Antinociceptive effects of the endogenous cannabinoid peptide agonist VD-hemopressin(β) in mice

Cannabinoids (CBs) play important roles in pain modulation. Recently, VD-hemopressin(β) [VD-Hpβ], a 12-residue β-hemoglobin-derived peptide, was reported to activate both CB₁ and CB₂ receptors in vitro. To further characterize in vivo actions of VD-Hpβ, its antinociceptive activity and site(s) were evaluated in the mouse tail-flick test, and supraspinal antinociception of VD-Hpβ was further assessed in the writhing test. Our results demonstrated that supraspinal, intrathecal, subcutaneous and intraperitoneal administrations of VD-Hpβ produced analgesia in the tail-flick test. When given at the same levels, the CB₁ antagonist AM251, rather than the CB₂ antagonist AM630 diminished VD-Hpβ-induced antinociception. Furthermore, our results indicated that supraspinal, intrathecal or subcutaneous pretreatment with AM251 significantly inhibited VD-Hpβ-induced systemic antinociception. In the writhing test, supraspinal VD-Hpβ inhibited pain-related behaviors, which was partially prevented by AM251. Notably, supraspinal administration of VD-Hpβ failed to affect motor function at the antinociceptive doses. These findings suggest that VD-Hpβ induces CB₁ receptor-mediated antinociception in tail-flick test in various routes of administration, and its systemic antinociception is mediated by both central and peripheral CB₁ receptor. In addition, VD-Hpβ produces analgesic activity in the writhing test, which is at least partially mediated by CB₁ receptor. Therefore, our present animal models show a CB₁ agonistic character of VD-Hpβ, an endogenous cannabinoid peptide.