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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
journal contribution
posted on 2019-04-04, 00:00 authored by 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 KhannaNo
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.