Brain-enriched guanylate kinase-associated protein in the spinal dorsal horn regulates mechanical allodynia in male mouse neuropathic and inflammatory pain model.

Mechanical allodynia results from plastic changes in the central nervous system. Identifying the molecules involved in this plasticity is essential for understanding the mechanism of pathological pain. In a previous report, brain-enriched guanylate kinase-associated protein (BEGAIN) was identified as a protein upregulated in the spinal dorsal horn in the spared nerve injury (SNI) model. Although global BEGAIN-knockout (BEGAIN-KO) mice exhibited attenuated mechanical allodynia, it remained unclear whether BEGAIN contributes to wits development via regulatory roles in the spinal dorsal horn or supraspinal regions. To address this, spinal dorsal horn-specific BEGAIN conditional knockout (cKO) mice were generated, which showed a partial reduction in mechanical allodynia similar to that observed in global BEGAIN-KO mice in the SNI model. Next, to identify BEGAIN-expressing neuronal populations, in situ hybridization was performed; however, messenger RNA was detected throughout the spinal cord, preventing specific identification. Therefore, BEGAIN-iCre::Ai9 mice, in which BEGAIN-expressing neurons are labeled with tdTomato, were used to analyze their distribution. As a result, 15.7% of neurons in laminae I-III expressed BEGAIN, including 4.5% of Pax2-positive inhibitory neurons. A marked reduction in inflammatory pain-induced cFos-positive cells in these laminae was observed in both BEGAIN-cKO and BEGAIN-KO mice compared with wild-type mice. In addition, mechanical allodynia was almost completely attenuated in both KO mice. Based on these findings in male mice, conditional deletion of BEGAIN was shown to effectively reduce both cellular activation in laminae I-III and allodynia under pathological pain conditions.