plate model, indicating that the analgesic effect is not associated with the activation of opioid receptors in the central nervous system. By contrast, we found that LAE (0.02 μg/ml) selectively inhibited prostaglandin E₂ production by cyclooxygenase (COX)-2, but not COX-1, which is a plausible mechanism for the analgesic effect. A crude methanol extract from the leaves also showed similar analgesic activity. An identical extract from the roots of N. procerum did not, however, block acetic acid-induced writhes, indicating that the analgesic compounds are concentrated in the leaves. Finally, we found that LAE inhibited an inflammatory reaction induced by lipopolysaccharide in the pleural cavity of mice.
Silver nitrate cauterization: Characterization of a new model of corneal inflammation and hyperalgesia in rat
2003, Pain
Chemical cauterization of the central cornea with silver nitrate was assessed as a superficial injury model of tissue sensitization accompanying acute inflammation. Adult male Sprague–Dawley rats were anesthetized with halothane gas, and the centers of their right corneas treated with a silver nitrate applicator stick (75% silver nitrate, 25% potassium nitrate) to produce a discrete lesion 1 mm in diameter.
Edema of the corneal stroma and elevated immune cell counts became significant 4 h after cauterization, and were still evident after 48 h. Behavioral sensitization to chemical stimuli was determined by counting the number of blinks following application of 1 μM capsaicin directly to the corneal surface. A significant increase in stimulus-induced blinking was evident 2 h after cauterization. Chemical sensitization peaked at 6 h, and was no longer significant at 12 h.
We conclude that silver nitrate cauterization produces acute corneal inflammation and hyperalgesia, and may prove a useful model for the study of primary afferent nociceptors.
Oral anti-inflammatory action of NPC 18884, a novel bradykinin B<inf>2</inf> receptor antagonist
1998, European Journal of Pharmacology
This study describes the anti-inflammatory actions of NPC 18884, a non-peptide bradykinin B₂ receptor antagonist in bradykinin and carrageenan-induced inflammation in the mouse model of pleurisy. The selectivity of NPC 18884 was assessed in the pleurisy caused by histamine, substance P and des-Arg⁹-bradykinin. NPC 18884 given intraperitoneally or orally inhibited bradykinin-induced leukocytes influx (ID₅₀ value of 63 nmol/kg and 141 nmol/kg, respectively). The NPC 18884 also inhibited the exudation induced by bradykinin (P<0.05). NPC 18884 given either intraperitoneally or orally caused dose-dependent inhibition of the exudation and total and differential cell content caused by intrapleural injection of carrageenan (1%, assessed 4 h after), with mean ID₅₀ values of 132 and 295 nmol/kg, respectively. The NPC 18884 actions installs rapidly (0.5 h), lasted for up to 4 h and were selective for the bradykinin B₂ receptors; at similar doses it had no significant effect against the inflammatory responses induced by des-Arg⁹-bradykinin, histamine or substance P. These results indicate that the novel non-peptide bradykinin B₂ receptor antagonist, NPC 18884, exhibited selective intraperitoneal and oral anti-inflammatory properties when assessed in the inflammatory reaction induced by bradykinin and carrageenan in the mice model of pleurisy.
Antinociceptive properties of the hydroalcoholic extract and preliminary study of a xanthone isolated from Polygala cyparissias (Polygalaceae)
1997, Life Sciences
