Involvement of glycine receptor alpha 1 subunits in cannabinoid-induced analgesia

Some cannabinoids have been shown to suppress chronic pain by targeting glycine receptors (GlyRs). Although cannabinoid potentiation of alpha 3 GlyRs is thought to contribute to cannabinoid-induced analgesia, the role of cannabinoid potentiation of alpha 1 GlyRs in cannabinoid suppression of chronic pain remains unclear. Here we report that dehydroxylcannabidiol (DH-CBD), a nonpsychoactive cannabinoid, significantly suppresses chronic inflammatory pain caused by noxious heat stimulation. This effect may involve spinal alpha 1 GlyRs since the expression level of alpha 1 subunits in the spinal cord is positively correlated with CFA-induced inflammatory pain and the GlyRs antagonist strychnine blocks the DH-CBD-induced analgesia. A point-mutation of S296A in TM3 of alpha 1 GlyRs significantly inhibits DH-CBD potentiation of glycine currents (I-Gly) in HEK-293 cells and neurons in lamina I-II of spinal cord slices. To explore the in vivo consequence of DH-CBD potentiation of alpha 1 GlyRs, we generated a GlyR alpha 1(s296A) knock-in mouse line. We observed that DH-CBD-induced potentiation of I-Gly and analgesia for inflammatory pain was absent in GlyR alpha 1(S296A) knock-in mice. These findings suggest that spinal alpha 1 GlyR is a potential target for cannabinoid analgesia in chronic inflammatory pain. (C) 2018 Elsevier Ltd. All rights reserved.