neurokinin-a and Edema

The aim of this article is to furnish a brief review of the role played by neurokinins in the inflammatory process. Further attention is given to the mechanisms, as well as to the receptor subtypes involved in neurokinin-mediated inflammation, in an attempt to clarify the participation of neurokinins in different models of acute and chronic inflammation. The involvement of SP, NKA and NKB is also examined in relation to the major signs of inflammation, including edema formation, protein plasma extravasation and vasodilatation. Finally, we provide a general overview on the potential clinical applications of neurokinin antagonists, along with the involvement of neurokinins in human diseases.

Topics: Animals; Edema; Humans; Inflammation; Neurokinin A; Neurokinin B; Substance P; Tachykinins

Recent studies have proposed that activation of the sensory nervous system after thermal injury induces the release of vasoactive neuropeptides, including tachykinins which contribute to the local inflammatory reaction as well as to the nociceptive transmission at the spinal cord level. Effects of the tachykinins substance P and neurokinin A are mediated by the neurokinin 1 and 2 (NK1, NK2) receptors. The aim of the present study was to investigate the modulatory role of NK1 and NK2 antagonists on edema formation, and on hindpaw withdrawal latency to experimentally asses nociception. Thermal injury was inflicted on the anaesthetized rat by dipping the right hindpaw into hot water at 60 degrees C for 20 s. The amount of edema formation was calculated by measuring the hindpaw volume with a plethysmograph before and during 420 min after scalding. In other studies scalding was inflicted under brief anesthesia, and hindpaw withdrawal latencies (HWL) to mechanical stimulation were recorded before injury and at 180 min after. The effect on edemic reactions of rats treated locally with NK1 and NK2 receptor antagonist were studied, as well as the effect of the same compounds on HWL after intrathecal injection. Scalding induced a progressive edema formation which was reduced significantly in rats treated with local injection of 100 nmol of NK1 and NK2 antagonists 45 min after the injury. The thermally induced inflammation was followed by significant decrease of the latency of hindpaw withdrawal response to mechanical stimulation. Intrathecal injection of 30 nmol of the same drugs 180 min after scalding was followed by significant increase in HWL. The results indicate that SP and NKA contribute to the inflammatory reactions after thermal injury and that the tachykinin receptor antagonists possess the ability to reduce both the local edemic reaction as well as the nociceptive transmission at the spinal cord level.

Topics: Animals; Burns; Disease Models, Animal; Edema; Follow-Up Studies; Inflammation; Male; Neurokinin A; Neurokinin-1 Receptor Antagonists; Nociceptors; Pain Measurement; Peptide Fragments; Pyrrolidonecarboxylic Acid; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Skin Diseases; Substance P

It has recently been hypothesized that both the sensory and sympathetic nervous system contribute to the inflammatory reaction. A scalding model was developed in anaesthetized rats to investigate the contribution of neuropeptides in heat-induced edema localized to the hindpaw. After immersing the paw in water at 60 degrees C for 10, 20, 30 and 60 s, edemic reactions were registered as change of paw volume in a plethysmograph and hindpaw perfusates collected to measure the content of neuropeptides by radioimmunoassay. A scalding period of 30 s induced the most prominent edemic reaction. There was a marked increase of the sensory neuropeptide neurokinin A and the sympathetic related transmitter neuropeptide Y in hindpaw perfusates after scalding. The effect of peripheral nerve ligation on edemic reaction and on the release of neuropeptides was investigated in rats scalded for 30 s at 60 degrees C. There was a significant decrease of edema formation in the scalded nerve ligated paw as compared with the scalded paw on the non-ligated side. Neurokinin A was not detected in nerve ligated rats before or after scalding, whereas mononeuropathic rats showed increased concentrations of neuropeptide Y. The present results indicate that the sensory as well as the sympathetic nervous system, possibly through the release of neuropeptides, may contribute to scald-induced edema.

Topics: Animals; Burns; Disease Models, Animal; Edema; Ganglia, Sensory; Hindlimb; Hot Temperature; Ligation; Male; Neurokinin A; Neuropeptide Y; Neuropeptides; Plethysmography; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Sympathetic Nervous System

