Abstract
Picrasma quassioides (D. Don) Benn, a medical plant, is used in clinic to treat inflammation, pain, sore throat, and eczema. The alkaloids are the main active components in P. quassioides. In this study, we examined the analgesic effect of dehydrocrenatidine (DHCT), a β-carboline alkaloid abundantly found in P. quassioides in a neuropathic pain rat model of a sciatic nerve chronic constriction injury. DHCT dose-dependently attenuated the mechanic allodynia. In acutely isolated dorsal root ganglion, DHCT completely suppressed the action potential firing. Further electrophysiological characterization demonstrated that DHCT suppressed both tetrodotoxin-resistant (TTX-R) and sensitive (TTX-S) voltage-gated sodium channel (VGSC) currents with IC50 values of 12.36 μM and 4.87 µM, respectively. DHCT shifted half-maximal voltage (V1/2) of inactivation to hyperpolarizing direction by ~16.7 mV in TTX-S VGSCs. In TTX-R VGSCs, DHCT shifted V1/2 of inactivation voltage to hyperpolarizing direction and V1/2 of activation voltage to more depolarizing potential by ~23.9 mV and ~12.2 mV, respectively. DHCT preferred to interact with an inactivated state of VGSCs and prolonged the repriming time in both TTX-S and TTX-R VGSCs, transiting the channels into a slow inactivated state from a fast inactivated state. Considered together, these data demonstrated that the analgesic effect of DHCT was likely though the inhibition of neuronal excitability.
Highlights
Neuropathic pain affects 6–8% of the population, among which 27% of patients are in a condition of chronic pain [1]
Given the inhibitory effect on action potential (AP) generation in acutely dissociated rat dorsal root ganglion (DRG) neurons and the pivotal role of voltage-gated sodium channel (VGSC) on neuroexcitability, we examined the activity of DHCT on VGSCs in DRG neurons
The mechanisms of neuropathic pain are complex, sensitization of nociceptors has been proposed to be the major cause for abnormal nociception [3]
Summary
Neuropathic pain affects 6–8% of the population, among which 27% of patients are in a condition of chronic pain [1]. Despite the existence of seven categories of pain drugs, only 30% of patients get adequate relief. Currently used analgesics produce significant side effects, such as addiction and sedation, which negatively affect life quality of the patients [2]. Neuropathic pain results from disorders of peripheral and/or central nervous systems. Sensitization of neurons leads to enhanced neuronal excitability representing the major cause of abnormal nociception [3]. Alterations in the activities and/or expression levels of ion channels, such as calcium, sodium, and potassium channels, have been demonstrated in neurons from neuropathic pain rodent models and contribute to the Toxins 2019, 11, 229; doi:10.3390/toxins11040229 www.mdpi.com/journal/toxins
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