There is a clear need for novel and improved therapeutic strategies for alleviating chronic neuropathic pain, as well as a need for better understanding of brain mechanisms of neuropathic pain, which are less understood than spinal and peripheral mechanisms. The G protein-coupled receptor 55 (GPR55), is a lysophosphatidylinositol (LPI)-sensitive receptor that has also been involved in cannabinoid signaling. It is expressed throughout the central nervous system, including the periaqueductal gray (PAG), a brainstem area and key element of the descending pain control system. Behaviors, pharmacology, biochemistry tools, and stereotaxic microinjections were used to determine if GPR55 plays a role in pain control in a chronic constriction injury (CCI) neuropathic pain model in rats. It was found that the blockade of GPR55 action in the PAG can restore and drive a descending control system to mitigate neuropathic pain. Our data demonstrate that GPR55 play a role in the descending pain control system, and identify GPR55 at supraspinal level as a neuropathic pain brain mechanism.
