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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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Acute prophylactic BBG treatment alleviates NTG-induced thermal hypersensitivity in wild-type mice. Mice were treated with 50 mg/kg BBG i.p. or an identical volume of saline 30 min before NTG treatment. PWT is expressed in % of baseline. Asterisks indicate statistical significant difference in respective PWT values from the saline-treated animals (n = 11-12 mice/group; Student’s t-test, **P < 0.01).
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Figure 3: Acute prophylactic BBG treatment alleviates NTG-induced thermal hypersensitivity in wild-type mice. Mice were treated with 50 mg/kg BBG i.p. or an identical volume of saline 30 min before NTG treatment. PWT is expressed in % of baseline. Asterisks indicate statistical significant difference in respective PWT values from the saline-treated animals (n = 11-12 mice/group; Student’s t-test, **P < 0.01).

Mentions: Next, we asked whether systemic administration of a specific P2X7 antagonist, BBG, can alleviate NTG-induced thermal allodynia in mice. When administered 5 min after the NTG injection, BBG had no effect on thermal hypersensitivity in wild-type mice (Figure 2). However, when BBG was given as a prophylactic agent, 30 min before administration of NTG, it was already effective upon single application (Figure 3), and it completely prevented the effect of NTG after 5-days treatment in wild-type mice. In contrast, an identical BBG administration was ineffective in NTG-treated P2X7 knockout mice (ANOVA genotype × treatment effect F1,45 = 6.36, p = 0.0153; Figure 4). The 5-day treatment with BBG did not change the baseline thermal sensitivity of either genotype (P2X7+/+: 44.38 ± 0.27°C, n = 16; p = 0.9929, P2X7-/-: 44.86 ± 0.39°C, n = 17; p = 0.167 vs. baseline PWT, Student’s t-test).


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)

Acute prophylactic BBG treatment alleviates NTG-induced thermal hypersensitivity in wild-type mice. Mice were treated with 50 mg/kg BBG i.p. or an identical volume of saline 30 min before NTG treatment. PWT is expressed in % of baseline. Asterisks indicate statistical significant difference in respective PWT values from the saline-treated animals (n = 11-12 mice/group; Student’s t-test, **P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Acute prophylactic BBG treatment alleviates NTG-induced thermal hypersensitivity in wild-type mice. Mice were treated with 50 mg/kg BBG i.p. or an identical volume of saline 30 min before NTG treatment. PWT is expressed in % of baseline. Asterisks indicate statistical significant difference in respective PWT values from the saline-treated animals (n = 11-12 mice/group; Student’s t-test, **P < 0.01).
Mentions: Next, we asked whether systemic administration of a specific P2X7 antagonist, BBG, can alleviate NTG-induced thermal allodynia in mice. When administered 5 min after the NTG injection, BBG had no effect on thermal hypersensitivity in wild-type mice (Figure 2). However, when BBG was given as a prophylactic agent, 30 min before administration of NTG, it was already effective upon single application (Figure 3), and it completely prevented the effect of NTG after 5-days treatment in wild-type mice. In contrast, an identical BBG administration was ineffective in NTG-treated P2X7 knockout mice (ANOVA genotype × treatment effect F1,45 = 6.36, p = 0.0153; Figure 4). The 5-day treatment with BBG did not change the baseline thermal sensitivity of either genotype (P2X7+/+: 44.38 ± 0.27°C, n = 16; p = 0.9929, P2X7-/-: 44.86 ± 0.39°C, n = 17; p = 0.167 vs. baseline PWT, Student’s t-test).

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