Pharmacological Studies Of Endogenous Cannabinoid Agonist VD-hemopressin(α):Its Cross-tolerance To Other Cannabinoids And Its Central Antinociception Modulated By NPFF System

Cannabinoids play an important role in the modulation of nociceptive signals. And cannabinoid drugs have been used as analgesics for thousands of years. Mouse VD-hemopressin(α) [(m)VD-Hpa], an 11-residue a-hemoglobin-derived peptide, was recently reported as a selective agonist of the cannabinoid receptor type 1 (CB1) in vitro. Furthermore, this work investigated the antinociceptive profiles of (m)VD-Hpa and its related mechanisms after supraspinal administration in the radiant heat tail-flick test. Thus, there are two aspects have been present in this study. (1) The cross-tolerance between (m)VD-Hpa and other cannabinoid ligands was investigated to explore whether the common mechanism is involved in the antinociception of these cannabinoid ligands. (2) Based on the previous results that the NPFF system modulated the antinociception of the classical cannabinoid ligand WTN55,212-2, the eflFects of neuropeptide FF (NPFF) system on the antinociception of (m)VD-Hpα were further explored.The cross-tolerance of nociceptive stimulation between (m)VD-Hpa, classical cannabinoid WIN55,212-2 and peptide ligand Hp was designed to investigate in the radiant heat tail-flick test. The present work demonstrated that hemopressin (11,22 and 45 nmol, i.cv.) dose-dependently produced antinociception after supraspinal administration in the radiant heat tail-flick test. Hp produced antinociception with an ED50 value of 14.86 (13.43-16.45) nmol. The tolerance significantly developed on day 4 after supraspinal injection of hemopressin (45 nmol), VD-hemopressin(α) (20 nmol) and WIN55.212-2 (7.5 nmol). Furthermore, our results indicated symmetrical cross-tolerance between hemopressin, VD-hemopressin(α) and WIN55.212-2 at the supraspinal level in mice. These results demonstrate that VD-hemopressm(α) have a time-course and extent of tolerance similar to WTN55,212-2 and hemopressin. In addition, our data imply that a common mechanism is involved in the antinociception of the three cannabinoid ligands.Our laboratory previously demonstrated that NPFF system significantly modulated the antinociception of the classical cannabinoid ligand WIN55,212-2. Thus, the modulatory effects of NPFF system on the central antinociception induced by (m)VD-Hpa were further investigated in the naive and cannabinoid-tolerant mice. In naive mice, intracerebroventricular injection of NPFF dose-dependently attenuated central analgesia of (m)VD-Hpa. In contrast, dNPA and NPVF (i.c.v.), two highly selective agonists for NPFF2 and NPFF1 receptors, dose-dependently enhanced (m)VD-Hpa antinociception. In (m)VD-Hpa-tolerant mice, NPFF failed to modify (m)VD-Hpa-induced antinociception. However, both dNPA and NPVF potentiated the antinociception of (m)VD-Hpa in a dose-dependent manner. In addition, the (m)VD-Hpa-modulating activities of NPFF and related peptides were antagonisized by NPFF receptors antagonist RF9. These results suggest that NPFF system plays important roles in central analgesia induced by (m)VD-Hpa, which were consistent with the WTN55,212-2-modulating character of NPFF system. Taken together, these findings further imply that a common mechanism is involved in the antinociception of (m)VD-Hpa and WIN55.212-2. In addition, a chronic cannabinoid treatment modifies the pharmacological profiles of NPFF, but not the cannabinoid-potentiating effects of dNPA and NPVF.