Analgesic effects of ivermectin, baicalin, and DL-kavain in a mouse model of thermal hypersensitivity correlate with modulation of recombinant alpha3 glycine receptor function.

The inhibitory glycine receptor (GlyR) mediates rapid synaptic inhibition in the mammalian nervous system. Spinal α3 GlyRs are involved in transmission of nociceptive signals. Their inhibition leads to increased pain sensitivity and allodynia, while potentiation of their activity results in analgesia. Here, we correlated modulation of recombinant α3K GlyR channels, expressed in HEK293 cells, by ivermectin, baicalin and DL-kavain to their modulatory activity on strychnine-induced thermal hyperalgesia in mice. Using whole-cell patch-clamp recording, we found ivermectin to be a strychnine-insensitive agonist (EC50 1.07 ± 0.05 µM), while baicalin and DL-kavain were moderate inhibitors of α3K GlyRs with Ki values of 155 ± 25 µM and 133 ± 12 µM, respectively. Despite being inhibitors when applied alone, both compounds reduced the inhibitory potency of strychnine in co-application experiments. In hotplate tests, ivermectin completely abolished strychnine-induced hyperalgesia and acted as analgesic when given alone. Single application of baicalin had no effect on pain-related behavior but attenuated strychnine-induced hyperalgesia, mirroring the in vitro reduction of strychnine inhibition. DL-kavain alone increased thermal sensitivity, but reduced strychnine-induced hyperalgesia when both drugs were given together, although the effect was not significant. The data confirm that agonist activity of ivermectin on recombinant α3K GlyRs correlates with analgesic action in vivo. Effects on pain-related behaviour by baicalin and DL-kavain followed the same pattern of modulation of strychnine inhibition that was seen in vitro, confirming the relevance of GlyR signaling in nociception.