Oral anti-hyperalgesic and anti-inflammatory activity of... : PAIN (original) (raw)
1. Introduction
The tachykinins, substance P (SP), neurokinin A (NK-A) and neurokinin B (NK-B), are the preferential endogenous ligands for the NK1, NK2 and NK3 receptors, respectively. They belong to a family of small peptides that are widely distributed in the central and peripheral nervous systems, where they mediate a broad range of biological activities (Maggi et al., 1993).
Substance P is released from both the central and peripheral terminals of primary afferent C-fibres and has been implicated in the pathophysiology of a variety of diseases involving pain and inflammation. In the rat, both NK1 and NK2 receptors are implicated during inflammation in the modulation of nociceptive transmission in the spinal cord (Thompson et al., 1994). The development of selective NK1 receptor antagonists has aided in the elucidation of their relative contribution to spinal transmission and further supported their development as novel therapeutic agents.
The non-peptide antagonists, for example, CP-96,345 (Snider et al., 1991), CP-99,994 (McLean et al., 1993; Watson et al., 1995), RP67580 (Garret et al., 1991) and RPR100893 (Fardin et al., 1994), highlighted clear species selectivity at the NK1 receptor. From pharmacological studies, it appears that the NK1 receptor in human, guinea-pig, gerbil, hamster and rabbit is distinct from that in rat, mouse and chicken (Beresford et al., 1991; Gitter et al., 1991; Barr and Watson, 1993; Maggi, 1994). The receptor diversity established from molecular biology studies confirms these findings (Krause et al., 1994). This has limited the evaluation of these compounds as analgesics, as most classical nociceptive models have been established in the rat and mouse.
The ‘rat selective’ compound RP67580 has anti-nociceptive and anti-inflammatory activity in some rat and mouse models (Nagahisa et al., 1992b; Seguin et al., 1992; Courteix et al., 1993; Rupniak et al., 1993) and despite its lower affinity in that species, CP-96,345 also shows anti-nociceptive and anti-inflammatory activity in rats (Birch et al., 1992); however, this was shown to be non-enantiomer selective (Nagahisa et al., 1992a). Additionally, the non-specific actions of these compounds, for example, blocking of calcium channels and voltage-dependent sodium currents, could mediate the nociceptive effects observed (Schmidt et al., 1992; Caesar et al., 1993; Guard et al., 1993; Rupniak et al., 1993).
Based on pharmacological and molecular studies, models in the gerbil and guinea-pig might be preferable as predictors of analgesic activity in man. Direct NK1 agonist-evoked responses have been studied in gerbils, for example, foot tapping, chromodacryorrhoea, biting and scratching (Bristow and Young, 1994; Rupniak and Williams, 1994; Smith et al., 1994) and thermal hyperalgesia induced by the NK1 receptor agonist GR73632 or formalin (Rupniak et al., 1995). In guinea-pigs, Moussaoui et al. (1994) reported ED50 values for RPR100893 of 3.1 mg kg−1 s.c. and 11 mg kg−1 p.o. against a brief nociceptive behaviour induced by formalin. More recently, Campbell et al. (1998) reported that several potent NK1 receptor antagonists, SDZ NKT 343, LY303870 (Gitter et al., 1995) and RPR100893, inhibited mechanical hyperalgesia in the guinea-pig model of neuropathic pain. However, there is no relevant animal model which would address the role of NK1 receptors in chronic inflammatory pain. Therefore, there is a need for a reliable and reproducible model of persistent hyperalgesia in an appropriate species to assess the therapeutic potential of NK1 receptor antagonists, in particular via the oral route of administration.
