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Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice.
Neuropeptides. 2017 Jun; 63:83-90.N

Abstract

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 CB1 receptor. In the tail-flick assay, (r)VD-Hpα dose-dependently exerted central antinociception through CB1 receptor, but not CB2 and opioid receptors. In mice, supraspinal administration of (r)VD-Hpα produced dose-dependent hypothermia, which was partially reduced by the CB1 receptor antagonist AM251, but not by the antagonists of CB2 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.

Authors+Show Affiliations

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.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.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.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.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.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. Electronic address: fangq@lzu.edu.cn.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. Electronic address: wangrui@lzu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28010996

Citation

Zheng, Ting, et al. "Pharmacological Characterization of Rat VD-hemopressin(α), an Α-hemoglobin-derived Peptide Exhibiting Cannabinoid Agonist-like Effects in Mice." Neuropeptides, vol. 63, 2017, pp. 83-90.
Zheng T, Zhang T, Zhang R, et al. Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice. Neuropeptides. 2017;63:83-90.
Zheng, T., Zhang, T., Zhang, R., Wang, Z. L., Han, Z. L., Li, N., Li, X. H., Zhang, M. N., Xu, B., Yang, X. L., Fang, Q., & Wang, R. (2017). Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice. Neuropeptides, 63, 83-90. https://doi.org/10.1016/j.npep.2016.12.006
Zheng T, et al. Pharmacological Characterization of Rat VD-hemopressin(α), an Α-hemoglobin-derived Peptide Exhibiting Cannabinoid Agonist-like Effects in Mice. Neuropeptides. 2017;63:83-90. PubMed PMID: 28010996.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice. AU - Zheng,Ting, AU - Zhang,Ting, AU - Zhang,Run, AU - Wang,Zi-Long, AU - Han,Zheng-Lan, AU - Li,Ning, AU - Li,Xu-Hui, AU - Zhang,Meng-Na, AU - Xu,Biao, AU - Yang,Xiong-Li, AU - Fang,Quan, AU - Wang,Rui, Y1 - 2016/12/16/ PY - 2016/10/22/received PY - 2016/12/08/revised PY - 2016/12/14/accepted PY - 2016/12/25/pubmed PY - 2018/3/27/medline PY - 2016/12/25/entrez KW - (r)VD-hemopressin(α) KW - Antinociception KW - Cannabinoid KW - Hypoactivity KW - Hypothermia KW - Mice KW - Neurite outgrowth SP - 83 EP - 90 JF - Neuropeptides JO - Neuropeptides VL - 63 N2 - 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 CB1 receptor. In the tail-flick assay, (r)VD-Hpα dose-dependently exerted central antinociception through CB1 receptor, but not CB2 and opioid receptors. In mice, supraspinal administration of (r)VD-Hpα produced dose-dependent hypothermia, which was partially reduced by the CB1 receptor antagonist AM251, but not by the antagonists of CB2 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. SN - 1532-2785 UR - https://www.unboundmedicine.com/medline/citation/28010996/Pharmacological_characterization_of_rat_VD_hemopressin_α__an_α_hemoglobin_derived_peptide_exhibiting_cannabinoid_agonist_like_effects_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0143-4179(16)30171-8 DB - PRIME DP - Unbound Medicine ER -