The involvement of tachykinin receptors in skin inflammation induced by substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) was investigated in mouse ears. Intradermal injection of tachykinins (0.1-100 pmol/site) into the ear skin produced oedema formation. RP 67580 (ED50: 0.34 mg/kg, i.v.) and SR 140333 (ED50: 0.19 mg/kg, i.v.), the non-peptide NK1 receptor antagonists, inhibited SP-induced oedema. SR 140333 was also effective in preventing NKA- and NKB-induced oedema. SR 48968 (1 mg/kg, i.v.), a non-peptide NK2 antagonist, induced a significant inhibition of NKA-induced oedema but had no effect on the response to SP and NKB. SR 142801 (3 mg/kg, i.v.), a non-peptide NK3 antagonist, prevented only NKB-induced oedema. In contrast, phosphoramidon (0.1 and 0.5 mg/kg, i.v.), an endopeptidase inhibitor, enhanced the oedema response to tachykinins. SR 140333, SR 48968, and SR 142801 blocked the enhancement by phosphoramidon of the response to SP, NKA, and NKB, respectively. Plasma extravasation in ear skin was induced by i.v. injection of tachykinins (0.7-17.6 nmol/kg). RP 67580 (ED50: 0.15 mg/kg, i.v. for SP) and SR 140333 (ED50: 14.3 micrograms/kg, i.v. for SP) inhibited tachykinin-induced plasma extravasation in ear skin. However, SR 48968 and SR 140281 had no effect on the vascular response to tachykinins. Chlorpheniramine (4 mg/kg, i.v.), a histamine H1 blocker, inhibited the response to local SP but not to i.v. SP. These results suggest that in addition to the NK1 receptors, functional NK2 and NK3 receptors may participate in the oedema response to local NKA and NKB in the ear skin. However, it appears that NK1 receptors on blood vessels are involved predominantly in plasma extravasation induced by i.v. tachykinins in the ear.

Topics: Animals; Capillary Permeability; Edema; Glycopeptides; Male; Mice; Neurokinin A; Neurokinin B; Piperidines; Quinuclidines; Receptors, Tachykinin; Substance P

1. Measurement of plasma protein extravasation induced by the natural tachykinins following intradermal administration in rat skin indicated equipotency between substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). The selective NK1 receptor agonist, [Sar9]SP sulphone was 10-100 times more potent than SP. The synthetic hexapeptide, septide, [pGlu6, Pro9]SP-(6-11), which has been proposed to act on a distinct NK1 receptor subtype/binding site was equipotent with [Sar9]SP sulphone. 2. The selective NK2 receptor agonist [beta Ala8]NKA(4-10) (0.1-1 nmol) and the selective NK3 receptor agonist, senktide (0.1-1 nmol) were both ineffective in producing oedema. The selective NK2 receptor antagonist, SR 48, 968 (0.3 mumol kg-1) had no significant inhibitory effects upon oedema induced by approximately equiactive doses of SP (0.2 nmol), septide (0.002 nmol), [Sar9]SP sulphone (0.002 nmol), or NKB (0.3 nmol). These results together suggest that neither NK2 nor NK3 receptors are involved in oedema formation in rat skin. 3. The non-peptide tachykinin NK1 receptor antagonist, RP 67,580 (1-3 mumol kg-1), inhibited plasma protein extravasation induced by septide (0.002 nmol) to a greater extent than that to SP (0.2 nmol). RP 67,580 (1 mumol kg-1) produced a significant inhibition of approximately 66% of the response to septide (0.002 nmol) only. Increasing the dose of RP 67,580 3 fold resulted in inhibition of the response to SP (0.2 nmol) and [Sar9]SP sulphone (0.002 nmol) by approximately 66% and 64% respectively with the response to septide being inhibited by approximately 70%. 4. Co-administration of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME)(0.1 micromol) with the relevant tachykinin, resulted in a significant attenuation of the oedemaresponse to septide (0.1 nmol) producing only an approximate 56% inhibition of the response. The response to 0.2 nmol SP was unaffected whereas the response to a higher dose of 1 nmol was lowered byL-NAME but this did not reach significance.5. Degranulation of mast cells, achieved by pretreatment with compound 48/80 (5 mg kg-1) for 3 consecutive days, significantly inhibited the oedema responses to only high dose SP (1 nmol) and[Sar9SP sulphone (0.002 nmol). SP (0.2 nmol), septide (0.002 nmol), NKA (0.2 nmol) and NKB(0.3 nmol) were unaffected by this treatment.6. RP 67,580 (0.3-3 microM kg-1) inhibited oedema induced by both 0.002 nmol and 0.1 nmol of septide.When using equiactive doses o

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Capillary Permeability; Dermatitis, Contact; Dose-Response Relationship, Drug; Edema; Indoles; Isoindoles; Male; Neurokinin A; Neurokinin B; Neurokinin-1 Receptor Antagonists; Nitric Oxide Synthase; p-Methoxy-N-methylphenethylamine; Peptide Fragments; Pyrrolidonecarboxylic Acid; Rats; Rats, Wistar; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P

The effect of the neurokinin-1 (NK1) receptor antagonist RP67580 in modulating inflammatory oedema formation has been investigated in guinea-pig skin. Oedema formation was measured over 30 min by the extravascular accumulation of intravenously-injected 125I-albumin in the anaesthetised guinea-pig. RP67580 was injected intradermally with the agents under test. Intradermal RP67580 (10 nmol/site) inhibits oedema formation induced by substance P (30 pmol) and neurokinin A (100 pmol), but not that induced by bradykinin (10-1000 pmol) or histamine (10 nmol). Substance P-induced oedema formation is similar in control (saline) and mepyramine (histamine H1 receptor antagonist) pretreated guinea-pigs suggesting a minimal involvement of histamine in substance P induced oedema formation in guinea-pig skin. Oedema formation induced by intradermal carrageenin (0.2%) was not inhibited by RP67580 (1-10 nmol). A significant but partial inhibition of oedema formation induced in a passive cutaneous anaphylaxis (PCA) response was observed. The oedema formation in the PCA was inhibited 50% by mepyramine pretreatment but in the presence of mepyramine no further inhibition of the PCA response by RP67580 was observed.