In this study we describe the effects of selective NK1 receptor antagonists in a novel model of inflammatory mechanical and thermal hyperalgesia in the guinea-pig which responds to conventional opioid and NSAID treatment. The oral anti-hyperalgesic activity of three NK1 receptor antagonists, SDZ NKT 343 (Walpole et al., 1998), RPR100893 (Fardin et al., 1994) and (±)-SR140333 (Edmonds-Alt et al., 1993), was determined in this in vivo hyperalgesia assay. In addition, the anti-inflammatory effect (plasma protein extravasation) of SDZ NKT 343 and RPR100893 was evaluated in the arthritic knee joint (Freund's complete adjuvant (FCA) model) of the guinea-pig.
2. Methods
2.1. Carrageenan-induced inflammatory hyperalgesia model of the guinea-pig
Male or female Dunkin–Hartley guinea-pigs (220–250 g, _n_=6 per group) were maintained at 21°C on a 12 h light/dark cycle with free access to food and water. Animals received an intraplantar injection (100 μl) of either 0.5, 1.0 or 2.0% carrageenan into the left paw, and mechanical (Fig. 1A) and thermal (Fig. 1B) thresholds were determined at various times up to 4 days to establish the magnitude and duration of the hyperalgesia.
Time course of mechanical (A) and thermal (B) hyperalgesia following intraplantar injection of carrageenan or saline into one paw. Results are expressed as withdrawal threshold (g) or withdrawal latency (s) in the left (inflamed) paw. Symbols indicate saline (▪), or carrageenan at 0.5% (•), 1.0% (□) or 2.0% (♦). Each point is expressed as mean±SEM, _n_=6 per group. *P<0.05, **P<0.01, ***P<0.001.
Mechanical hyperalgesia was measured with an Ugo Basile Analgesymeter. Using a wedge-shaped probe, an increasing weight was applied to the paw (250 g maximum) and the withdrawal threshold determined as the first sign of a pain response. Thermal hyperalgesia was measured with an Ugo Basile Plantar Test (Hargreaves Method). Animals were placed in a Perspex box on a thin glass plate, a ramp heat stimulus was applied to the plantar surface of the paw and latency to paw withdrawal was measured. The withdrawal thresholds to mechanical and thermal stimuli were measured in both the inflamed and non-inflamed paws.
For all subsequent studies a concentration of 1% carrageenan (100 μl intraplantar into left paw) was used and the effects of analgesic drugs were studied 24 h after induction of inflammation. Data are presented as the absolute threshold values in grams (g, mechanical) or seconds (s, thermal) or as a percentage reversal of hyperalgesia.
Where possible ED50 values were calculated as the dose required to produce a 50% reversal of the hyperalgesia.
2.2. Freund's complete adjuvant (FCA)-induced plasma protein extravasation model of the guinea-pig
Male Dunkin–Hartley rats were maintained as described above. Arthritis was induced by the injection of 100 μl of Freund's complete adjuvant (FCA) into the right knee joint. Animals received an oral dose of 30 mg kg−1 of SDZ NKT 343 or the vehicle (stock in microemulsion, diluted by tragacanth) 24 h after FCA injection. One, 2, 3 and 5 h after the SDZ NKT 343 injection animals were anaesthetized and were injected with 50 mg kg−1 Evans Blue, i.v. One hour after the Evans Blue injection guinea-pigs were exsanguinated, and the synovium was dissected from each knee joint. Evans Blue was extracted (70% acetone; 30% of 1% sodium sulphate) from the samples for spectrophotometric analysis at 620 nm. As Evans Blue binds to plasma proteins, its presence within the synovium is indicative of intraarticular plasma extravasation. By subtracting the Evans Blue content of the control (left) knee from the FCA-injected (right) knee it is possible to quantify the ongoing plasma extravasation into the arthritic joint (Bradford, 1976; Cruwys et al., 1994).
The time of the maximum plasma protein extravasation was determined by studying the dose–response curve for SDZ NKT 343. For comparison indomethacin and the non-peptide NK1 receptor antagonist RPR100893 were used. All compounds were given orally. Each group consisted of five animals. Data were expressed in microgram Evans Blue/100 mg tissue, and differences between the injected and control side were calculated.
