New morphine analogues produce peripheral antinociception within a certain dose range of their systemic administration

Abstract

Growing data support the peripheral opioid antinociceptive effect, particularly, in inflammatory pain models. Here, we examined the antinociceptive effects of the subcutaneously (s.c.) administered, recently synthesized 14-O-Methylmorphine-6-O-sulfate (14-O-MeM6SU) compared to morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain, induced by an injection of Complete Freund's Adjuvant (CFA) and a mouse model of visceral pain evoked by acetic acid. The s.c. doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively produced significant and s.c. or intraplantar (i.pl.) naloxone methiodide (NAL-M) reversible antinociception in inflamed paws compared to non-inflamed paws. These certain doses neither of them affected significantly the thiobutabarbital's sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M indicating CNS contribution. In mouse writhing test, 14-O-MeM6SU was more potent than M6SU after s.c. or intracerebroventricular (i.c.v.) injections. Both displayed high s.c./i.c.v. ED50 ratios. The antinociceptive effects of s.c. 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively were fully antagonized by s.c. NAL-M. In addition, the test compounds inhibit the mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that the systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges showed peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply for male animals, and need to be confirmed in females. Therefore titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.