The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray
The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray
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DOI：
10.1124/mol.115.099333
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发表时间：
2015-08-01
影响因子：
3.6
通讯作者：
Abood, Mary E.
中科院分区：
文献类型：
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作者：
Deliu, Elena;Sperow, Margaret;Abood, Mary E.
新出现的证据表明，GPR 55和它的建议内源性配体，溶血磷脂酰肌醇（LPI），在伤害性感受的参与，但他们在中枢疼痛处理的作用还没有被探讨。使用Ca 2+成像，我们在这里显示，LPI elevant浓度依赖性和GPR 55介导的细胞内Ca 2+水平的增加，在分离的大鼠中脑导水管周围灰质（PAG）神经元，表达GPR 55 mRNA。这种作用是通过1，4，5-三磷酸肌醇受体从内质网释放Ca 2+和通过P/Q型电压门控Ca 2+通道进入Ca 2+介导的。此外，LPI使PAG神经元去极化，并且在PAG内微量注射时，降低热板试验中的伤害性阈值。这两种作用都依赖于GPR 55活化，因为它们被ML-193 [N-（4-（N-（3，4-二甲基异恶唑-5-基）氨磺酰基）-苯基）-6，8-二甲基-2-（吡啶-2-基）喹啉-4-甲酰胺]（一种选择性GPR 55拮抗剂）预处理所消除。因此，我们提供了第一个药理学证据表明，GPR 55激活在中央水平是pronociceptive，这表明干扰GPR 55信号在PAG可能会促进镇痛。
Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role in central pain processing has not been explored. Using Ca2+ imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca2+ levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca2+ release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca2+ entry via P/Q-type of voltage-gated Ca2+ channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot-plate test. Both these effects are dependent on GPR55 activation, because they are abolished by pretreatment with ML-193 [N-(4-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)-phenyl)-6,8-dimethyl-2-(pyridin-2-yl)quinoline-4-carboxamide], a selective GPR55 antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.