Limits...
A role for Piezo2 in EPAC1-dependent mechanical allodynia.

Eijkelkamp N, Linley JE, Torres JM, Bee L, Dickenson AH, Gringhuis M, Minett MS, Hong GS, Lee E, Oh U, Ishikawa Y, Zwartkuis FJ, Cox JJ, Wood JN - Nat Commun (2013)

Bottom Line: Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton.Piezo2 knockdown also enhanced thresholds for light touch.Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. N.Eijkelkamp@umcutrecht.nl

ABSTRACT
Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1-/- mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1-Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain.

Show MeSH

Related in: MedlinePlus

Piezo2 is required for allodynia in two models of chronic neuropathic pain.Mice were subjected to a unilateral L5 spinal nerve transaction (L5 SNT; a) or to a unilateral chronic constriction injury of the sciatic nerve (CCI; b). The 50% threshold to von Frey was measured at the ipsilateral and contralateral paw. Piezo2 (L5 SNT, n=5; CCI, n=6) or mismatch antisense (L5 SNT, n=9; CCI, n=10) was administered after full development of allodynia (2–3 weeks after operation) as indicated by the grey bars. (c) Fold reduction of 50% threshold to von Frey of the ipsilateral paw compared the contralateral paw in both models of neuropathic pain at day 21 (L5 SNT; n=5–9) or 26 (CCI; n=6–10). Piezo2 mRNA expression in the ipsi- and contralateral DRG expression was measured 1 day after the last antisense ODN administration(d, L 5 SNT, n=5–9; e, CCI, n=6–10). Two-way one-way analysis of variance showed a significant overall reduction in Piezo2 mRNA P<0.01. Data are expressed as mean±s.e.m. Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. *P<0.05, **P<0.001, ***P<0.001. In a and b ‘###’indicate P<0.001 compared to the contralateral paw of mismatch antisense ODN treated mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3644070&req=5

f8: Piezo2 is required for allodynia in two models of chronic neuropathic pain.Mice were subjected to a unilateral L5 spinal nerve transaction (L5 SNT; a) or to a unilateral chronic constriction injury of the sciatic nerve (CCI; b). The 50% threshold to von Frey was measured at the ipsilateral and contralateral paw. Piezo2 (L5 SNT, n=5; CCI, n=6) or mismatch antisense (L5 SNT, n=9; CCI, n=10) was administered after full development of allodynia (2–3 weeks after operation) as indicated by the grey bars. (c) Fold reduction of 50% threshold to von Frey of the ipsilateral paw compared the contralateral paw in both models of neuropathic pain at day 21 (L5 SNT; n=5–9) or 26 (CCI; n=6–10). Piezo2 mRNA expression in the ipsi- and contralateral DRG expression was measured 1 day after the last antisense ODN administration(d, L 5 SNT, n=5–9; e, CCI, n=6–10). Two-way one-way analysis of variance showed a significant overall reduction in Piezo2 mRNA P<0.01. Data are expressed as mean±s.e.m. Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. *P<0.05, **P<0.001, ***P<0.001. In a and b ‘###’indicate P<0.001 compared to the contralateral paw of mismatch antisense ODN treated mice.

Mentions: To investigate the role of Piezo2 in neuropathy-induced allodynia, a unilateral L5 nerve transaction (L5 SNT) or a sciatic nerve ligation (chronic constriction injury (CCI)) was performed in mice to induce neuropathic pain. In both models mice developed mechanical allodynia in the ipsilateral paw, while mechanical thresholds to touch in the contralateral paw were unaffected (Fig. 8a–e). In the L5 SNT model, mice were treated intrathecally with Piezo2 antisense ODN starting at day 15. Piezo2 antisense treatment significantly attenuated L5 SNT-induced allodynia compared with mismatch-treated mice (Fig. 8a). Piezo2 antisense ODN treatment also increased thresholds to touch compared with mismatch antisense-treated mice at the unaffected contralateral paw (Fig. 8a). In the CCI model of neuropathic pain, multiple intrathecal Piezo2 antisense injections also significantly attenuated CCI-induced mechanical allodynia (Fig. 8b). At the unaffected contralateral paw, Piezo2 antisense ODN treatment also increased thresholds to touch (Fig. 8b). Although Piezo2 antisense ODN increased mechanical thresholds both at the ipsi- and contralateral paw in both models of neuropathic pain, Piezo2 antisense ODN reduced the neuropathic pain-induced difference in mechanosensitivity between the contra and ipsilateral paw (Fig. 8c).


A role for Piezo2 in EPAC1-dependent mechanical allodynia.

