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Effect of genetic deletion and pharmacological antagonism of P2X7 receptors in a mouse animal model of migraine.

Gölöncsér F, Sperlágh B - J Headache Pain (2014)

Bottom Line: Purine receptors participate in peripheral and central sensitization and are associated with migraine headache.The effect of genetic deletion of P2X7 and the selective P2X7 antagonist Brilliant Blue G (BBG) were examined on hyperalgesia and c-fos induction.NTG decreased the paw withdrawal threshold in both wild-type and P2X7 knockout mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083, Budapest, Szigony u,, 43, Hungary. sperlagh@koki.hu.

ABSTRACT

Background: Purine receptors participate in peripheral and central sensitization and are associated with migraine headache. We investigated the role of P2X7 receptor (P2X7) in a nitroglycerin (NTG)-induced mouse model of migraine.

Methods: Intraperitoneal NTG injection (15 mg/kg) triggered thermal hyperalgesia in the hindpaws of wild-type C57BL/6J mice, followed by the induction of c-fos in upper cervical spinal cord and trigeminal nucleus caudalis. The effect of genetic deletion of P2X7 and the selective P2X7 antagonist Brilliant Blue G (BBG) were examined on hyperalgesia and c-fos induction.

Results: NTG decreased the paw withdrawal threshold in both wild-type and P2X7 knockout mice. Nevertheless, subacute BBG treatment (50 mg/kg/day i.p.) completely prevented the effect of NTG in wild-type, but not in knockout mice. Whereas P2X7 deficiency differentially affected the expression of c-fos, the average number of fos-immuno-reactive neurons in trigeminal nucleus caudalis, but not in upper cervical spinal cord was lower in BBG-treated wild-type mice after NTG treatment.

Conclusions: Our results show that P2X7 receptors might participate in the pathogenesis of migraine, although upregulation of other P2X receptors probably compensate for the loss of its action in knockout mice. The data also suggest the therapeutic potential of P2X7 antagonists for the treatment of migraine.

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NTG induces thermal hypersensitivity in wild-type and P2X7 knockout mice. The changes in nociceptive threshold after i.p. NTG treatment are presented on the graph, as PWT, expressed in % of baseline. PWT was decreased in animals that received 15 mg/kg NTG compared with animals that received vehicle (ANOVA, effect of treatment, F1,41 = 37.34, p < 0.0001). NTG-induced decrease in PWT was not significantly different in wild-type and knockout mice. Asterisks denote significant changes between respective PWT values of vehicle- and NTG-treated mice (n = 10-13 animals/group; ANOVA + Fischer LSD post hoc test, *P < 0.05, **P < 0.01, ***P < 0.001).
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Figure 1: NTG induces thermal hypersensitivity in wild-type and P2X7 knockout mice. The changes in nociceptive threshold after i.p. NTG treatment are presented on the graph, as PWT, expressed in % of baseline. PWT was decreased in animals that received 15 mg/kg NTG compared with animals that received vehicle (ANOVA, effect of treatment, F1,41 = 37.34, p < 0.0001). NTG-induced decrease in PWT was not significantly different in wild-type and knockout mice. Asterisks denote significant changes between respective PWT values of vehicle- and NTG-treated mice (n = 10-13 animals/group; ANOVA + Fischer LSD post hoc test, *P < 0.05, **P < 0.01, ***P < 0.001).

Mentions: The baseline nociceptive threshold in wild-type (P2X7+/+) mice was 45.95 ± 0.14°C (n = 68). NTG significantly and time-dependently reduced PWT, when compared with vehicle treatment (at 1 h: 100.70 ± 1.25%, n = 12; and 93.56 ± 0.95%, n = 13; 2 h: 100.92 ± 1.13%, n = 12; and 95.06 ± 1.13%, n = 13, in vehicle and NTG-treated mice, respectively, ***P < 0.0001; Figure 1).