Topics: Animals; Bradykinin; Calcitonin Gene-Related Peptide; Carrageenan; Edema; Guinea Pigs; Indoles; Inflammation; Injections, Intradermal; Isoindoles; Male; Neurokinin A; Neurokinin-1 Receptor Antagonists; Pyrilamine; Skin; Substance P; Tachykinins

The increase in tracheal vascular permeability evoked by hypertonic saline depends on capsaicin-sensitive sensory nerves, which contain substance P and other neuropeptides. The present study was performed to determine whether a novel, nonpeptide, selective antagonist of the NK1 tachykinin receptor CP-99,994, [(+)-(2S-3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], can prevent the effect of substance P, capsaicin and hypertonic saline on tracheal vascular permeability. CP-99,994 was also tested against a nonpeptide inflammatory mediator, platelet-activating factor (PAF), to assess the selectivity of its action. Anesthetized F-344 rats were injected with either substance P (5 micrograms/kg i.v.), capsaicin (100 micrograms/kg i.v.) or PAF (10 micrograms/kg i.v.), or were exposed to ultrasonically nebulized 3.6% NaCl. In each group, some of the rats were pretreated with CP-99,994 (1 to 4 mg/kg i.v.), and some with its vehicle (0.9% NaCl). Groups of rats injected with substance P or exposed to hypertonic saline were pretreated with the (2R, 3R)-enantiomer CP-100,263, [(-)-(2R-3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine] (2 or 4 mg/kg i.v.). The magnitude of the increase in tracheal vascular permeability was measured by quantifying the extravasation of Evans blue dye. CP-99,994 prevented the increase in tracheal vascular permeability produced by inhalation of hypertonic saline, by substance P and by capsaicin, but did not prevent the effect of PAF. CP-100,263 did not affect substance P- and hypertonic saline-induced increase in vascular permeability. These results indicate that the NK1 receptor antagonist CP-99,994 produces stereoselective inhibition of neurogenic plasma extravasation evoked by inhalation of hypertonic saline.

Topics: Animals; Capillary Permeability; Capsaicin; Dose-Response Relationship, Drug; Edema; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Hypertonic Solutions; Neurokinin A; Neurons, Afferent; Piperidines; Platelet Activating Factor; Rats; Rats, Inbred F344; Receptors, Neurotransmitter; Receptors, Tachykinin; Sodium Chloride; Stimulation, Chemical; Substance P; Trachea; Tracheal Diseases

Topics: Animals; Bronchoconstriction; Capsaicin; Cell Membrane; Dipeptides; Edema; Guinea Pigs; Histamine; Ileum; In Vitro Techniques; Indoles; Kinetics; Lung; Muscle Contraction; Muscle, Smooth; Neurokinin A; Receptors, Neurokinin-1; Substance P

1. The mechanisms involved in tachykinin-induced oedema were investigated in rat skin and interactions between the tachykinins and calcitonin gene-related peptide (CGRP) were studied. 2. Intradermal injections of the tachykinins, substance P, neurokinin A and neurokinin B, stimulated local oedema formation which was in each case potentiated by co-injection of the vasodilator CGRP. Oedema induced by substance P, in the presence and absence of CGRP, was significantly inhibited by pretreatment of rats with a combination of the histamine H1 antagonist, mepyramine, and the 5-hydroxytryptamine antagonist, methysergide. Oedema induced by neurokinin A or B was not inhibited by this pretreatment. 3. Intradermally-injected CGRP induced a long lasting increase in local blood flow, which was measured with a laser Doppler blood flow meter. The simultaneous injection of substance P, but not of the structurally-related neurokinins, caused a loss of the prolonged vasodilator activity of CGRP. 4. These results show that oedema induced by substance P is partially dependent on mast cell amines and that only substance P causes a loss of the prolonged vasodilator activity of CGRP. 5. We suggest that the ability of substance P to prevent the persistent vasodilator activity of CGRP may be a direct consequence of substance P-induced activation of mast cells.

Topics: Animals; Calcitonin Gene-Related Peptide; Drug Interactions; Edema; Histamine Antagonists; Male; Neurokinin A; Neurokinin B; Neuropeptides; Rats; Rats, Inbred Strains; Regional Blood Flow; Rheology; Serotonin Antagonists; Skin; Substance P; Tachykinins