2.3. Assessment of gastrointestinal damage
At 4 h after drug administration the guinea-pigs were killed by cervical dislocation, their abdomens opened and their stomachs excised. The stomachs were opened along the greater curvature, washed in 0.9% saline, and then pinned out onto damp cork boards for estimation of damage. The damage, which is usually presented as mucosal erosions (an erosion being defined as surface epithelial damage which does not penetrate the muscularis mucosa), was assessed on a severity scale of 0–8 (the lesion index): 0, no morphological damage; 1, one erosion; 2, up to three erosions; 3, up to six erosions; 4, up to ten erosions; 5, up to 20 erosions; 6, up to 40 erosions; 7, large haemorrhagic streaks up to 1 cm in length; 8, the presence of one or more ulcers (an ulcer being defined as epithelial damage extending beyond the mucosa into the muscularis mucosa).
In each of the animals in the top dose group a 20 cm section of the ileum was also removed, cut along the anti-mesenteric border and checked for damage.
2.4. Statistics
Data are presented as percentage inhibition of hyperalgesia and ED30 or ED50 values were calculated by determining the dose which produced 30 or 50% reversal of hyperalgesia, respectively. Data were analyzed by Student's _t_-test or ANOVA followed by post-hoc analysis of means using Tukey's (HSD) test where appropriate. Gastric damage scores were analyzed using the Mann–Whitney _U_-test.
2.5. Reagents
Morphine sulphate was obtained from MacFarlane Smith Ltd, Edinburgh and carrageenan (Viscarin GP 109) from FM Litex, Denmark. The neurokinin (NK1) receptor antagonists, SDZ NKT 343, the inactive enantiomer (R,R) SDZ NKT 343, RPR100893 and (±)-SR140333, were synthesized by the Medicinal Chemistry Department at the Novartis Institute for Medical Sciences. All other reagents were obtained from Sigma.
For in vivo studies, carrageenan and morphine were prepared in 0.9% sterile saline. Aspirin and indomethacin were administered in 1% tragacanth and the NK1 antagonists in 10% DMSO/90% tragacanth (1%).
3. Results
3.1. Characterization of carrageenan-induced hyperalgesia
Three different concentrations of carrageenan (0.5, 1.0 and 2.0%) were tested, all of which produced a similar, marked mechanical and thermal hyperalgesia after intraplantar injection into the paw. No contralateral effects were observed. The maximum reduction in threshold was measured 4 h after injection (mechanical threshold: control, 124.2±5.1 g; carrageenan 0.5%, 77.5±7.5 g; carrageenan 1.0%, 63.3±3.1 g; carrageenan 2.0%, 61.6±5.3 g; withdrawal latency: control, 18.9±0.4 s; carrageenan 0.5%, 6.0±0.6 s; carrageenan 1.0%, 4.7±0.9 s; carrageenan 2.0%, 3.3±0.4 s). The time courses of both mechanical and thermal hyperalgesia were similar (Fig. 1A,B). After rapid development, hyperalgesia was sustained for 24 h and subsequently declined (Fig. 1A,B). By day 4 there was still a small but significant mechanical hyperalgesia (Fig. 1A). By day 2, thermal hyperalgesia was only apparent in animals treated with the highest concentration of carrageenan (Fig. 1B). From these experiments a concentration of 1% carrageenan was selected and the potential analgesic activity of all compounds was studied 24 h after intraplantar injection when significant thermal and mechanical hyperalgesia were evident.
