Analgesic tolerance and cross-tolerance to the cannabinoid receptors ligands hemopressin, VD-hemopressin(α) and WIN55,212-2 at the supraspinal level in mice

The nonapeptide,hemopressin and its N-terminal extension VD-hemopressin(alpha), Were,reported as an antagonist/inverse agonist and an agonist of CB1 receptor, respectively. These novel cannabinoid pep.-tides hive been demonstrated to modulate the acute pain. In the present study, hemopressin (11, 22; and 45 nmol, i.c.v.) dose-dependently produced antinociception after supraspinal administration in the radiant heat tail-flick test. Furthermore, the development of antinociceptive tolerance to hemopressin, VD-hemopressin(alpha) and WIN55,212-2, and cross-tolerance among these cannabinoids were investigated in mice. the tolerance developed on day 4 after supraspinal injection of hemopressin (45 nmol), VD-hemopressin(alpha) (20 nmol) and WIN55,212-2 (7.5 nmol). Our results indicated symmetrical cross-tolerance between hemopressin, VD-hemopressin(alpha) and WIN55,212-2 at the supraspinal level in mice. These results demonstrate that both hemopressin and VD-hemopressin(alpha) have a time-course and extent of tolerance similar to the synthetic cannabinoid WIN55,212-2. In addition, our data imply that a common Mechanism is involved in the antinociception of the three cannabinoid ligands. (C) 2014 Published by Elsevier Ireland Ltd.