title: Antinociceptive effects of central administration of the endogenous cannabinoid receptor type 1 agonist VDPVNFKLLSH-OH [(m)VD-hemopressin(α)], an N-terminally extended hemopressin peptide.
abstract: The cannabinoid system has been demonstrated to modulate the acute and chronic pain of multiple origins. Mouse VD-hemopressin(α) [(m)VD-Hpα], an 11-residue α-hemoglobin-derived peptide, was recently reported to function as a selective agonist of the cannabinoid receptor type 1 (CB₁) in vitro. To characterize its behavioral and physiological properties, we investigated the in vivo effects of (m)VD-Hpα in mice. In the mouse tail-flick test, (m)VD-Hpα dose-dependently induced antinociception after supraspinal (EC₅₀ = 6.69 nmol) and spinal (EC₅₀ = 2.88 nmol) administration. The antinociceptive effects of (m)VD-Hpα (intracerebroventricularly and intrathecally) were completely blocked by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide (AM251; CB₁ antagonist), but not by 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl(4-methoxyphenyl)-methanone (AM630; CB₂ antagonist) or naloxone (opioid antagonist), showing its selectivity to the CB₁ receptor. Furthermore, the central nervous system (CNS) effects of (m)VD-Hpα were evaluated in body temperature, locomotor activity, tolerance development, reward, and food intake assays. At the highly antinociceptive dose (3 × EC₅₀), (m)VD-Hpα markedly exerted hypothermia and hypoactivity after supraspinal administration. Repeated intracerebroventricular injection of (m)VD-Hpα resulted in both development of tolerance to antinociception and conditioned place aversion. In addition, central injection of (m)VD-Hpα dose-dependently stimulated food consumption. These findings demonstrate that this novel cannabinoid peptide agonist induces CB₁-mediated central antinociception with some CNS effects, which further supports a CB₁ agonist character of (m)VD-Hpα. Moreover, the current study will be helpful to understand the in vivo properties of the endogenous peptide agonist of the cannabinoid CB₁ receptor.
authors.affiliation: Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, People's Republic of China.
authors.forename: Zheng-lan
authors.initials: ZL
authors.lastname: Han
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.forename: Zi-long
authors.initials: ZL
authors.lastname: Wang
authors.forename: Xu-hui
authors.initials: XH
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xue-mei
authors.initials: XM
authors.lastname: Chang
authors.forename: Jia-xin
authors.initials: JX
authors.lastname: Pan
authors.forename: Hong-zhu
authors.initials: HZ
authors.lastname: Tang
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D063387:Cannabinoid Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D006454:Hemoglobins / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D057967:Infusions, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009292:Narcotic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism
chemical_list: D000700:Analgesics; C578453:CNR1 protein, mouse; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; C571431:Cnr2 protein, mouse; D006454:Hemoglobins; D009292:Narcotic Antagonists; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011957:Receptors, Opioid; C586692:VDPVNFKLLSH-OH; C473218:hemopressin