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Blockade of Nav1.8 Currents in Nociceptive Trigeminal Neurons Contributes to Anti-trigeminovascular Nociceptive Effect of Amitriptyline

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Abstract

Amitriptyline (AMI), a tricyclic antidepressant, has been widely used to prevent migraine attacks and alleviate other various chronic pain, but the underlying mechanism remains unclear. Accumulated evidence suggests that the efficacy of AMI is related to the blockade of voltage-gated sodium channels. The aim of the present study was to investigate the effect of AMI on Nav1.8 currents in nociceptive trigeminal neurons and trigeminovascular nociception induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (SSS) in rats, as in the animal model of vascular headaches such as migraines. Using a whole-cell voltage recording technique, we showed that Nav1.8 currents were blocked by AMI in a concentration-dependent manner, with an IC50 value of 6.82 μM in acute isolated trigeminal ganglion neurons of the rats. AMI caused a hyperpolarizing shift in the voltage-dependent activation and steady-state inactivation and significantly blocked in a use-dependent manner and slowed the recovery from the inactivation of Nav1.8 currents. In addition, the systemic administration of AMI and A-803467 (a selective Nav1.8 channel blocker) potently alleviated the nociceptive behaviors (head flicks and grooming) induced by the electrical stimulation of the dura mater surrounding the SSS. Taken together, our data suggest that Nav1.8 currents in nociceptive trigeminal neurons are blocked by AMI through modulating the activation and inactivation kinetics, which may contribute to anti-nociceptive effect of AMI in animal models of migraines.

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Acknowledgments

This study was supported by the National Science Foundation of China (Nos. 30970417 and 81171058) and the China Postdoctoral Science Foundation (No. 20100481477).

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Authors and Affiliations

  1. Department of Neurology, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China

    Jingyao Liang, Meiyan Pan, Wei Dai, Zhao Dong, Xiaolin Wang, Ruozhuo Liu & Shengyuan Yu

  2. Department of Biochemical Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, People’s Republic of China

    Xiaoyan Liu & Jianquan Zheng

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  1. Jingyao Liang
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Correspondence to Shengyuan Yu.

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Jingyao Liang and Xiaoyan Liu have contributed equally to this work.

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Liang, J., Liu, X., Pan, M. et al. Blockade of Nav1.8 Currents in Nociceptive Trigeminal Neurons Contributes to Anti-trigeminovascular Nociceptive Effect of Amitriptyline. Neuromol Med 16, 308–321 (2014). https://doi.org/10.1007/s12017-013-8282-6

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  • DOI: https://doi.org/10.1007/s12017-013-8282-6

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