Eijkelkamp N, Linley JE, Torres JM, Bee L, Dickenson AH, Gringhuis M, Minett MS, Hong GS, Lee E, Oh U, Ishikawa Y, Zwartkuis FJ, Cox JJ, Wood JN - Nat Commun (2013)

Piezo2 is required for allodynia in two models of chronic neuropathic pain.Mice were subjected to a unilateral L5 spinal nerve transaction (L5 SNT; a) or to a unilateral chronic constriction injury of the sciatic nerve (CCI; b). The 50% threshold to von Frey was measured at the ipsilateral and contralateral paw. Piezo2 (L5 SNT, n=5; CCI, n=6) or mismatch antisense (L5 SNT, n=9; CCI, n=10) was administered after full development of allodynia (2–3 weeks after operation) as indicated by the grey bars. (c) Fold reduction of 50% threshold to von Frey of the ipsilateral paw compared the contralateral paw in both models of neuropathic pain at day 21 (L5 SNT; n=5–9) or 26 (CCI; n=6–10). Piezo2 mRNA expression in the ipsi- and contralateral DRG expression was measured 1 day after the last antisense ODN administration(d, L 5 SNT, n=5–9; e, CCI, n=6–10). Two-way one-way analysis of variance showed a significant overall reduction in Piezo2 mRNA P<0.01. Data are expressed as mean±s.e.m. Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. *P<0.05, **P<0.001, ***P<0.001. In a and b ‘###’indicate P<0.001 compared to the contralateral paw of mismatch antisense ODN treated mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3644070&req=5

f8: Piezo2 is required for allodynia in two models of chronic neuropathic pain.Mice were subjected to a unilateral L5 spinal nerve transaction (L5 SNT; a) or to a unilateral chronic constriction injury of the sciatic nerve (CCI; b). The 50% threshold to von Frey was measured at the ipsilateral and contralateral paw. Piezo2 (L5 SNT, n=5; CCI, n=6) or mismatch antisense (L5 SNT, n=9; CCI, n=10) was administered after full development of allodynia (2–3 weeks after operation) as indicated by the grey bars. (c) Fold reduction of 50% threshold to von Frey of the ipsilateral paw compared the contralateral paw in both models of neuropathic pain at day 21 (L5 SNT; n=5–9) or 26 (CCI; n=6–10). Piezo2 mRNA expression in the ipsi- and contralateral DRG expression was measured 1 day after the last antisense ODN administration(d, L 5 SNT, n=5–9; e, CCI, n=6–10). Two-way one-way analysis of variance showed a significant overall reduction in Piezo2 mRNA P<0.01. Data are expressed as mean±s.e.m. Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. *P<0.05, **P<0.001, ***P<0.001. In a and b ‘###’indicate P<0.001 compared to the contralateral paw of mismatch antisense ODN treated mice.
Mentions: To investigate the role of Piezo2 in neuropathy-induced allodynia, a unilateral L5 nerve transaction (L5 SNT) or a sciatic nerve ligation (chronic constriction injury (CCI)) was performed in mice to induce neuropathic pain. In both models mice developed mechanical allodynia in the ipsilateral paw, while mechanical thresholds to touch in the contralateral paw were unaffected (Fig. 8a–e). In the L5 SNT model, mice were treated intrathecally with Piezo2 antisense ODN starting at day 15. Piezo2 antisense treatment significantly attenuated L5 SNT-induced allodynia compared with mismatch-treated mice (Fig. 8a). Piezo2 antisense ODN treatment also increased thresholds to touch compared with mismatch antisense-treated mice at the unaffected contralateral paw (Fig. 8a). In the CCI model of neuropathic pain, multiple intrathecal Piezo2 antisense injections also significantly attenuated CCI-induced mechanical allodynia (Fig. 8b). At the unaffected contralateral paw, Piezo2 antisense ODN treatment also increased thresholds to touch (Fig. 8b). Although Piezo2 antisense ODN increased mechanical thresholds both at the ipsi- and contralateral paw in both models of neuropathic pain, Piezo2 antisense ODN reduced the neuropathic pain-induced difference in mechanosensitivity between the contra and ipsilateral paw (Fig. 8c).

Bottom Line: Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton.Piezo2 knockdown also enhanced thresholds for light touch.Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres.

View Article: PubMed Central - PubMed

Affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. N.Eijkelkamp@umcutrecht.nl

ABSTRACT
Aberrant mechanosensation has an important role in different pain states. Here we show that Epac1 (cyclic AMP sensor) potentiation of Piezo2-mediated mechanotransduction contributes to mechanical allodynia. Dorsal root ganglia Epac1 mRNA levels increase during neuropathic pain, and nerve damage-induced allodynia is reduced in Epac1-/- mice. The Epac-selective cAMP analogue 8-pCPT sensitizes mechanically evoked currents in sensory neurons. Human Piezo2 produces large mechanically gated currents that are enhanced by the activation of the cAMP-sensor Epac1 or cytosolic calcium but are unaffected by protein kinase C or protein kinase A and depend on the integrity of the cytoskeleton. In vivo, 8-pCPT induces long-lasting allodynia that is prevented by the knockdown of Epac1 and attenuated by mouse Piezo2 knockdown. Piezo2 knockdown also enhanced thresholds for light touch. Finally, 8-pCPT sensitizes responses to innocuous mechanical stimuli without changing the electrical excitability of sensory fibres. These data indicate that the Epac1-Piezo2 axis has a role in the development of mechanical allodynia during neuropathic pain.

Show MeSH
Related in: MedlinePlus