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Papers of the Week

Papers: 30 Mar 2019 - 5 Apr 2019

Animal Studies, Pharmacology/Drug Development

2019 Jun 19

ACS Chem Neurosci



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.


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 JM, Gunatilaka LAA, Khanna R
ACS Chem Neurosci. 2019 Jun 19; 10(6):2939-2955.
PMID: 30946560.


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.