Studies on the roles of brain orexin receptors in regulation of chronic pain

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K10081
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Nihon University
• Principal Investigator: SAIGUSA Tadashi 日本大学, 松戸歯学部, 教授 (50277456)
• Co-Investigator(Kenkyū-buntansha): 小菅 康弘 日本大学, 薬学部, 教授 (70383726)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Orexin / Dopamine / 行動薬理学 / 脳 / ラット / マウス

Outline of Final Research Achievements

The nucleus accumbens, a terminal area of the mesolimbic dopaminergic (DAergic) system, contains orexinergic neural inputs and OX1 and OX2 receptors (-Rs). We analyzed the roles of these orexin-Rs in regulating accumbal dopamine (DA) efflux in rats with or without experimentally induced chronic pain, as chronic pain has been shown to affect orexin-R-mediated orexinergic neural activity on the c-fibers and brain DAergic neural transmission might be altered by pain. Additionally, we studied the effects of repeated administration of nandrolone, an anabolic androgenic steroid, on accumbal DA efflux in rats, since drugs of abuse activate mesolimbic DAergic neurons, and nandrolone has been suspected of inducing dependence. Finally, we analyzed the effects of lipopolysaccharides from Porphyromonas gingivalis, known to be involved in the progression of periodontal disease, on novel-environment-induced locomotion in mice, which is known to be induced by increased mesolimbic DAergic activity.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

中脳辺縁系DA神経の投射する側坐核でOX2受容体はDA放出を抑制するが，この抑制の慢性痛による変化を報告できた。つまりorexin類の脳内での作用を慢性の痛みとの関連から新たに示せた。また，思春期に相当する時期のnandroloneの反復投与は中脳辺縁系DA神経活動を高めないが，nandroloneと併用して乱用されるopioidによるDA神経活動の賦活化を低下させた。即ち，nandroloneの反復投与が依存につながるopioidの過剰摂取の誘因となる危険を指摘できた。また，新環境でのマウスの活動亢進はP. gingivalis由来のリポ多糖の全身投与の影響は受けないことが示された。