Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels

Abstract

Lappaconitine (LA) has been widely used for postoperative and cancer pain control. LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine. However, the mechanisms underlying the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Nav1.7 in a voltage-dependent manner with an IC value (with 95% confidence limits) of 27.67 (15.68-39.66) µmol/L when the cell was clamped at -70 mV. In comparison with the quick and reversible inhibition of Nav1.7 by tetracaine and bupivacaine, the inhibitory effect of LA was rather slow and irreversible. It took more than 10 min to achieve steady-state inhibition when LA (300 µmol/L) was administered. Unlike tetracaine and bupivacaine, LA affected neither the voltage-dependent activation nor the inactivation of the channels. Five residues in domain III and domain IV have been reported to be critical for the effects of the two local anesthetics on Nav channels. But our mutant study revealed that only two residues (F1737, N1742) located in domain IV were necessary for the inhibitory activity of LA. The slow onset, irreversibility, and lack of influence on channel activation and inactivation accompanied with the different molecular determinants suggest that LA may inhibit Nav1.7 channels in a manner different from local anesthetics. These results may help to understand the featured analgesic activity of LA, thus benefiting its application in the clinic and future drug development.

Hybrides of Alkaloid Lappaconitine with Pyrimidine Motif on the Anthranilic Acid Moiety: Design, Synthesis, and Investigation of Antinociceptive Potency

“…So the synthesized derivative 12 exhibits 20 times less toxicity compared to lappaconitine 1 [21]. Inhibitors selective for peripherally expressed Nav1.7, Nav1.8, and Nav1.9 isoforms have been identified as potential analgesics for the treatment of pain [18,19,52]. XRD studies of the active site of antagonists of the voltage-gated sodium channel 1.7 revealed three main pockets in its structure: anion-binding, selectivity, and lipid-exposed ( Figure 3).…”

“…Among Nav channels, Nav1.7 and Nav1.8, followed by Nav1.9, are the isoforms more implicated in pain signaling [18]. Recently, lappaconitine 1 was found to be an inhibitor of the Nav1.7 channel [19], which has been proposed as a promising analgesic target predominantly distributed in the nervous system [20].…”

The toxicology and detoxification of Aconitum: traditional and modern views

“…Thus, lappaconitine (LA) shines as a better candidate for analgesics, due to its low toxicity [ 35 , 36 ]. LA has more or less level of analgesic activity, when comparing to morphine, in different tests on mice and rats [ 37 , 38 ].…”

The Analgesic Effect of Aconitum Sinomontanum Nakai Pharmacopuncture in Sprague-Dawley Rats

“…ASN acts as an antiinflammatory agent, antipyretic, and an analgesic. In particular, it is used in China as an analgesic for various diseases, and studies have been conducted on methods of extracting the main ingredients of ASN [11,12].…”