3.2. Effect of aspirin and morphine on carrageenan-induced hyperalgesia
Both aspirin (p.o.) and morphine (s.c.) reduced the mechanical and thermal hyperalgesia in this model. Morphine reversed both the mechanical and thermal hyperalgesia in a dose-related manner (Fig. 2A,B). At the highest dose (10 mg kg−1) it inhibited mechanical and thermal hyperalgesia by 79.9±12.2 and 71.2±7.34% with ED50 values of 1.85 and 2.51 mg kg−1, respectively, as measured at 3 h after administration. Aspirin was unable to fully reverse the hyperalgesia when tested up to 300 mg kg−1 p.o. There was 55.0±6.84 and 45.2±14.3% inhibition of mechanical and thermal hyperalgesia, respectively (Fig. 2A,B).
Effect of morphine (•) and aspirin (▪) on the mechanical and thermal hyperalgesia induced by intraplantar injection of carrageenan (1.0%). Results were obtained 3 h after drug administration and are expressed as the percentage inhibition of hyperalgesia. Each point is expressed as mean±SEM, _n_=6 per group.
3.3. Effect of NK1 receptor antagonists on carrageenan-induced mechanical hyperalgesia
In the dose range studied, oral administration of the NK1 receptor antagonist SDZ NKT 343 produced a significant, dose-related but incomplete reversal of both mechanical and thermal hyperalgesia (Fig. 3A,C). The maximum effect was observed 3 h after the oral administration of 30 mg kg−1, with 68% inhibition of mechanical hyperalgesia. The D30 value for SDZ NKT 343 was calculated at 1.1 mg kg−1. The anti-hyperalgesic effect showed a gradual development (Fig. 3B) and lasted at least 5 h with an almost full recovery to the baseline hyperalgesia by 6 h after administration of SDZ NKT 343 (Fig. 3). The inactive enantiomer of SDZ NKT 343, (R,R) SDZ NKT 343, did not reverse the carrageenan-induced hyperalgesia (Fig. 3C).
Effect of SDZ NKT 343 p.o. on the mechanical hyperalgesia induced by intraplantar injection of carrageenan (1.0%). (A) Results were obtained 1, 3 and 6 h after drug administration and are expressed as the percentage inhibition of hyperalgesia. Each bar is represented as mean±SEM, _n_=12 per group. Doses are given in mg kg−1. (B) Time course of the anti-hyperalgesic effect of SDZ NKT 343 (10 mg kg−1; p.o.) and aspirin (300 mg kg−1; p.o.). (C) Dose–response relationship of SDZ NKT 343 (▪) and the enantiomer (R,R) SDZ NKT 343 (▴). The effect was measured 3 h after drug administration. _n_=6 at each time point; ANOVA followed by Tukey's HSD test: *P<0.05, **P<0.01, ***P<0.001.
The non-peptide NK1 receptor antagonists RPR100893 and SR140333 also produced a dose-dependent reversal of mechanical hyperalgesia up to a dose of 30 mg kg−1 p.o., after which no further increase was observed (D30s were calculated at 17 and >100 mg kg−1, respectively). The effect of RPR100893 (Fig. 4B) peaked at 3 h (36% reversal at 30 mg kg−1) but was still evident for up to 6 h after administration at the two highest doses. SR140333 (Fig. 4A) produced a significant inhibition of the hyperalgesia, peaking at 1 h (27% at 30 mg kg−1) but with a much shorter duration of action (3 h at the highest dose). In the dose ranges studied none of the NK1 antagonists had any effect on the withdrawal latencies of the non-inflamed paw.
Effect of (A) SR14033 and (B) RPR100893 p.o. on the mechanical hyperalgesia induced by intraplantar injection of carrageenan (1.0%). Results were obtained 1, 3 and 6 h after drug administration and are expressed as the percentage inhibition of hyperalgesia. Each point is represented as mean±SEM, _n_=6 per group. Doses are given in mg kg−1; ANOVA followed by Tukey's HSD test: *P<0.05, **P<0.01, ***P<0.001.
