RT Journal Article
SR Electronic
T1 New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 171
OP 181
DO 10.1124/jpet.116.233551
VO 359
IS 1
A1 Erzsébet Lackó
A1 Pál Riba
A1 Zoltán Giricz
A1 András Váradi
A1 Laura Cornic
A1 Mihály Balogh
A1 Kornél Király
A1 Kata Csekő
A1 Shaaban A. Mousa
A1 Sándor Hosztafi
A1 Michael Schäfer
A1 Zoltán Sándor Zádori
A1 Zsuzsanna Helyes
A1 Péter Ferdinandy
A1 Susanna Fürst
A1 Mahmoud Al-Khrasani
YR 2016
UL http://jpet.aspetjournals.org/content/359/1/171.abstract
AB Growing data support peripheral opioid antinociceptive effects, particularly in inflammatory pain models. Here, we examined the antinociceptive effects of subcutaneously administered, recently synthesized 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU) compared with morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain induced by an injection of complete Freund’s adjuvant and in a mouse model of visceral pain evoked by acetic acid. Subcutaneous doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively, produced significant and subcutaneous or intraplantar naloxone methiodide (NAL-M)–reversible antinociception in inflamed paws compared with noninflamed paws. Neither of these doses significantly affected thiobutabarbital-induced sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M, indicating contribution of the central nervous system. In the mouse writhing test, 14-O-MeM6SU was more potent than M6SU after subcutaneous or intracerebroventricular injections. Both displayed high subcutaneous/intracerebroventricular ED50 ratios. The antinociceptive effects of subcutaneous 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively, were fully antagonized by subcutaneous NAL-M. In addition, the test compounds inhibited mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges shows peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply to male animals and must be confirmed in female animals. Therefore, titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.