GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception

Abstract

GPR3 is an orphan G-protein coupled receptor broadly expressed in brain structures controlling emotional-like behaviors and pain. GPR3 receptor up-regulates cAMP and promotes neurite outgrowth in mammalian neurons, being a good candidate to participate in the pathophysiology of neurodegenerative diseases as well as brain and spinal cord injuries. In this study, we evaluated the role of GPR3 receptor in the development and expression of neuropathic pain after sciatic nerve ligature, and the inflammatory reaction in the dorsal horn of the spinal cord in both Gpr3−/− and Gpr3+/+ mice. Hyperalgesia to noxious thermal stimulus and allodynia to cold and mechanical stimuli were evaluated using the plantar test, the cold-plate test and the Von Frey filament model, respectively. Additionally, we evaluated the involvement of GPR3 receptors in morphine-induced antinociception using the tail immersion test. After nerve injury, Gpr3−/− mice showed a higher sensitivity to thermal non-noxious and noxious stimuli than Gpr3+/+ mice, whereas no differences were observed between genotypes in mechanical allodynia. In addition, no differences in microglia and astrocytes activation were found when compared the ipsilateral dorsal horn of Gpr3−/− and Gpr3+/+ mice exposed to nerve ligature. On the other hand, the genetic deletion of GPR3 receptors reduced morphine antinociception in the tail immersion test in mice without any changes in basal thermal threshold. Taken together, our results demonstrate, for the first time, the involvement of the orphan GPR3 receptor in the expression and development of neuropathic pain and in the analgesia induced by morphine. The lack of GPR3 receptors produced hypersensitivity to thermal non-noxious and noxious stimuli without affecting the spinal inflammatory response associated to sciatic nerve injury and reduced morphine antinociception in the tail immersion test. Our findings propose GPR3 receptors as a new molecular target in neuropathic pain therapy as well as a new component of a pro-opioid receptor system.