The cannabinoid system has been demonstrated to modulate the acute and chronic pain of multiple origins. Mouse VD-hemopressin(á) [(m)VD-Hpá], an 11-residue á-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-Hpá in mice. In the mouse tail-flick test, (m)VD-Hpá dose-dependently induced antinociception after supraspinal (EC₅₀ = 6.69 nmol) and spinal (EC₅₀ = 2.88 nmol) administration. The antinociceptive effects of (m)VD-Hpá (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-Hpá were evaluated in body temperature, locomotor activity, tolerance development, reward, and food intake assays. At the highly antinociceptive dose (3 ? EC₅₀), (m)VD-Hpá markedly exerted hypothermia and hypoactivity after supraspinal administration. Repeated intracerebroventricular injection of (m)VD-Hpá resulted in both development of tolerance to antinociception and conditioned place aversion. In addition, central injection of (m)VD-Hpá 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-Hpá. Moreover, the current study will be helpful to understand the in vivo properties of the endogenous peptide agonist of the cannabinoid CB₁ receptor.
Analgesics Animals