As the most potent anti-hyperalgesic agent of the three NK1 receptor antagonists, SDZ NKT 343 was also tested in the thermal hyperalgesia model of the guinea-pig. The duration of action of SDZ NKT 343 was similar to that in mechanical hyperalgesia, but with a prolonged plateau phase between 2 and 5 h after drug administration (Fig. 5). The maximum reversal was measured at about 25% between 2 and 5 h post-administration of a dose of 10 mg kg−1. At a higher dose (30 mg kg−1) no further increase in reversal was observed. The estimated ED30 value for SDZ NKT 343 was 3.89 mg kg−1.
Time course of the anti-hyperalgesic effects of SDZ NKT 343 and aspirin in the thermal hyperalgesia model in the guinea-pig. Each point represents _n_=6. *P<0.05, **P<0.01, ***P<0.001.
The effects of SDZ NKT 343 were compared to those of aspirin, a NSAID analgesic in both mechanical and thermal hyperalgesia (Figs. 2 and 4). In the mechanical hyperalgesia model aspirin produced analgesia with a short duration and lesser efficacy. In the thermal hyperalgesia measurements aspirin (300 mg kg−1) had a similar effect to SDZ NKT 343 (10 and 30 mg kg−1).
3.4. Effects of NK1 receptor antagonists on plasma protein extravasation
Basal plasma protein extravasation was elevated in the injected knee in comparison to the knee on the untreated side (2.95±0.3 μg/100 mg in the right knee versus 0.80±0.15 μg/100 mg). During 1–5 h after oral administration of the vehicle, plasma protein extravasation did not show any difference in comparison to the untreated control (Fig. 6A). On the contrary, a single oral dose of 30 mg kg−1 of SDZ NKT 343 attenuated intraarticular plasma extravasation by 14% at 1 h, 63% at 2 h, 56% by 3 h, and 42% by 5 h after treatment. Differences between vehicle-treated and SDZ NKT 343-treated animals were significantly different at 2, 3 and 5 h (P<0.05). SDZ NKT 343 did not affect the plasma protein extravasation in the contralateral joint.
Effects of NK1 receptor antagonists on plasma protein extravasation in the inflamed knee joint of the guinea-pig. (A) Time course of the effect of SDZ NKT 343. (B) Dose–response relation of the anti-inflammatory effect of SDZ NKT 343, RPR100893 and aspirin, measured as inhibition plasma protein extravasation. Each point represents 6 animals. Student's _t_-test: *P<0.01.
Although the inhibition of basal plasma protein extravasation was greatest 2 h post-treatment (62.8±13.7%), the 3 h time point proved to offer both greater consistency and a significant inhibition (55.5±7.6%) and was therefore utilized in the subsequent dose–response studies.
The ability of SDZ NKT 343 and RPR100893 to inhibit basal plasma extravasation was assessed 3 h after dosing with 1–100 mg kg−1 of the antagonist (Fig. 6B). SDZ NKT 343 significantly inhibited the basal plasma extravasation over a dose range from 3 to 100 mg kg−1. The maximum inhibition was 51.9±7.6%. Whilst RPR100893 was able to inhibit the basal plasma extravasation over a dose range from 10 to 100 mg kg−1, it was significantly less potent than SDZ NKT 343 (maximum inhibition 29.3±4.4%).
The ED50 for SDZ NKT 343 was calculated at 14 mg kg−1. The ability of SDZ NKT 343 to inhibit basal plasma extravasation was compared with that of indomethacin (1–30 mg kg−1, Fig. 6B). The maximum inhibition observed with indomethacin was 60.0±5.3% at 30 mg kg−1, with an ED50 of 11 mg kg−1.
3.5. Comparison of gastric effects after oral administration of NSAIDs and SDZ NKT 343
SDZ NKT 343 was compared to a representative NSAID, indomethacin, in an assay designed to measure the propensity of compounds to induce gastrointestinal lesions. Indomethacin caused dose-related gastric ulceration (Fig. 7). The majority of the guinea-pigs had large, bleeding, antral ulcers and numerous mucosal erosions after 30 mg kg−1 indomethacin p.o. The NSAID-induced toxicity was evident at doses between 1 and 30 mg kg−1, occurring even at the lower doses that do not produce significant anti-nociceptive effects (1 and 3 mg kg−1).
