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. 1999 Jan;126(1):326-32.
doi: 10.1038/sj.bjp.0702258.

The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat

S G Hamilton  1 , A Wade, S B McMahon
Affiliations

The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat

S G Hamilton et al. Br J Pharmacol. 1999 Jan.

Abstract

1. We have studied the behavioural effects of intraplantar injections of adenosine 5'-triphosphate (ATP) and related compounds in freely moving rats and investigated whether these nociceptive effects are augmented in the presence of inflammatory mediators. 2. We find that in normal animals ATP and analogues produce dose-dependent nocifensive behaviour (seen as bursts of elevation of the treated hindpaw), and localized thermal hyperalgesia. The rank order of potency was: alpha,beta-methyleneadenosine 5'-triphosphate (alpha,beta-methylene ATP) > 2-methylthioadenosine triphosphate (2-methylthio ATP) > ATP. After neonatal treatment with capsaicin, to destroy small calibre primary sensory neurones, nocifensive behaviour was largely absent. 3. The effects of ATP analogues were assessed in three models of peripheral sensitization: 2 h after dilute intraplantar carrageenan (0.25% w v(-1)); 24 h after irradiation of the hindpaw with ultraviolet (U.V.) B; immediately following prostaglandin E2 (PGE2) treatment. In all models the effect of alpha,beta-methylene ATP was greatly augmented. After carrageenan, significant hindpaw-lifting behaviour activity was induced by injection of only 0.05 nmol of alpha,beta-methylene ATP, some 100 times less than necessary in normal skin. 4. Our data suggest that it is much more likely that endogenous levels of ATP will reach levels capable of exciting nociceptors in inflamed versus normal skin. Our data also suggest the involvement of P2X3 receptor subunits in ATP-induced nociception.

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Figures

Figure 1
Figure 1
The time spent (in 2 min time bins) in hindpaw-lifting in rats given an intraplantar injection of α,β-methylene ATP or PBS. The ATP was given to normal rats or rats treated as indicated in the legend. The pattern of nocifensive behaviour was the same in normal rats and in the presence of inflammatory mediators, with maximal hindpaw-lifting occurring within the first 5 min and rapidly diminishing thereafter. Negligible hindpaw-lifting was observed in rats injected with equal volume of phosphate-buffered saline vehicle. n=5 animals in all groups. Ten nmol of α,β-methylene ATP was given, except for carrageenan-treated rats, which received 5 nmol. Values are means±s.e.mean.
Figure 2
Figure 2
Total hindpaw-lifting time occurring in the 6 min following intraplantar injections of different doses of free ATP, α,β-methylene ATP and 2-methylthio-ATP, injected in a volume of 100 μl. n=5–10 for each drug/dose. Values are means±s.e.mean. All compounds induce significant hindpaw lifting (P<0.05, ANOVA). The asterisks indicate which individual groups at a particular dose differ significantly from PBS (Dunnet's post hoc test).
Figure 3
Figure 3
Thermal sensitivity of hindpaws determined 6 min after intraplantar injections of different doses of ATP, α,β-methylene ATP and 2-methylthio ATP, expressed as a percentage of the hindpaw withdrawal latency determined prior to intraplantar injection. Values less than 100 therefore indicate hyperalgesia. n=5–10 for each drug/dose. Values are means±s.e.mean. The effects of α,β-methylene ATP are statistically significant (P<0.05, ANOVA).
Figure 4
Figure 4
Total hindpaw-lifting time in the 6 min following intraplantar injections of ATP. α,β-methylene ATP and 2-methylthio ATP, in naïve rats and in rats treated neonatally with capsaicin. n=3–5 per drug per dose. The reduction in hindpaw-lifting time in capsaicin-treated rats is highly significant in all cases (single asterisk indicates P<0.05; double asterisk indicates P<0.01, Mann-Whitney Rank Sum t-test).
Figure 5
Figure 5
Nocifensive behaviour induced by intraplantar injections of α,β-methylene ATP or vehicle (50 μl) into a hindpaw inflamed with carrageenan (50 μl of 0.25%) 2 h previously. n=5 per group. The total hindpaw-lifting time in the 10 min period following intraplantar injection is plotted. The increases seen in carrageenan-inflamed skin are significant (P<0.05, ANOVA). Asterisks indicate significant differences (P<0.05) between inflamed and normal animals (Dunnet's post hoc test).
Figure 6
Figure 6
Effect of PGE2 on lifting behaviour induced by 1 nmol of α,β-methylene ATP. PGE2 was given at a dose of 0.7 or 7 μmol either alone or mixed with 1 nmol of α,β-methylene ATP, and the ensuing hindpaw-lifting time accumulated over the following 10 min n=5 for each group. PGE2 potentiates ATP-induced hindpaw-lifting behaviour. Asterisks indicate a significant difference between groups (single asterisk P<0.05, double asterisk P<0.01, Mann-Whitney Rank Sum t-test).
Figure 7
Figure 7
Effect of U.V. inflammation on hindpaw-lifting behaviour occurring in the 6 min after intraplantar injections of 1000 nmol of ATP, 100 nmol of α,β-methylene ATP or vehicle. The dose of U.V.B irradiation given was 1500 mJ cm−2. U.V. inflammation potentiates the nocifensive activity of ATP analogues. The paw lifting behaviour was significantly augmented for both compounds (P<0.05, ANOVA). The asterisks indicate significant difference between individual groups at a particular dose (P<0.05, Dunnet's post hoc test).
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References

    1. BEAN B.P. ATP activated channels in rat and bullfrog sensory neurones: concentration dependence and kinetics. J. Neurosci. 1990;10:1–10. - PMC - PubMed
    1. BLAND-WARD P.A., HUMPHREY P.P.A. Acute nociception mediated by hindpaw P2X receptor activation in the rat. Br. J. Pharmacol. 1997;122:365–371. - PMC - PubMed
    1. BLEEHEN T., KEELE C.A. Observations on the algogenic actions of adenosine compounds on the human blister base preparation. Pain. 1977;3:367–377. - PubMed
    1. BRADBURY E.J., BURNSTOCK G., MCMAHON S.B. The expression of P2X3 purinoreceptors in sensory neurones: effects of axotomy and glial-derived neurotrophic factor (GDNF) Mol. Cell. Neursci.in press - PubMed
    1. BRAKE A.J., JULIUS D. Signalling by extracellular nucleotides. Annu. Rev. Cell. Dev. Biol. 1996;12:519–541. - PubMed

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