Effect of genetic deletion and pharmacological antagonism of P2X7 receptors in a mouse animal model of migraine.

Gölöncsér F, Sperlágh B - J Headache Pain (2014)

NTG induces thermal hypersensitivity in wild-type and P2X7 knockout mice. The changes in nociceptive threshold after i.p. NTG treatment are presented on the graph, as PWT, expressed in % of baseline. PWT was decreased in animals that received 15 mg/kg NTG compared with animals that received vehicle (ANOVA, effect of treatment, F1,41 = 37.34, p < 0.0001). NTG-induced decrease in PWT was not significantly different in wild-type and knockout mice. Asterisks denote significant changes between respective PWT values of vehicle- and NTG-treated mice (n = 10-13 animals/group; ANOVA + Fischer LSD post hoc test, *P < 0.05, **P < 0.01, ***P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016653&req=5

Figure 1: NTG induces thermal hypersensitivity in wild-type and P2X7 knockout mice. The changes in nociceptive threshold after i.p. NTG treatment are presented on the graph, as PWT, expressed in % of baseline. PWT was decreased in animals that received 15 mg/kg NTG compared with animals that received vehicle (ANOVA, effect of treatment, F1,41 = 37.34, p < 0.0001). NTG-induced decrease in PWT was not significantly different in wild-type and knockout mice. Asterisks denote significant changes between respective PWT values of vehicle- and NTG-treated mice (n = 10-13 animals/group; ANOVA + Fischer LSD post hoc test, *P < 0.05, **P < 0.01, ***P < 0.001).
Mentions: The baseline nociceptive threshold in wild-type (P2X7+/+) mice was 45.95 ± 0.14°C (n = 68). NTG significantly and time-dependently reduced PWT, when compared with vehicle treatment (at 1 h: 100.70 ± 1.25%, n = 12; and 93.56 ± 0.95%, n = 13; 2 h: 100.92 ± 1.13%, n = 12; and 95.06 ± 1.13%, n = 13, in vehicle and NTG-treated mice, respectively, ***P < 0.0001; Figure 1).

Bottom Line: Purine receptors participate in peripheral and central sensitization and are associated with migraine headache.The effect of genetic deletion of P2X7 and the selective P2X7 antagonist Brilliant Blue G (BBG) were examined on hyperalgesia and c-fos induction.NTG decreased the paw withdrawal threshold in both wild-type and P2X7 knockout mice.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083, Budapest, Szigony u,, 43, Hungary. sperlagh@koki.hu.

ABSTRACT

Background: Purine receptors participate in peripheral and central sensitization and are associated with migraine headache. We investigated the role of P2X7 receptor (P2X7) in a nitroglycerin (NTG)-induced mouse model of migraine.

Methods: Intraperitoneal NTG injection (15 mg/kg) triggered thermal hyperalgesia in the hindpaws of wild-type C57BL/6J mice, followed by the induction of c-fos in upper cervical spinal cord and trigeminal nucleus caudalis. The effect of genetic deletion of P2X7 and the selective P2X7 antagonist Brilliant Blue G (BBG) were examined on hyperalgesia and c-fos induction.

Results: NTG decreased the paw withdrawal threshold in both wild-type and P2X7 knockout mice. Nevertheless, subacute BBG treatment (50 mg/kg/day i.p.) completely prevented the effect of NTG in wild-type, but not in knockout mice. Whereas P2X7 deficiency differentially affected the expression of c-fos, the average number of fos-immuno-reactive neurons in trigeminal nucleus caudalis, but not in upper cervical spinal cord was lower in BBG-treated wild-type mice after NTG treatment.

Conclusions: Our results show that P2X7 receptors might participate in the pathogenesis of migraine, although upregulation of other P2X receptors probably compensate for the loss of its action in knockout mice. The data also suggest the therapeutic potential of P2X7 antagonists for the treatment of migraine.

Show MeSH
Related in: MedlinePlus