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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.

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In vivo electrophysiology of WDR neuron firing response after intraplantar 8-pCPT or 6-Bnz-cAMP.Evoked responses to von Frey filaments before and after administration of (a) 8-pCPT (n=8), (b) 6-Bnz-cAMP (n=8), or (c) saline (n=7). 8-pCPT shifted the stimulus–response curve to the left and enhanced responses to innocuous von Frey, while 6-Bnz-cAMP only enhanced response of von Frey >16 g. Responses to transcutaneous electrical stimulation of the receptive field before and after intraplantar injection of (d) 8-pCPT (n=8), (e) 6-Bnz-cAMP (n=9), or (f) saline (n=7). Data are expressed as mean±s.e.m. (a–c) Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. (d–f) Data are analysed by t-test *P<0.05, **P<0.01.
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f6: In vivo electrophysiology of WDR neuron firing response after intraplantar 8-pCPT or 6-Bnz-cAMP.Evoked responses to von Frey filaments before and after administration of (a) 8-pCPT (n=8), (b) 6-Bnz-cAMP (n=8), or (c) saline (n=7). 8-pCPT shifted the stimulus–response curve to the left and enhanced responses to innocuous von Frey, while 6-Bnz-cAMP only enhanced response of von Frey >16 g. Responses to transcutaneous electrical stimulation of the receptive field before and after intraplantar injection of (d) 8-pCPT (n=8), (e) 6-Bnz-cAMP (n=9), or (f) saline (n=7). Data are expressed as mean±s.e.m. (a–c) Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. (d–f) Data are analysed by t-test *P<0.05, **P<0.01.

Mentions: Lamina V wide dynamic range (WDR) neurons in the dorsal horn respond to all sensory modalities. Extracellular recording from rat WDR neurons in response to mechanical input to the receptive field showed that 8-pCPT enhanced WDR neuron firing in response to mechanical stimuli applied to the hind paw that was ≤26 g (Fig. 6a). In contrast, 6-Bnz-cAMP only enhanced WDR neuron firing in response to mechanical stimuli applied to the receptive field (hind paw) that were larger than 15 g (Fig. 6b). Intraplantar injection of saline did not change WDR neuron firing responses evoked by any mechanical stimuli (Fig. 6c).


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)

In vivo electrophysiology of WDR neuron firing response after intraplantar 8-pCPT or 6-Bnz-cAMP.Evoked responses to von Frey filaments before and after administration of (a) 8-pCPT (n=8), (b) 6-Bnz-cAMP (n=8), or (c) saline (n=7). 8-pCPT shifted the stimulus–response curve to the left and enhanced responses to innocuous von Frey, while 6-Bnz-cAMP only enhanced response of von Frey >16 g. Responses to transcutaneous electrical stimulation of the receptive field before and after intraplantar injection of (d) 8-pCPT (n=8), (e) 6-Bnz-cAMP (n=9), or (f) saline (n=7). Data are expressed as mean±s.e.m. (a–c) Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. (d–f) Data are analysed by t-test *P<0.05, **P<0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: In vivo electrophysiology of WDR neuron firing response after intraplantar 8-pCPT or 6-Bnz-cAMP.Evoked responses to von Frey filaments before and after administration of (a) 8-pCPT (n=8), (b) 6-Bnz-cAMP (n=8), or (c) saline (n=7). 8-pCPT shifted the stimulus–response curve to the left and enhanced responses to innocuous von Frey, while 6-Bnz-cAMP only enhanced response of von Frey >16 g. Responses to transcutaneous electrical stimulation of the receptive field before and after intraplantar injection of (d) 8-pCPT (n=8), (e) 6-Bnz-cAMP (n=9), or (f) saline (n=7). Data are expressed as mean±s.e.m. (a–c) Data were analysed using two-way analysis of variance followed by the Bonferroni post hoc test. (d–f) Data are analysed by t-test *P<0.05, **P<0.01.
Mentions: Lamina V wide dynamic range (WDR) neurons in the dorsal horn respond to all sensory modalities. Extracellular recording from rat WDR neurons in response to mechanical input to the receptive field showed that 8-pCPT enhanced WDR neuron firing in response to mechanical stimuli applied to the hind paw that was ≤26 g (Fig. 6a). In contrast, 6-Bnz-cAMP only enhanced WDR neuron firing in response to mechanical stimuli applied to the receptive field (hind paw) that were larger than 15 g (Fig. 6b). Intraplantar injection of saline did not change WDR neuron firing responses evoked by any mechanical stimuli (Fig. 6c).

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