The effects of SDZ NKT 343 and indomethacin on carrageenan-induced mechanical hyperalgesia and gastric mucosa in the guinea-pig. Hyperalgesia readings were taken at 3 h after administration (columns). Gastric damage was assessed at 4 h after administration (line graph). _n_=5 animals/treatment group. Values are mean±SEM. (For description of the severity scale, see Section 2.)
SDZ NKT 343 did not produce any significant gastric damage (Fig. 7). A single (non-bleeding) erosion was recorded in two of the animals; these were probably not drug-induced.
4. Discussion
In this report we described a model of inflammatory hyperalgesia in the guinea-pig for the evaluation of neurokinin receptor antagonists with species selectivity for the human type NK1 receptor. Using this model, the oral anti-hyperalgesic and anti-inflammatory activity of several NK1 receptor antagonists was confirmed.
The intraplantar injection of carrageenan into one paw of the guinea-pig induced mechanical and thermal hyperalgesia which persisted for 2–4 days depending on the dose of carrageenan. The maximum reduction in mechanical threshold at 4 h compares favourably with the second phase of carrageenan-induced inflammation in rats which reached a plateau at 2–3 h and persisted for over 5 h (Vinegar et al., 1976).
Twenty-four hours after induction of inflammation, standard analgesic drugs, aspirin and morphine, attenuated the carrageenan-induced hyperalgesia. Morphine, in the dose range studied, produced almost complete reversal of the hyperalgesia, while aspirin, tested up to a maximum dose of 300 mg kg−1, inhibited hyperalgesia by approximately 50%. For all three NK1 receptor antagonists used in the present study, there was a good correlation between the affinity at the human NK1 receptor and the activity in the functional assay of the guinea-pig ileum, but not with affinity for the rat NK1 receptor (Edmonds-Alt et al., 1993; Walpole et al., 1998). When tested in the guinea-pig in vivo assay, however, the same antagonists inhibited the carrageenan-induced hyperalgesia to varying degrees.
Though a role for tachykinins has been implicated in different models of pain (Radhakrishnan and Henry, 1991; Yamamoto and Yaksh, 1991; Hua et al., 1998; for review see Woolf et al., 1998), the relative contribution of NK1 and NK2 receptors to sensory transmission may change dependent on whether the stimulus is acute or chronic. In animal models of persistent pain, the evidence suggests that the role of NK1 receptors becomes increasingly important (Xu et al., 1992; Thompson et al., 1994; Urban et al., 1994).
In inflammatory hyperalgesia, it is well documented that NK1 receptor expression and the release of tachykinins are increased within the spinal cord (Schaible et al., 1990; McCarson and Krause, 1994). Substance P released from the peripheral terminals of these primary afferents will also contribute to the local inflammatory response. Thus, NK1 antagonists could potentially have dual effects acting both in the spinal cord and in the periphery.
Varying potencies and duration of action were noted for the NK1 antagonists in the carrageenan hyperalgesia assay. Peak efficacy for RPR100893 was noted at 3 h after drug administration and for SR140333 at 1 h. SDZ NKT 343 was the most effective anti-hyperalgesic drug with a maximum reversal of about 60–70%. With RPR100893 and SR140333 it was clear that a plateau effect was reached with a maximum reversal of hyperalgesia of approximately 30–40% at a dose of 30 mg kg−1. The relatively poor activity of SR140333 and RPR100893 may be indicative of low CNS penetration.
