Zheng Ting, Zhang Ting, Zhang Run, Wang Zi-Long, Han Zheng-Lan, Li Ning, Li Xu-Hui, Zhang Meng-Na, Xu Biao, Yang Xiong-Li, Fang Quan, Wang Rui
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou 730000, PR China.
Neuropeptides. 2017 Jun;63:83-90. doi: 10.1016/j.npep.2016.12.006. Epub 2016 Dec 16.
Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. Moreover, hemopressin and its truncated peptides were also reported to produce a slight modulatory effect on opioid system. In the present work, based on the amino acid sequence analyses of hemoglobin subunit α, rat VD-hemopressin(α) [(r)VD-Hpα] was predicted as a cannabinoid peptide derived from rat α-hemoglobin. Furthermore, (r)VD-Hpα was synthesized and characterized in a series of in vitro and in vivo assays. Our results demonstrated that (r)VD-Hpα induced neurite outgrowth in Neuro 2A cells via CB receptor. In the tail-flick assay, (r)VD-Hpα dose-dependently exerted central antinociception through CB receptor, but not CB and opioid receptors. In mice, supraspinal administration of (r)VD-Hpα produced dose-dependent hypothermia, which was partially reduced by the CB receptor antagonist AM251, but not by the antagonists of CB and opioid receptors. In addition, (r)VD-Hpα caused hypoactivity after intracerebroventricular injection, and this effect was insensitive to the antagonists of cannabinoid and opioid receptors. Further assessment of the side-effects demonstrated that (r)VD-Hpα evoked the limited effects on gastrointestinal transit at antinociceptive doses, but repeated i.c.v. injection of (r)VD-Hpα induced development of antinociceptive tolerance. Taken together, these data suggest that the predicted peptide (r)VD-Hpα produces antinociception, hypothermia and hypoactivity via different pharmacological mechanisms, at least partially, which may offer an attractive strategy for separating cannabinoid analgesia from hypoactivity. Moreover, it implies that (r)VD-Hpα has therapeutic potential in pain management with limited side-effects.
血加压素及相关肽已被证明可作为内源性配体或大麻素受体的调节剂。此外，据报道血加压素及其截短肽对阿片系统也有轻微的调节作用。在本研究中，基于血红蛋白α亚基的氨基酸序列分析，预测大鼠VD - 血加压素(α) [(r)VD - Hpα]是一种源自大鼠α - 血红蛋白的大麻素肽。此外，合成了(r)VD - Hpα并在一系列体外和体内试验中对其进行了表征。我们的结果表明，(r)VD - Hpα通过CB受体诱导Neuro 2A细胞的神经突生长。在甩尾试验中，(r)VD - Hpα通过CB受体剂量依赖性地发挥中枢镇痛作用，但不通过CB和阿片受体。在小鼠中，脊髓上给予(r)VD - Hpα产生剂量依赖性体温过低，CB受体拮抗剂AM251可部分降低这种体温过低，但CB和阿片受体拮抗剂则不能。此外，脑室内注射(r)VD - Hpα后会导致活动减少，且这种作用对大麻素和阿片受体拮抗剂不敏感。对副作用的进一步评估表明，(r)VD - Hpα在镇痛剂量下对胃肠蠕动的影响有限，但反复脑室内注射(r)VD - Hpα会诱导镇痛耐受性的产生。综上所述，这些数据表明，预测的肽(r)VD - Hpα至少部分地通过不同的药理机制产生镇痛、体温过低和活动减少作用，这可能为将大麻素镇痛与活动减少区分开来提供一种有吸引力的策略。此外，这意味着(r)VD - Hpα在疼痛管理方面具有治疗潜力且副作用有限。
