期刊
PAIN
卷 160, 期 1, 页码 117-135出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/j.pain.0000000000001385
关键词
Desert lavender extract; Betulinic acid; T-type calcium channels; Cav3.2/3.3; Nonopioid; HIV-induced sensory neuropathy; Paclitaxel-induced peripheral neuropathy
资金
- College of Agriculture and Life Sciences (University of Arizona)
- National Institute of Neurological Disorders and Stroke [R01NS098772]
- National Institute on Drug Abuse [R01DA042852]
- Department of Defense Congressionally Directed Military Medical Research and Development Program [NF1000099]
- Children's Tumor Foundation NF1 Synodos award [2015-04-009A]
- Children's Tumor Foundation [2015-01-011]
- Alberta Innovates
- Canadian Institutes for Health Research
The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of vottage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca2+, but not Na+, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.
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