There is little direct evidence on the relative ability of the three NK1 antagonists used in this study to penetrate the blood–brain barrier or on their pharmacokinetics. However, data exist from other studies for SR140333 which suggests that it is able to cross the blood–brain barrier and have an action within the CNS. Edmonds-Alt et al. (1993) proposed a central action for SR140333 following i.p. or i.v. administration based on antagonism of direct NK1-mediated responses and anti-nociceptive effects. However, other studies have shown, following subcutaneous administration of SR140333, no effect on thermal or chemical nociception despite a clear inhibition of neurogenic inflammation (Amann et al., 1995). The effects of p.o. and i.t. SDZ NKT 343 and RPR100893 were compared earlier in the guinea-pig model of peripheral neuropathy (Campbell et al., 1998) and provided clear evidence that limited blood–brain barrier penetration was responsible for the poor anti-hyperalgesic performance of RPR100893.
The most potent anti-hyperalgesic NK1 receptor antagonist, SDZ NKT 343, also inhibited thermal hyperalgesia in the carrageenan model of the guinea-pig, but with diminished effectiveness and potency. The reason for this lesser activity is not known at present.
These results, together with previously published data (Campbell et al., 1998), suggest that failed clinical trials with NK1 receptor antagonists should not be interpreted as a definite evidence of lack of action of all selective NK1 antagonists in clinical pain syndromes (Rupniak and Kramer, 1999). While most of the NK1 antagonists entering clinical phase trials show high potency at the human NK1 receptor (Walpole et al., 1998), their pharmacokinetic and metabolic profiles may prevent adequate drug exposure at the sites of the receptor. The significant differences in efficacy and potency of in vivo anti-hyperalgesic action of the compound used in this study underline this possibility. Furthermore, development and in vivo evaluation of NK1 receptor antagonists were hindered by the lack of suitable animal models for species-specific compounds (Beresford et al., 1991). Thus, rat hyperalgesia models were unable to predict clinical potency and efficacy. The discovery that many of the NK1 receptor antagonists have similar high affinity to the human and guinea-pig NK1 receptors suggested the suitability of a guinea-pig model. Results from early studies in the rat which suggested an anti-hyperalgesic effect for NK1 antagonists might have been misinterpreted by their direct effects at various ion channels (Caesar et al., 1993; Lambet and Spedding, 1994). SDZ NKT 343 has a negligible effect at ion channels (Walpole et al., 1998). The lack of anti-hyperalgesic effects of the inactive enantiomer (R,R) SDZ NKT 343 further supports the NK1 receptor-specific reversal of hyperalgesia in this and the neuropathic pain models of the guinea-pig (Campbell et al., 1998).
In addition to their anti-hyperalgesic effects, NK1 receptor antagonists inhibit inflammatory mechanisms, such as plasma protein extravasation and immune cell functions (Figini et al., 1995; Walsh et al., 1995; for review see Quartara and Maggi, 1998). SDZ NKT 343 and RPR100893 were active in the guinea-pig plasma protein extravasation model. Again, SDZ NKT 343 was significantly more effective, with similar oral potency and efficacy to indomethacin. The low potency and efficacy of RPR100893 may be due, as described before, to its poor bioavailability.
We chose a 30 mg kg−1 oral dose of indomethacin and a 3–100 mg kg−1 dose range of SDZ NKT 343 to compare the effect of NSAIDs and NK1 receptor antagonists on the gastrointestinal tract. There was no significant sign of mucosal erosion after treatment with SDZ NKT 343. On the other hand, indomethacin produced severe gastric erosion and occasional bleeding in the stomach and small intestine.
The models of persistent hyperalgesia and plasma protein extravasation in the guinea-pig provided suitable tools for the assessment of the oral anti-hyperalgesic and anti-inflammatory activity of NK1 receptor antagonists which showed selectivity for the guinea-pig and human receptor. Data obtained using this model may therefore be predictive of anti-hyperalgesic activity in man.
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Keywords:
Hyperalgesia; Inflammation; Guinea-pig; NK1 receptor antagonists; Anti-hyperalgesia; Gastric erosion
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