Polygala cyparissias (Polygalaceae) grows abundantly on Brazil's Atlantic coast, belonging to the typical underbrush vegetation of dunes and have been used in folk medicine for treatment of several diseases, such as disturbances of bowel and kidney. The hydroalcoholic extract of P. cyparissias (HE, 3 to 60 mg kg⁻¹, i.p. or 25 to 200 mg kg⁻¹, p.o.) produced significant and graded inhibition of acetic acid-induced abdominal constrictions, with mean ID₅₀ values of 6 and 72 mg kg⁻¹, respectively. The HE (at this same range of doses) also produced dose-related inhibition of both the early and the late phase of formalin-induced licking. The calculated mean ID₅₀ values for the early phase were: > 60 and > 200 mg kg⁻¹, while for the late phase they were 11 and 101 mg kg⁻¹, respectively, by i.p. and p.o. routes. The HE also caused dose-related inhibition of formalin-induced edema formation (P < 0.01). The HE (3 to 60 mg kg⁻¹, i.p. or 50 to 200 mg kg⁻¹, p.o.) produced significant and dose-related inhibition of the neurogenic nociception caused by topical injection of capsaicin, with mean ID₅₀ values of 12 and 71 mg kg⁻¹, respectively. Given orally, the HE (50 to 200 mg kg⁻¹) prevented in a dose-dependent manner, bradykinin (3 $nmol paw$ ) and substance P (10 $nmol paw$ )-induced hyperalgesia in the rat paw, with mean ED₅₀ values of 122 and 121 mg kg⁻¹, respectively, but was ineffective in the hot-plate model of nociception. The antinociception caused by the HE, in contrast to that of morphine (5 mg kg⁻¹, s.c.), was not reversed by naloxone (5 mg kg⁻¹, i.p.) when assessed in the acetic acid writhing test. The HE, at antinociceptive doses, did not affect motor coordination of animals when assessed in the rota-rod model. The xanthone isolated from P. cyparissias, identified as 1,7-dihydroxy-2,3-dimethoxy xanthone (0.3 to 30 mg kg⁻¹, i.p.), produced dose-related inhibition of acetic acid-induced abdominal constriction, with mean ID₅₀ value of 1.5 mg kg⁻¹. These data show that the active principle(s) present in the HE of P. cyparissias, elicited pronounced antinociception when assessed by i.p or p.o. routes, against both inflammatory and neurogenic nociception, and was able to prevent bradykinin and substance P-induced hyperalgesia. Its precise mechanism of action still remains unclear.
Effects of the bradykinin B<inf>1</inf> receptor antagonist des- Arg<sup>9</sup>[Leu<sup>8</sup>]bradykinin and genetic disruption of the B<inf>2</inf> receptor on nociception in rats and mice
1997, Pain
The contributions of B₁ and B₂ bradykinin receptors to acute and chronic inflammatory hyperalgesia were examined using the peptide B₁ receptor antagonist des-Arg⁹[Leu⁸]bradykinin and transgenic Bk2r^-/- mice. In normal rats and mice, des-Arg⁹[Leu⁸]bradykinin (30 nmol/kg i.v. or s.c.) inhibited carrageenan-induced hyperalgesia and the late phase nociceptive response to formalin. The active dose range was narrow, suggesting partial agonist activity of this peptide. In rats with monoarthritis, des-Arg⁹[Leu⁸]bradykinin (up to 30 nmol/kg i.v.) failed to reduce the number of vocalisations elicited by gentle flexion and extension of the inflamed limb; however, hyperalgesia was exacerbated by administration of the B₁ receptor agonist des-[Arg⁹]bradykinin (100 nmol/kg i.v.), consistent with other evidence for local induction of B₁ receptors during adjuvant-induced arthritis. The nociceptive response to intraplantar injection of bradykinin (10 nmol) and hyperalgesia induced by carrageenan (0.6 mg) were absent in Bk2r^-/- mice, indicating that stimulation of B₂ receptors is an essential step in the initiation of some nociceptive and inflammatory reactions. However, the nociceptive response to formalin (2.5% intraplantar), including inhibition of the late phase by des-Arg⁹[Leu⁸]bradykinin (0.3 nmol), and induction of thermal hyperalgesia by Freund's adjuvant (0.1%) appeared intact in Bk2r^-/- mice. These findings support other evidence for an involvement of B₁ receptors in inflammatory hyperalgesia and suggest that B₁ receptor antagonists may be clinically useful as anti-inflammatory and analgesic drugs.

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Short communicationSuppression of carrageenan-induced hyperalgesia, hyperthermia and edema by a bradykinin antagonist

Abstract

Pain

Pain

Peptides

European J. Pharmacol.

Inflammation: mechanisms and mediators

Short communication
Suppression of carrageenan-induced hyperalgesia, hyperthermia and edema by a bradykinin antagonist