title: Pharmacological characterization of rat VD-hemopressin(α), an α-hemoglobin-derived peptide exhibiting cannabinoid agonist-like effects in mice.
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 CB1receptor. In the tail-flick assay, (r)VD-Hpα dose-dependently exerted central antinociception through CB1receptor, but not CB2and opioid receptors. In mice, supraspinal administration of (r)VD-Hpα produced dose-dependent hypothermia, which was partially reduced by the CB1receptor antagonist AM251, but not by the antagonists of CB2and 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.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Run
authors.initials: R
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Zi-Long
authors.initials: ZL
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Zheng-Lan
authors.initials: ZL
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xu-Hui
authors.initials: XH
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Meng-Na
authors.initials: MN
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Biao
authors.initials: B
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Xiong-Li
authors.initials: XL
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005772:Gastrointestinal Transit / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000071446:Neuronal Outgrowth / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D059225:Nociception / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010147:Pain Measurement; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; D009842:Oligopeptides; D043884:Receptor, Cannabinoid, CB1; C586692:VDPVNFKLLSH-OH
keywords: (r)VD-hemopressin(α); Antinociception; Cannabinoid; Hypoactivity; Hypothermia; Mice; Neurite outgrowth