Abstract
Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.
Highlights
According to the International Association for the Study of Pain, pain is an unpleasant sensory and emotional experience associated with real or potential tissue damage, which helps the body to be aware of harmful stimuli
We identified that both voltage-gated Ca2+ and Na+ channels are the pharmacological targets of 1-O-acetylgeopyxin A
HIV-induced sensory neuropathy is alleviated by treatment with 1-O-acetylgeopyxin a Since voltage-gated Ca2+ and Na+ channels have been shown to play an important role in neuropathic pain [22,23,24,25,26], we explored the potential of 1-O-acetylgeopyxin A in alleviating neuropathic pain in an experimental model
Summary
According to the International Association for the Study of Pain, pain is an unpleasant sensory and emotional experience associated with real or potential tissue damage, which helps the body to be aware of harmful stimuli. This type of pain is short in duration and disappears with the resolution of the pathological process [1]. An estimated 20% of patients with pain-related diagnoses (including acute and chronic pain) receive an opioid prescription. Opioids are associated with multiple side effects including respiratory depression, tolerance, dependence, hyperalgesia, constipation, and mental fog among others [4]. Due to their inefficiency and side effects they affect the quality of life of patients, a reduction in the prescription of opioids to treat pain, has been recommended [4]. There is a tremendous need to develop novel non-opioid pain-relieving therapeutics to provide alternative treatments to manage neuropathic pain
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