Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Physalin F via Block of CaV2.3 (R-Type) and CaV2.2 (N-Type) Voltage-Gated Calcium Channels

Zhiming Shan, Song Cai, Jie Yu, Zhongjun Zhang, Tissiana Gabriela Menna Vallecillo, Maria Jin Serafini, Ann Mary Thomas, Nancy Yen Ngan Pham, Shreya Sai Bellampalli, Aubin Moutal, Yuan Zhou, Guo Bo Xu, Ya Ming Xu, Shizhen Luo, Marcel Patek, John M. Streicher, A. A.Leslie Gunatilaka, Rajesh Khanna

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

No universally efficacious therapy exists for chronic pain, a disease affecting one-fifth of the global population. An overreliance on the prescription of opioids for chronic pain despite their poor ability to improve function has led to a national opioid crisis. In 2018, the NIH launched a Helping to End Addiction Long-term plan to spur discovery and validation of novel targets and mechanisms to develop alternative nonaddictive treatment options. Phytochemicals with medicinal properties have long been used for various treatments worldwide. The natural product physalin F, isolated from the Physalis acutifolia (family: Solanaceae) herb, demonstrated antinociceptive effects in models of inflammatory pain, consistent with earlier reports of its anti-inflammatory and immunomodulatory activities. However, the target of action of physalin F remained unknown. Here, using whole-cell and slice electrophysiology, competition binding assays, and experimental models of neuropathic pain, we uncovered a molecular target for physalin F's antinociceptive actions. We found that physalin F (i) blocks CaV2.3 (R-type) and CaV2.2 (N-type) voltage-gated calcium channels in dorsal root ganglion (DRG) neurons, (ii) does not affect CaV3 (T-type) voltage-gated calcium channels or voltage-gated sodium or potassium channels, (iii) does not bind G-protein coupled opioid receptors, (iv) inhibits the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in spinal cord slices, and (v) reverses tactile hypersensitivity in models of paclitaxel-induced peripheral neuropathy and spinal nerve ligation. Identifying CaV2.2 as a molecular target of physalin F may spur its use as a tool for mechanistic studies and position it as a structural template for future synthetic compounds.

Original languageEnglish (US)
Pages (from-to)2939-2955
Number of pages17
JournalACS Chemical Neuroscience
Volume10
Issue number6
DOIs
StatePublished - Jun 19 2019

Keywords

  • N-type voltage-gated calcium channels
  • natural products
  • neuropathic pain
  • non-opioid
  • physalin F

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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    Shan, Z., Cai, S., Yu, J., Zhang, Z., Vallecillo, T. G. M., Serafini, M. J., Thomas, A. M., Pham, N. Y. N., Bellampalli, S. S., Moutal, A., Zhou, Y., Xu, G. B., Xu, Y. M., Luo, S., Patek, M., Streicher, J. M., Gunatilaka, A. A. L., & Khanna, R. (2019). Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Physalin F via Block of CaV2.3 (R-Type) and CaV2.2 (N-Type) Voltage-Gated Calcium Channels. ACS Chemical Neuroscience, 10(6), 2939-2955. https://doi.org/10.1021/acschemneuro.9b00166