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
- 4 April 2019
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Chemical Neuroscience
- Vol. 10 (6), 2939-2955
- https://doi.org/10.1021/acschemneuro.9b00166
Abstract
No universally efficacious therapy exists for chronic pain, a disease affecting one-fifth of the global population. An overreliance in 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 non-addictive 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.Keywords
Funding Information
- National Institute of Neurological Disorders and Stroke (R01NS098772)
- Ministry of Science and Technology of the People's Republic of China (2018YFC1705501)
- National Center for Complementary and Integrative Health (R01AT009716)
- China Scholarship Council
- National Institute on Drug Abuse (R01DA042852)
- National Natural Science Foundation of China (81603088)
- Medical Scientific Research Foundation of Guangdong Province (A2017047)
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