The cannabinoid dehydroxylcannabidiol suppresses neuropathic pain by upregulating a spinal glycine receptor-mediated compensation mechanism

Neuropathic pain (NP) is well-known to be complicated and challenging to manage. Organisms have been shown to initiate various intrinsic compensatory strategies to alleviate NP, which could be utilized to aid the development of therapeutic treatments. However, these mechanisms that alleviate NP have not been fully elucidated. Here we show that spinal glycine receptor & alpha;1 (GlyR & alpha;1) is a key element of an intrinsic compensatory mechanism to alleviate NP. This spinal GlyR & alpha;1-mediated compensatory mechanism is manifested in many ways, including enhanced inhibitory glycinergic transmission and increased GlyR & alpha;1 protein expression levels. We show such GlyR & alpha;1 upregulation is achieved via an intracellular calmodulin kinase II/IV (CaMKII/IV)-cAMP response element binding protein signaling pathway. We demonstrate that dehydroxylcannabidiol, a synthetic nonpsychoactive cannabinoid that specifically targets GlyRs, significantly potentiates spinal GlyR function, inhibits spared nerve injury-induced spinal neuronal hyperactivity, and ultimately abrogates the development of hyperalgesia. These results suggest that the compensatory upregulated spinal GlyR & alpha;1 is efficacious in alleviating NP. Thus, our study reveals a potential strategy for the clinical treatment of NP by utilizing this central compensatory mechanism.